U.S. patent application number 10/426475 was filed with the patent office on 2004-06-03 for nanofilm compositions with polymeric components.
Invention is credited to Bivin, Donald B., Harris, Jeremy J., Kriesel, Joshua W., Olson, David J..
Application Number | 20040106741 10/426475 |
Document ID | / |
Family ID | 32396975 |
Filed Date | 2004-06-03 |
United States Patent
Application |
20040106741 |
Kind Code |
A1 |
Kriesel, Joshua W. ; et
al. |
June 3, 2004 |
Nanofilm compositions with polymeric components
Abstract
Nanofilms useful for filtration are prepared from amphiphilic
species and one or more polymeric components. The amphiphilic
species or components may be oriented on an interface or surface. A
nanofilm may be prepared by coupling one or more of the components.
The nanofilm may also be deposited or attached to a substrate.
Inventors: |
Kriesel, Joshua W.; (San
Francisco, CA) ; Bivin, Donald B.; (Oakland, CA)
; Olson, David J.; (San Francisco, CA) ; Harris,
Jeremy J.; (San Mateo, CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
32396975 |
Appl. No.: |
10/426475 |
Filed: |
April 29, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60411588 |
Sep 17, 2002 |
|
|
|
Current U.S.
Class: |
525/329.5 |
Current CPC
Class: |
C08F 8/30 20130101 |
Class at
Publication: |
525/329.5 |
International
Class: |
C08F 120/00 |
Claims
What is claimed is:
1. A nanofilm composition comprising a reaction product of
macrocyclic modules and at least one polymeric component.
2. The nanofilm composition of claim 1, wherein the macrocyclic
modules are coupled to each other.
3. The nanofilm composition of claim 2, wherein the macrocyclic
modules are coupled to each other through linker molecules.
4. The nanofilm composition of claim 3, wherein the linker
molecules are selected from the group consisting of 307and mixtures
therefor; wherein m is 1-10, n is 1-6, R is --H or --CH.sub.3, R'
is --(CH.sub.2).sub.n-- or phenyl, R" is --(CH.sub.2).sub.n--,
polyenthylene glycol (PEG), or polypropylene glycol (PPG), and X is
Br, Cl, I, or other leaving group.
5. The nanofilm composition of claim 1, wherein the macrocyclic
modules are coupled to the at least one polymeric component.
6. The nanofilm composition of claim 5, wherein the macrocyclic
modules are coupled to the at least one polymeric component through
linker molecules.
7. The nanofilm composition of claim 6, wherein the linker
molecules are selected from the group consisting of 308and mixtures
thereof; wherein m is 1-10, n is 1-6, R is --H or --CH.sub.3, R' is
--(CH.sub.2).sub.n-- or phenyl, R" is --(CH.sub.2).sub.n--,
polyethylene glycol (PEG), or polypropylene glycol (PPG), and X is
Br, Cl, I, or other leaving group.
8. The nanofilm composition of claim 1, wherein the macrocyclic
modules are selected from the group consisting of Hexamer 1a,
Hexamer 1dh, Hexamer 3j-amine, Hexamer 1jh, Hexamer 1jh-AC, Hexamer
2j-amine/ester, Hexamer 1dh-acryl, Octamer 5jh-aspartic, Octamer
4jh-acryl, and mixtures thereof.
9. The nanofilm composition of claim 8, wherein the macrocyclic
modules are Hexamer 1dh.
10. The nanofilm composition of claim 1, wherein the polymeric
component is selected from the group consisting of poly(maleic
anhydride)s, poly(ethylene-co-maleic anhydride)s, poly(maleic
anhydride-co-alpha olefin)s, polyacrylates, polymethylmethacrylate,
polymers containing at least one oxacyclopropane group,
polyethyleneimides, polyetherimides, polyethylene oxides,
polypropylene oxides, polyurethanes, polystyrenes, poly(vinyl
acetate)s, polytetrafluoroethylenes, polyethylenes,kpolypropyl-
enes, ethylene-propylene copolymers, polyisoprenes,
polyneopropenes, polyamides, polyimides, polysulfones,
polyethersulfones, polyethylene terephthalates, polybutylene
terephthalates, polysulfonamides, polysulfoxides, polyglycolic
acids, polyacrylamides, polyvinylalcohols, polyesters, polyester
ionomers, polycarbonates, polyvinylchlorides, polyvinylidene
chlorides, polyvinylidene fluorides, polyvinylpyrrolidones,
polylactic acids, polypeptides, polysorbates, polylysines,
hydrogels, carbohydrates, polysaccharides, agaroses, amyloses,
amylopectins, glycogens, dextrans, celluloses, cellulose acetates,
chitins, chitosans, peptidoglycans, glycosaminoglycans,
polynucleotides, poly(T), poly(A), nucleic acids, proteoglycans,
glycoproteins, glycolipids, and mixtures thereof.
11. The nanofilm composition of claim 1, wherein the polymeric
component is poly(maleic anhydride-co-alpha olefin).
12. The nanofilm composition of claim 1, wherein the polymeric
component comprises a polymerizable monomer.
13. The nanofilm composition of claim 12, wherein the polymerizable
monomer comprises CH.sub.2.dbd.CHC(O)OCH.sub.2CH.sub.2OH.
14. The nanofilm composition of claim 1, wherein the polymeric
component comprises a polymerizable amphiphile.
15. The nanofilm composition of claim 13, wherein the polymerizable
amphiphile is selected from the group consisting of amphiphilic
acrylates, amphiphilic acrylamides, amphiphilic vinyl esters,
amphiphilic anilines, amphiphilic diynes, amphiphilic dienes,
amphiphilic acrylic acids, amphiphilic enes, amphiphilic cinnamic
acids, amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic
amines, amphiphilic diesters, amphiphilic diacids, amphiphilic
diols, amphiphilic polyols, and amphiphilic diepoxides.
16. The nanofilm of claim 1, further comprising a non-polymerizable
amphiphile.
17. The nanofilm of claim 16, wherein the non-polymerizable
amphiphile is selected from the group consisting of decylamine and
stearic acid.
18. The nanofilm composition of claim 1 prepared by spin coating,
spray coating, dip coating, grafting, casting, phase inversion,
electroplating, or knife-edge coating.
19. The nanofilm composition of claim 1, wherein the area fraction
of the polymeric components is from 0.5 to 98 percent.
20. The nanofilm composition of claim 1, wherein the area fraction
of the polymeric components is less than about 20 percent.
21. The nanofilm composition of claim 1, wherein the area fraction
of the polymeric components is less than about 5 percent.
22. The nanofilm composition of claim 1, wherein the thickness of
the nanofilm composition is less than about 30 nanometers.
23. The nanofilm composition of claim 1, wherein the thickness of
the nanofilm composition is less than about 6 nanometers.
24. The nanofilm composition of claim 1, wherein the thickness of
the nanofilm composition is less than about 2 nanometers.
25. The nanofilm composition of claim 1, wherein the surface loss
modulus of the nanofilm composition at a surface pressure from 5-30
mN/m is less than about 50% of the surface loss modulus of the same
nanofilm composition made without the polymeric components.
26. The nanofilm composition of claim 1, wherein the surface loss
modulus of the nanofilm composition at a surface pressure from 5-30
mN/m is less than about 30% of the surface loss modulus of the same
nanofilm composition made without the polymeric components.
27. The nanofilm composition of claim 1, wherein the surface loss
modulus of the nanofilm composition at a surface pressure from 5-30
mN/m is less than about 20% of the surface loss modulus of the same
nanofilm composition made without the polymeric components.
28. The nanofilm composition of claim 1, having the following
filtration function:
22 MOLECULAR SOLUTE WEIGHT PASS/NO PASS Albumin 68 kDa NP Ovalbumin
44 kDa P Myoglobin 17 kDa P .beta..sub.2-Microglobulin 12 kDa P
Insulin 5.2 kDa P Vitamin B.sub.12 1350 Da P Urea, H.sub.2O, ions
<1000 Da P
29. The nanofilm composition of claim 1, having the following
filtration function:
23 MOLECULAR SOLUTE WEIGHT PASS/NO PASS .beta..sub.2-Microglobulin
12 kDa NP Insulin 5.2 kDa NP Vitamin B.sub.12 1350 Da NP Glucose
180 Da NP Creatinine 131 Da NP H.sub.2PO.sub.4.sup.-,
HPO.sub.4.sup.2- .apprxeq.97 Da NP HCO.sub.3.sup.- 61 Da NP Urea 60
Da NP K+ 39 Da P Na+ 23 Da P
30. The nanofilm composition of claim 1, wherein the nanofilm is
impermeable to viruses and larger species.
31. The nanofilm composition of claim 1, wherein the nanofilm is
impermeable to immunoglobulin G and larger species.
32. The nanofilm composition of claim 1, wherein the nanofilm is
impermeable to albumin and larger species.
33. The nanofilm composition of claim 1, wherein the nanofilm is
impermeable to .beta..sub.2-Microglobulin and larger species.
34. The nanofilm composition of claim 1, wherein the nanofilm is
permeable only to water and smaller species.
35. The nanofilm composition of claim 1, having a molecular weight
cut-off of 13 kDa.
36. The nanofilm composition of claim 1, having a molecular weight
cut-off of 190 Da.
37. The nanofilm composition of claim 1, having a molecular weight
cut-off of 100 Da.
38. The nanofilm composition of claim 1, having a molecular weight
cut-off of 45 Da.
39. The nanofilm composition of claim 1, having a molecular weight
cut-off of 20 Da.
40. The nanofilm composition of claim 1, having high permeability
for water molecules and Na.sup.+, K.sup.+, and Cs.sup.+ in
water.
41. The nanofilm composition of claim 36, having low permeability
for glucose and urea.
42. The nanofilm composition of claim 1, having high permeability
for water molecules and Cl.sup.- in water.
43. The nanofilm composition of claim 1, having high permeability
for water molecules and K.sup.+ in water, and low permeability for
Na.sup.+ in water.
44. The nanofilm composition of claim 1, having high permeability
for water molecules and Na.sup.+ in water, and low permeability for
K.sup.+ in water.
45. The nanofilm composition of claim 1, having low permeability
for urea, creatinine, Li.sup.+, Ca.sup.2.sup.+, and Mg.sup.2.sup.+
in water.
46. The nanofilm composition of claim 41, having high permeability
for Na.sup.+, K.sup.+, hydrogen phosphate, and dihydrogen phosphate
in water.
47. The nanofilm composition of claim 41, having high permeability
for Na.sup.+, K.sup.+, and glucose in water.
48. The nanofilm composition of claim 1, having low permeability
for myoglobin, ovalbumin, and albumin in water.
49. The nanofilm composition of claim 1, having high permeability
for organic compounds and low permeability for water.
50. The nanofilm composition of claim 1, having low permeability
for organic compounds and high permeability for water.
51. The nanofilm composition of claim 1, having low permeability
for water molecules and high permeability for helium and hydrogen
gases.
52. A nanofilm composition comprising at least two layers of the
nanofilm of claim 1.
53. The nanofilm composition of claim 52, fuirther comprising at
least one spacing layer between any two of the nanofilm layers.
54. The nanofilm composition of claim 53, wherein the spacing layer
comprises a layer of a polymer, a gel, or inorganic particles.
55. The nanofilm composition of claim 1, deposited on a
substrate.
56. The nanofilm composition of claim 55, wherein the nanofilm is
coupled to the substrate through the polymeric component.
57. The nanofilm composition of claim 55, wherein the substrate is
porous.
58. The nanofilm composition of claim 55, wherein the substrate is
non-porous.
59. The nanofilm composition of claim 55, wherein the nanofilm is
coupled to the substrate through biotin-strepavidin mediated
interaction.
60. A nanofilm composition comprising a reaction product of a
polymeric component and an amphiphile.
61. The nanofilm of claim 60, wherein the amphiphile is a
polymerizable amphiphile.
62. The nanofilm composition of claim 61, wherein the polymerizable
amphiphile is selected from the group consisting of amphiphilic
acrylates, amphiphilic acrylamides, amphiphilic vinyl esters,
amphiphilic anilines, amphiphilic diynes, amphiphilic dienes,
amphiphilic acrylic acids, amphiphilic enes, amphiphilic cinnamic
acids, amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic
amines, amphiphilic diesters, amphiphilic diacids, amphiphilic
diols, amphiphilic polyols, and amphiphilic diepoxides.
63. The nanofilm of claim 60, wherein the amphiphile is
non-polymerizable.
64. The nanofilm of claim 63, wherein the non-polymerizable
amphiphile is selected from the group consisting of decylamine and
stearic acid.
65. The nanofilm composition of claim 60, wherein the polymeric
component is selected from the group consisting of poly(maleic
anhydride)s, poly(ethylene-co-maleic anhydride)s, poly(maleic
anhydride-co-alpha olefin)s, polyacrylates, polymethylmethacrylate,
polymers containing at least one oxacyclopropane group,
polyethyleneimides, polyetherimides, polyethylene oxides,
polypropylene oxides, polyurethanes, polystyrenes, poly(vinyl
acetate)s, polytetrafluoroethylenes, polyethylenes, polypropylenes,
ethylene-propylene copolymers, polyisoprenes, polyneopropenes,
polyamides, polyimides, polysulfones, polyethersulfones,
polyethylene terephthalates, polybutylene terephthalates,
polysulfonamides, polysulfoxides, polyglycolic acids,
polyacrylamides, polyvinylalcohols, polyesters, polyester ionomers,
polycarbonates, polyvinylchlorides, polyvinylidene chlorides,
polyvinylidene fluorides, polyvinylpyrrolidones, polylactic acids,
polypeptides, polysorbates, polylysines, hydrogels, carbohydrates,
polysaccharides, agaroses, amyloses, amylopectins, glycogens,
dextrans, celluloses, cellulose acetates, chitins, chitosans,
peptidoglycans, glycosaminoglycans, polynucleotides, poly(T),
poly(A), nucleic acids, proteoglycans, glycoproteins, glycolipids,
and mixtures thereof.
66. The nanofilm of claim 60, wherein the polymeric component is
amphiphilic.
67. The nanofilm of claim 60, wherein the polymeric component
comprises a polymerizable monomer.
68. The nanofilm of claim 60, wherein the polymeric component
comprises a polymerizable amphiphile.
69. The nanofilm composition of claim 61, wherein the nanofilm is
prepared by a process comprising polymerizing the polymerizable
amphiphiles at an air-water interface.
70. The nanofilm composition of claim 60, wherein the nanofilm is
prepared by a process comprising polymerizing the polymeric
component at an air-water interface.
71. The nanofilm of claim 63, wherein the polymeric component is a
polymer, and wherein the non-polymerizable amphiphiles are coupled
to the polymer.
72. A nanofilm composition comprising a reaction product of a
polymeric component, wherein the polymeric components are linked by
linker molecules.
73. The nanofilm composition of claim 72, wherein the polymeric
component is selected from the group consisting of poly(maleic
anhydride)s, poly(ethylene-co-maleic anhydride)s, poly(maleic
anhydride-co-alpha olefin)s, polyacrylates, polymethylmethacrylate,
polymers containing at least one oxacyclopropane group,
polyethyleneimides, polyetherimides, polyethylene oxides,
polypropylene oxides, polyurethanes, polystyrenes, poly(vinyl
acetate)s, polytetrafluoroethylenes, polyethylenes, polypropylenes,
ethylene-propylene copolymers, polyisoprenes, polyneopropenes,
polyarnides, polyimides, polysulfones, polyethersulfones,
polyethylene terephthalates, polybutylene terephthalates,
polysulfonamides, polysulfoxides, polyglycolic acids,
polyacrylamides, polyvinylalcohols, polyesters, polyester ionomers,
polycarbonates, polyvinylchlorides, polyvinylidene chlorides,
polyvinylidene fluorides, polyvinylpyrrolidones, polylactic acids,
polypeptides, polysorbates, polylysines, hydrogels, carbohydrates,
polysaccharides, agaroses, amyloses, amylopectins, glycogens,
dextrans, celluloses, cellulose acetates, chitins, chitosans,
peptidoglycans, glycosaminoglycans, polynucleotides, poly(T),
poly(A), nucleic acids, proteoglycans, glycoproteins, glycolipids,
and mixtures thereof.
74. A nanofilm composition comprising a reaction product of at
least two polymeric components, wherein the first polymeric
component is a polymerizable amphiphile, and the second polymeric
component is a polymerizable monomer.
75. A composition comprising a mixture of macrocyclic modules and
at least one polymeric component in organic solvent.
76. A composition comprising a thin film of a reaction product of
macrocyclic modules and at least one polymeric component, wherein
the composition is prepared by a process comprising contacting the
macrocyclic modules and the at least one polymeric component at an
air-liquid or liquid-liquid interface.
77. A method for making a nanofilm composition comprising: (a)
providing a mixture of macrocyclic modules and at least one
polymeric component; and (b) forming the mixture into a thin film
at an air-liquid or liquid-liquid interface.
78. The method of claim 77, wherein the polymeric component is
polymerizable, further comprising polymerizing the polymeric
component at the air-liquid or liquid-liquid interface.
79. A method for making a nanofilm composition comprising the
reaction product of macrocyclic modules and at least one polymeric
component, comprising: (a) providing a subphase containing the at
least one polymeric component; and (b) contacting macrocyclic
modules with the surface of the subphase.
80. The method of claim 79, further comprising: (c) contacting a
linker molecule with the surface of the subphase.
81. A method for making a nanofilm composition comprising the
reaction product of macrocyclic modules and at least one polymeric
component, comprising: (a) providing a first liquid phase
comprising the macrocyclic modules; (b) providing a second liquid
phase comprising the at least one polymeric component; and (c)
forming a liquid-liquid interface from the first liquid phase and
the second liquid phase.
82. A method for filtration comprising using the nanofilm
composition of claim 1 to separate a component from a fluid.
83. A method for filtration comprising using the nanofilm
composition of claim 1 to separate a component from a mixture of at
least two gases.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application Serial No. 60/411,588, filed Sep. 17, 2002, herein
incorporated by reference in its entirety.
TECHNICAL FIELD
[0002] This invention relates to thin layer compositions which are
nanofilms prepared from various macrocyclic module components and
various polymeric and amphiphilic components. This invention also
relates to the fields of organic chemistry and nanotechnology, in
particular, it relates to nanofilm compositions useful for
filtration.
BACKGROUND OF THE INVENTION
[0003] Nanotechnology involves the ability to engineer novel
structures at the atomic and molecular level. One area of
nanotechnology is to develop chemical building blocks from which
hierarchical molecules of predicted properties can be assembled. An
approach to making chemical building blocks or nanostructures
begins at the atomic and molecular level by designing and
synthesizing starting materials with highly tailored properties.
Precise control at the atomic level is the foundation for
development of rationally tailored synthesis-structure-property
relationships which can provide materials of unique structure and
predictable properties. This approach to nanotechnology is inspired
by nature. For example, biological organization is based on a
hierarchy of structural levels: atoms formed into biological
molecules which are arranged into organelles, cells, and
ultimately, into organisms. These building block capabilities are
unparalleled by conventional materials and methods such as
polymerizations which produce statistical mixtures or confinement
of reactants to enhance certain reaction pathways. For example,
from twenty common amino acids found in natural proteins, more than
105 stable and unique proteins are made.
[0004] One field that will benefit from nanotechnology is
filtration using membranes. Conventional membranes used in a
variety of separation processes can be made selectively permeable
to various molecular species. The permeation properties of
conventional membranes generally depend on the pathways of
transport of species through the membrane structure. For example,
while the diffusion pathway in conventional selectively permeable
materials can be made tortuous in order to control permeation,
porosity is not well defined or controlled by conventional methods.
The ability to fabricate regular or unique pore structures of
membranes is a long-standing goal of separation technology.
[0005] Resistance to flow of species through a membrane may also be
governed by the flow path length. Resistance can be greatly reduced
by using a very thin film as a membrane, at the cost of reduced
mechanical strength of the membrane material. Conventional
membranes may have a barrier thickness of at least one to two
hundred nanometers, and often up to millimeter thickness. In
general, a thin film of membrane barrier material can be deposited
on a porous substrate of greater thickness to restore material
strength.
[0006] Membrane separation processes are used to separate
components from a fluid in which atomic or molecular components
having sizes smaller than a certain "cut-off" size can be separated
from components of larger size. Normally, species smaller than the
cut-off size are passed by the membrane. The cut-off size may be an
approximate empirical value which reflects the phenomenon that the
rate of transport of components smaller than the cut-off size is
merely faster than the rate of transport of larger components. In
conventional pressure-driven membrane separation processes, the
primary factors affecting separation of components are size,
charge, and diffusivity of the components in the membrane
structure. In dialysis, the driving force for separation is a
concentration gradient, while in electrodialysis electromotive
force is applied to ion selective membranes.
[0007] In all these methods what is required is a selectively
permeable membrane barrier to components of the fluid to be
separated.
SUMMARY OF THE INVENTION
[0008] In one aspect, the invention provides nanofilm compositions.
In some embodiments, the nanofilm composition comprises a reaction
product of macrocyclic modules and at least one polymeric
component. In some embodiments, the nanofilm composition comprises
a reaction product of a polymeric component and an amphiphile. In
other embodiments, the nanofilm composition comprises a reaction
product of a polymeric component, wherein the polymeric components
are linked by linker molecules. In still other embodiments, the
nanofilm composition comprises a reaction product of at least two
polymeric components, wherein the first polymeric component is a
polymerizable amphiphile, and the second polymeric component is a
polymerizable monomer.
[0009] In some embodiments, the macrocyclic modules are selected
from the group consisting of Hexamer 1a, Hexamer 1dh, Hexamer
3j-amine, Hexamer 1jh, Hexamer 1jh-AC, Hexamer 2j-amine/ester,
Hexamer 1dh-acryl, Octamer 5j-haspartic, Octamer 4jh-acryl, and
mixtures thereof In some preferred embodiments, the macrocyclic
modules are Hexamer 1dh.
[0010] In some embodiments, the polymeric component comprises a
polymerizable monomer. In some embodiments, the polymerizable
monomer comprises CH.sub.2.dbd.CHC(O)OCH.sub.2CH.sub.2OH. In other
embodiments, the polymeric component comprises a polymerizable
amphiphile. In some embodiments, the polymerizable amphiphile is
selected from the group consisting of amphiphilic acrylates,
amphiphilic acrylamides, amphiphilic vinyl esters, amphiphilic
anilines, amphiphilic diynes, amphiphilic dienes, amphiphilic
acrylic acids, amphiphilic enes, amphiphilic cinnamic acids,
amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic amines,
amphiphilic diesters, amphiphilic diacids, amphiphilic diols,
amphiphilic polyols, and amphiphilic diepoxides. In some
embodiments, the polymeric component is a polymer. In some
embodiments, the polymeric component is amphiphilic.
[0011] In some embodiments, the polymeric component is selected
from the group consisting of poly(maleic anhydride)s,
poly(ethylene-co-maleic anhydride)s, poly(maleic anhydride-co-alpha
olefin)s, polyacrylates, polymethylmethacrylate, polymers
containing at least one oxacyclopropane group, polyethyleneimides,
polyetherimides, polyethylene oxides, polypropylene oxides,
polyurethanes, polystyrenes, poly(vinyl acetate)s,
polytetrafluoroethylenes, polyethylenes, polypropylenes,
ethylene-propylene copolymers, polyisoprenes, polyneopropenes,
polyamides, polyimides, polysulfones, polyethersulfones,
polyethylene terephthalates, polybutylene terephthalates,
polysulfonamides, polysulfoxides, polyglycolic acids,
polyacrylamides, polyvinylalcohols, polyesters, polyester ionomers,
polycarbonates, polyvinylchlorides, polyvinylidene chlorides,
polyvinylidene fluorides, polyvinylpyrrolidones, polylactic acids,
polypeptides, polysorbates, polylysines, hydrogels, carbohydrates,
polysaccharides, agaroses, amyloses, amylopectins, glycogens,
dextrans, celluloses, cellulose acetates, chitins, chitosans,
peptidoglycans, glycosaminoglycans, polynucleotides, poly(T),
poly(A), nucleic acids, proteoglycans, glycoproteins, glycolipids,
and mixtures thereof. In some preferred embodiments, the polymeric
component is poly(maleic anhydride-co-alpha olefin).
[0012] In some embodiments, the amphiphile is a polymerizable
amphiphile. In some embodiments, the polymerizable amphiphile is
selected from the group consisting of amphiphilic acrylates,
amphiphilic acrylamides, amphiphilic vinyl esters, amphiphilic
anilines, amphiphilic diynes, amphiphilic dienes, amphiphilic
acrylic acids, amphiphilic enes, amphiphilic cinnamic acids,
amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic amines,
amphiphilic diesters, amphiphilic diacids, amphiphilic diols,
amphiphilic polyols, and amphiphilic diepoxides. In some
embodiments, the amphiphile is non-polymerizable. In some
embodiments, the non-polymerizable amphiphile is selected from the
group consisting of decylamine and stearic acid.
[0013] In some embodiments, the nanofilm composition may further
comprise a non-polymerizable amphiphile. In some embodiments, the
non-polymerizable amphiphile is selected from the group consisting
of decylamine and stearic acid. In some embodiments, the polymeric
component is a polymer, and the non-polymerizable amphiphiles are
coupled to the polymer.
[0014] In some embodiments, the macrocyclic modules are coupled to
each other. In some embodiments, the macrocyclic modules are
coupled to the at least one polymeric component. In some
embodiments, the polymeric components are coupled to each other. In
some embodiments, the at least one polymeric component is coupled
to an amphiphile. In some embodiments, the coupling is through
linker molecules. In some embodiments, the linker molecules are
selected from the group consisting of 1
[0015] and mixtures thereof; wherein m is 1-10, n is 1-6, R is --H
or --CH.sub.3, R' is --(CH.sub.2).sub.n-- or phenyl, R" is
--(CH.sub.2).sub.n--, polyethylene glycol (PEG), or polypropylene
glycol (PPG), and X is Br, Cl, I, or other leaving group.
[0016] In some embodiments, the nanofilm composition is prepared by
a process comprising polymerizing the at least one polymeric
component at an air-water interface. In some embodiments, the
nanofilm composition is prepared by a process comprising
polymerizing polymerizable amphiphiles at an air-water
interface.
[0017] In some embodiments, the area fraction of the polymeric
components is from 0.5 to 98 percent. In other embodiments, the
area fraction of the polymeric components is less than about 20
percent. In yet other embodiments, the area fraction of the
polymeric components is less than about 5 percent.
[0018] In some embodiments, the thickness of the nanofilm
composition is less than about 30 nanometers. In other embodiments,
the thickness of the nanofilm composition is less than about 6
nanometers. In yet other embodiments, the thickness of the nanofilm
composition is less than about 2 nanometers.
[0019] In some embodiments, the nanofilm composition comprises at
least two layers of a nanofilm. In some embodiments, the nanofilm
composition further comprises at least one spacing layer between
any two of the nanofilm layers. In some embodiments, the spacing
layer comprises a layer of a polymer, a gel, or inorganic
particles.
[0020] In some embodiments, the nanofilm composition is deposited
on a substrate. In some embodiments, the nanofilm is coupled to the
substrate through the polymeric component. In some embodiments, the
substrate is porous. In other embodiments, the substrate is
non-porous. In other embodiments, the nanofilm is coupled to the
substrate through biotin-strepavidin mediated interaction.
[0021] In some embodiments, the surface loss modulus of the
nanofilm composition at a surface pressure from 5-30 mN/m is less
than about 50% of the surface loss modulus of the same nanofilm
composition made without the polymeric components. In other
embodiments, the surface loss modulus of the nanofilm composition
at a surface pressure from 5-30 mN/m is less than about 30% of the
surface loss modulus of the same nanofilm composition made without
the polymeric components. In yet other embodiments, the surface
loss modulus of the nanofilm composition at a surface pressure from
5-30 mN/m is less than about 20% of the surface loss modulus of the
same nanofilm composition made without the polymeric
components.
[0022] The nanofilm compositions may have a filtration function
which may be used to describe the species that pass through the
nanofilm compositions. A nanofilm composition may be permeable only
to a particular species, including anions, cations, and neutral
solutes in a particular fluid, and species smaller than the
particular species. A particular nanofllm composition may have high
permeability for a certain species in a certain solvent. A nanofilm
composition may have low permeability for certain species in a
certain solvent. A nanofilm composition may have high permeability
for certain species and low permeability for other species in a
certain solvent. In one embodiment, a nanofilm composition may have
the following filtration function:
1 MOLECULAR SOLUTE WEIGHT PASS/NO PASS Albumin 68 kDa NP Ovalbumin
44 kDa P Myoglobin 17 kDa P .beta..sub.2-Microglobulin 12 kDa P
Insulin 5.2 kDa P Vitamin B.sub.12 1350 Da P Urea, H.sub.2O, ions
<1000 Da P
[0023] In another embodiment, a nanofilm composition may have the
following filtration function:
2 MOLECULAR SOLUTE WEIGHT PASS/NO PASS .beta..sub.2-Microglobulin
12 kDa NP Insulin 5.2 kDa NP Vitamin B.sub.12 1350 Da NP Glucose
180 Da NP Creatinine 131 Da NP H.sub.2PO.sub.4.sup.-,
HPO.sub.4.sup.2- .apprxeq.97 Da NP HCO.sub.3.sup.- 61 Da NP Urea 60
Da NP K+ 39 Da P Na+ 23 Da P
[0024] In another embodiment, the nanofilm composition is
impermeable to viruses and larger species. In other embodiments,
the nanofilm composition is impermeable to immunoglobulin G and
larger species. In other embodiments, the nanofilm composition is
impermeable to albumin and larger species. In other embodiments,
the nanofilm composition is impermeable to
.beta..sub.2-Microglobulin and larger species. In other
embodiments, the nanofilm composition is permeable only to water
and smaller species. In another embodiment, the nanofilm
composition has permeability for water molecules and Na.sup.+,
K.sup.+, and Cs.sup.+ in water. In another embodiment, the nanofilm
composition has low permeability for glucose and urea. In another
embodiment, the nanofilm composition has high permeability for
water molecules and Cl.sup.- in water. In another embodiment, the
nanofilm composition has high permeability for water molecules and
K.sup.+ in water, and low permeability for Na.sup.+ in water. In
another embodiment, the nanofilm composition has high permeability
for water molecules and Na.sup.+ in water, and low permeability for
K.sup.+ in water. In another embodiment, the nanofilm composition
has low permeability for urea, creatinine, Li.sup.+, Ca.sup.2+, and
Mg.sup.2+ in water. In another embodiment, the nanofilm composition
has high permeability for Na.sup.+, K.sup.+, hydrogen phosphate,
and dihydrogen phosphate in water. In another embodiment, the
nanofilm composition has high permeability for Na.sup.+, K.sup.+,
and glucose in water. In another embodiment, the nanofilm
composition has low permeability for myoglobin, ovalbumin, and
albumin in water. In another embodiment, the nanofilm composition
has high permeability for organic compounds and low permeability
for water. In another embodiment, the nanofilm composition has low
permeability for organic compounds and high permeability for water.
In another embodiment, the nanofilm composition has low
permeability for water molecules and high permeability for helium
and hydrogen gases.
[0025] A nanofilm composition may have a molecular weight cut off.
In one embodiment, the nanofilm composition has a molecular weight
cut-off of about 13 kDa. In another embodiment, the nanofilm
composition has a molecular weight cut-off of about 190 Da. In
another embodiment, the nanofilm composition has a molecular weight
cut-off of about 100 Da. In yet another embodiment, the nanofilm
composition has a molecular weight cut-off of about 45 Da. In
another embodiment, the nanofilm composition has a molecular weight
cut-off of about 20 Da.
[0026] In another aspect the invention provides compositions
comprising a mixture of macrocyclic modules and at least one
polymeric component in organic solvent.
[0027] In another aspect the invention provides compositions
comprising a thin film of a reaction product of macrocyclic modules
and at least one polymeric component, wherein the composition is
prepared by a process comprising contacting the macrocyclic modules
and the at least one polymeric component at an air-liquid or
liquid-liquid interface.
[0028] In another aspect the invention provides methods for making
nanofilm compositions. In one embodiment, a method for making a
nanofilm composition comprising the reaction product of macrocyclic
modules and at least one polymeric component comprises: (a)
providing a mixture of macrocyclic modules and at least one
polymeric component; and (b) forming the mixture into a thin film
at an air-liquid or liquid-liquid interface. In some embodiments,
the polymeric component is polymerizable, further comprising
polymerizing the polymeric component at the air-liquid or
liquid-liquid interface. In another embodiment, a method for making
a nanofilm composition comprising the reaction product of
macrocyclic modules and at least one polymeric component,
comprises: (a) providing a subphase containing the at least one
polymeric component; and (b) contacting macrocyclic modules with
the surface of the subphase. In some embodiments, the method
further comprises: (c) contacting a linker molecule with the
surface of the subphase. In another embodiment, a method for making
a nanofilm composition comprising the reaction product of
macrocyclic modules and at least one polymeric component,
comprises: (a) providing a first liquid phase comprising the
macrocyclic modules; (b) providing a second liquid phase comprising
the at least one polymeric component; and (c) forming a
liquid-liquid interface from the first liquid phase and the second
liquid phase.
[0029] In some embodiments, the nanofilm compositions may be
prepared by spin coating, spray coating, dip coating, grafting,
casting, phase inversion, electroplating, or knife-edge
coating.
[0030] In another aspect of the invention is provided methods for
filtration using the nanofilm compositions described herein. In one
embodiment, the method comprises using the nanofilm composition to
separate one or more components from a fluid. In another
embodiment, the method comprises using the nanofilm composition to
separate one or more components from a mixture of at least two
gases.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIGS. 1(A-C) illustrates examples of ellipsometric images of
a nanofilm of Hexamer 1dh and poly(maleic
anhydride-alt-1-octadecene) (PMAOD).
[0032] FIGS. 2(A-C) illustrates examples of ellipsometric images of
a nanofilm of Hexamer 1dh and PMAOD after sonication in various
solvents.
[0033] FIGS. 3(A-D) illustrates examples of the surface rheometric
storage and loss moduli for a nanofilm of Hexamer 1dh and
PMAOD.
[0034] FIGS. 4(A-D) illustrates examples of scanning electron
micrographs of a nanofilm of Hexamer 1dh and PMAOD on a
polycarbonate substrate.
[0035] FIGS. 5(A-B) illustrates examples of scanning electron
micrographs of a polycarbonate substrate.
[0036] FIG. 6 illustrates an example of an attenuated total
reflectance Fourier transform infrared (FTIR-ATR) spectrum of CHCl3
rinsings of a nanofilm of PMAOD.
[0037] FIG. 7 illustrates an example of an FTIR-ATR spectrum of
Hexamer 1dh.
[0038] FIG. 8 illustrates an example of an FTIR-ATR spectrum of
CHCl3 rinsings of a nanofilm of Hexamer 1dh and PMAOD.
[0039] FIG. 9 illustrates an example of an FTIR-ATR spectrum of
CHCl3 rinsings of a nanofilm of Hexamer 1dh prepared on a water
subphase containing diethyl malonimidate (DEM).
[0040] FIG. 10 illustrates an example of an FTIR-ATR spectrum of
CHCl3 rinsings of a nanofilm of Hexamer 1 dh and PMAOD prepared on
a water subphase containing DEM.
[0041] FIG. 11 illustrates examples of atomic force microscopy
(AFM) images of a polycarbonate substrate.
[0042] FIGS. 12(A-B) illustrates examples of AFM images of a
nanofilm of Hexamer 1dh and PMAOD on a
(3-aminopropyl)triethoxysilane (APTES) modified SiO.sub.2
substrate.
[0043] FIG. 13 illustrates examples of AFM images of a nanofilm of
Hexamer 1dh and PMAOD prepared on a water subphase containing DEM
deposited on a polycarbonate substrate.
[0044] FIG. 14 illustrates examples of surface pressure-area
isotherms of a nanofilm of octadecylamine (ODA) and
polymethylmethacrylate (PMMA).
[0045] FIG. 15 illustrates examples of surface pressure-area
isotherms of a nanofilm of ODA and PMAOD.
[0046] FIG. 16 illustrates examples of AFM images of a nanofilm of
Hexamer 1dh and PMMA on a silicon substrate.
[0047] FIG. 17 illustrates examples of the surface rheometric
storage and loss moduli for a nanofilm of Hexamer 1dh and PMAOD
made on a subphase containing 2 mg/ml DEM.
[0048] FIG. 18 illustrates examples of the surface rheometric
storage and loss moduli for a nanofilm of polyglycidyl methacrylate
(PGM) made on a subphase containing 1% ethylene diamine compared
with a nanofilm of PGM made on a basic subphase.
[0049] FIGS. 19A and 19B show representations of examples of the
structure of embodiments of a hexamer macrocyclic module.
[0050] FIG. 20A shows an example of the Langmuir isotherm of an
embodiment of a hexamer macrocyclic module.
[0051] FIG. 20B shows an example of the isobaric creep of an
embodiment of a hexamer macrocyclic module.
[0052] FIG. 21A shows an example of the Langmuir isotherm of an
embodiment of a hexamer macrocyclic module.
[0053] FIG. 21B shows an example of the isobaric creep of an
embodiment of a hexamer macrocyclic module.
DETAILED DESCRIPTION OF THE INVENTION
[0054] Definitions
[0055] As used herein, the tenn "reaction product" refers to a
product formed from the indicated components. Coupling may or may
not occur between the components in forming a reaction product.
Polymeric components may or may not be polymerized in forming a
reaction product. In a non-limiting example, a nanofilm comprising
a reaction product of macrocyclic modules and a polymeric component
may have coupling between the modules, and/or coupling between the
modules and the polymeric component, and/or coupling between the
polymeric components, or may have no coupling at all. In some
cases, the polymeric components are polymerized. The polymeric
components may be fully or partially polymerized. Alternatively,
the polymeric components may not be polymerized.
[0056] As used herein, the term "synthon" refers to a monomeric
molecular unit from which a macrocyclic module may be made; a
macrocyclic module is a closed ring of coupled synthons. Structures
arid syntheses of synthons and macrocyclic modules are described in
greater detail hereinbelow.
[0057] As used herein, the terms "polymer" and "polymeric molecule"
refer to a polymer or a molecule which is predominantly a polymer,
but may have some non-polymer atoms or species attached. The term
polymer includes copolymers, terpolymers, and polymers containing
any number of different monomers.
[0058] As used herein, the term "polymeric component" refers to a
molecule or species which is either a polymer, or may form a
polymer by polymerization. A polymerizable monomer or polymerizable
molecule may be a polymeric component. In some cases, the polymeric
component may be amphiphilic.
[0059] As used herein, "polymerizable" indicates a molecular
species which may polymerize under the reaction conditions in which
the nanofilm is prepared. "Non-polymerizable" is used herein to
indicate a molecular species which will not polymerize under the
reaction conditions in which the nanofilm is prepared. A species
which is "non-polymerizable" under one set of reaction conditions
may be "polymerizable" under another set of reaction
conditions.
[0060] As used herein, the terms "amphiphile" or "amphiphilic"
refer to a molecule or species which exhibits both hydrophilic and
lipophilic character. In general, an amphiphile contains a
lipophilic moiety and a hydrophilic moiety. The terms "lipophilic"
and "hydrophobic" are interchangeable as used herein. An amphiphile
may form a Langmuir film. An amphiphile may be polymerizable.
Alternatively, the amphiphile may not be polymerizable.
[0061] Non-limiting examples of hydrophobic groups or moieties
include lower alkyl groups, alkyl groups having 7, 8, 9, 10, 11,
12, or more carbon atoms, including alkyl groups with 14-30, or 30
or more carbon atoms, substituted alkyl groups, alkenyl groups,
alkynyl groups, aryl groups, substituted aryl, saturated or
unsaturated cyclic hydrocarbons, heteroaryl, heteroarylalkyl,
heterocyclic, and corresponding substituted groups. A hydrophobic
group may contain some hydrophilic groups or substituents insofar
as the hydrophobic character of the group is not outweighed. In
further variations, a hydrophobic group may include substituted
silicon atoms, and may include fluorine atoms. The lipophilic
moieties may be linear, branched, or cyclic.
[0062] Non-limiting examples of groups which may be coupled to a
synthon or macrocyclic module as a lipophilic group include alkyls,
--CH.dbd.CH--R, --C.ident.C--R, --OC(O)--R, --C(O)O--R,
--NHC(O)--R, --C(O)NH--R, and --O--R, where R is 4-18C alkyl.
[0063] Non-limiting examples of hydrophilic groups or moieties
include hydroxyl, methoxy, phenol, carboxylic acids and salts
thereof, methyl, ethyl, and vinyl esters of carboxylic acids,
amides, amino, cyano, isocyano, nitrile, ammonium salts, sulfonium
salts, phosphonium salts, mono- and di-alkyl substituted amino
groups, polypropyleneglycols, polyethylene glycols, epoxy groups,
acrylates, sulfonamides, nitro,
--OP(O)(OCH.sub.2CH.sub.2N.sup.+RR'R")O.sup.-, guanidinium,
aminate, acrylamide, pyridinium, piperidine, and combinations
thereof, wherein R, R' and R" are each independently selected from
H or alkyl. A hydrophilic group may contain some hydrophobic groups
or substituents insofar as the hydrophilic character of the group
is not outweighed. Further examples include polymethylene chains
substituted with alcohol, carboxylate, acrylate, methacrylate, or
2
[0064] groups, where y is 1-6. Hydrophilic moieties may also
include alkyl chains having internal amino or substituted amino
groups, for example, internal --NH--, --NC(O)R--, or
--NC(O)CH.dbd.CH.sub.2-- groups. Hydrophilic moieties may also
include polycaprolactones, polycaprolactone diols, poly(acetic
acid)s, poly(vinyl acetates)s, poly(2-vinyl pyridine)s, cellulose
esters, cellulose hydroxyl ethers, poly(L-lysine hydrobromide)s,
poly(itaconic acid)s, poly(maleic acid)s, poly(styrenesulfonic
acid)s, poly(aniline)s, or poly(vinyl phosphonic acid)s.
[0065] As used herein, the terms "coupling" and "coupled" with
respect to molecular moieties or species, polymeric components,
synthons, and macrocyclic modules refers to their attachment or
association with other molecular moieties or species, molecules,
synthons, or macrocyclic modules. The attachment or association may
be specific or non-specific, reversible or non-reversible, the
result of chemical reaction, or complexation. The bonds formed by a
coupling reaction are often covalent bonds, or polar-covalent
bonds, or mixed ionic-covalent bonds, and may sometimes be
Coulombic forces, ionic or electrostatic forces or interactions. In
some preferred embodiments, the bonds formed by a coupling reaction
are covalent.
[0066] As used herein, the terms "R," "R'," "R"", and "R"" in a
chemical formula refer to a hydrogen or a functional group, each
independently selected, unless stated otherwise. In some preferred
embodiments, the fuinctional group may be an organic group.
[0067] As used herein, the term "functional group" includes, but is
not limited to, chemical groups, organic groups, inorganic groups,
organometallic groups, aryl groups, heteroaryl groups, cyclic
hydrocarbon groups, amino (--NH.sub.2), hydroxyl (--OH), cyano
(--C.ident.N), nitro (--NO.sub.2), carboxyl (--COOH), formyl
(--CHO), keto (--CH.sub.2C(O)CH.sub.2--), alkenyl (--C.dbd.C--),
alkynyl, (--C.ident.C--), and halo (F, Cl, Br and I) groups. In
some embodiments, the functional group is an organic group.
[0068] As used herein, the term "alkyl" refers to a branched or
unbranched monovalent hydrocarbon radical. An "n-mC" alkyl or
"(nC-mC)alkyl" refers to all alkyl groups containing from n to m
carbon atoms. For example, a 1-4C alkyl refers to a methyl, ethyl,
propyl, or butyl group. All possible isomers of an indicated alkyl
are also included. Thus, propyl includes isopropyl, butyl includes
n-butyl, isobutyl and t-butyl, and so on. An alkyl group with from
1-6 carbon atoms is referred to as "lower alkyl." The term alkyl
includes substituted alkyls. As used herein, the term "substituted
alkyl" refers to an alkyl group with an additional group or groups
attached to any carbon of the alkyl group. Additional groups
attached to a substituted alkyl may include one or more functional
groups such as alkyl, lower alkyl, aryl, acyl, halogen, alkylhalo,
hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy,
aryloxyalkyl, mercapto, both saturated and unsaturated cyclic
hydrocarbons, heterocycles, and others.
[0069] As used herein, the term "alkenyl" refers to any structure
or moiety having the unsaturation C.dbd.C. As used herein, the term
"alkynyl" refers to any structure or moiety having the unsaturation
C.ident.C.
[0070] As used herein, the term "aryl" refers to an aromatic group
which may be a single aromatic ring or multiple aromatic rings
which are fused together, linked covalently, or linked to a common
group such as a methylene, ethylene, or carbonyl, and includes
polynuclear ring structures. An aromatic ring or rings may include
substituted or unsubstituted phenyl, naphthyl, biphenyl,
diphenylmethyl, and benzophenone groups, among others. The term
"aryl" includes substituted aryls.
[0071] As used herein, the term "substituted aryl" refers to an
aryl group with an additional group or groups attached to any
carbon of the aryl group. Additional groups may include one or more
functional groups such as lower alkyl, aryl, acyl, halogen,
alkylhalos, hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy,
aryloxy, aryloxyalkyl, thioether, heterocycles, both saturated and
unsaturated cyclic hydrocarbons which are fused to the aromatic
ring(s), linked covalently or linked to a common group such as a
methylene or ethylene group, or a carbonyl linking group such as in
cyclohexyl phenyl ketone, and others.
[0072] As used herein, the term "heteroaryl" refers to an aromatic
ring(s) in which one or more carbon atoms of the aromatic ring(s)
are substituted by a heteroatom such as nitrogen, oxygen, or
sulfur. Heteroaryl refers to structures which may include a single
aromatic ring, multiple aromatic rings, or one or more aromatic
rings coupled to one or more nonaromatic rings. It includes
structures having multiple rings, fused or unfused, linked
covalently, or linked to a common group such as a methylene or
ethylene group, or linked to a carbonyl as in phenyl pyridyl
ketone. As used herein, the term "heteroaryl" includes rings such
as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole,
fuiran, or benzo-fused analogues of these rings.
[0073] As used herein, the term "acyl" refers to a carbonyl
substituent, --C(O)R, where R is alkyl or substituted alkyl, aryl
or substituted aryl, which may be called an alkanoyl substituent
when R is alkyl.
[0074] As used herein, the term "amino" refers to a group --NRR',
where R and R' may independently be hydrogen, lower alkyl,
substituted lower alkyl, aryl, substituted aryl or acyl.
[0075] As used herein, the term "alkoxy" refers to an --OR group,
where R is an alkyl, substituted lower alkyl, aryl, substituted
aryl. Alkoxy groups include, for example, methoxy, ethoxy, phenoxy,
substituted phenoxy, benzyloxy, phenethyloxy, t-butoxy, and
others.
[0076] As used herein, the term "thioether" refers to the general
structure R--S--R' in which R and R' are the same or different and
may be alkyl, aryl or heterocyclic groups. The group --SH may also
be referred to as "sulfhydryl" or "thiol" or "mercapto."
[0077] As used herein, the term "saturated cyclic hydrocarbon"
refers to ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, and others, including substituted groups. Substituents
to saturated cyclic hydrocarbons include substituting one or more
carbon atoms of the ring with a heteroatom such as nitrogen,
oxygen, or sulfur. Saturated cyclic hydrocarbons include bicyclic
structures such as bicycloheptanes and bicyclooctanes, and
multicyclic structures.
[0078] As used herein, the term "unsaturated cyclic hydrocarbon"
refers to nonaromatic cyclic groups with at least one double bond,
such as cyclopentenyl, cyclohexenyl, and others, including
substituted groups. Substituents to unsaturated cyclic hydrocarbons
include substituting one or more carbon atoms of the ring with a
heteroatom such as nitrogen, oxygen, or sulfur. Unsaturated cyclic
hydrocarbons include bicyclic structures such as bicycloheptenes
and bicyclooctenes, and multicyclic structures.
[0079] As used herein, the term "cyclic hydrocarbon" includes
substituted and unsubstituted, saturated and unsaturated cyclic
hydrocarbons, and includes unicyclic and multicyclic
structures.
[0080] As used herein, the term "heteroarylalkyl" refers to alkyl
groups in which the heteroaryl group is attached through an alkyl
group.
[0081] As used herein, the term "heterocyclic" refers to a
saturated or unsaturated nonaromatic group having a single ring or
multiple condensed rings comprising from 1-12 carbon atoms and from
1-4 heteroatoms selected from nitrogen, phosphorous, sulfur, or
oxygen within the ring. Examples of heterocycles include
tetrahydrofuran, morpholine, piperidine, pyrrolidine, and
others.
[0082] As used herein, each chemical term described above expressly
includes the corresponding substituted group. For example, the term
"heterocyclic" includes substituted heterocyclic groups.
[0083] As used herein, the term "activated acid" refers to a
--C(O)X moiety, where X is a leaving group, in which the X group is
readily displaced by a nucleophile to form a covalent bond between
the --C(O)-- and the nucleophile. Examples of activated acids
include acid chlorides, acid fluorides, p-nitrophenyl esters,
pentafluorophenyl esters, and N-hydroxysuccinimide esters.
[0084] As used herein, the term "amino acid residue" refers to the
product formed when a species comprising at least one amino
(--NH.sub.2) and at least one carboxyl (--C(O)O--) group couples
through either of its amino or carboxyl groups with an atom or
functional group of a synthon. Whichever of the amino or carboxyl
groups is not involved in the coupling may optionally be blocked
with a removable protective group.
[0085] Nanofilm Components
[0086] In one aspect, this invention relates variously to
nanotechnology in the preparation of porous structures and
materials having pores that are of atomic to molecular size.
Materials such as nanofilm compositions may be formed from
macrocyclic modules. Nanofilm compositions may also be formed from
macrocyclic modules in combination with one or more polymeric
components. Nanofilm compositions may also be formed from a polymer
and an amphiphile, wherein the amphiphile may be polymerizable or
non-polymerizable. Nanofilm compositions may also be formed from
polymeric components which have been coupled through linkers. In
some embodiments, pores may be supplied through the structure of
the nanofilm. In some embodiments, pores are supplied through the
structure of the macrocyclic modules.
[0087] In some variations, the nanofilm is prepared from coupled
macrocyclic modules, which may also be coupled to one or more
polymeric components. In other variations, the nanofilm includes
amphiphilic molecules, which optionally may be coupled to any of
the other components. These amphiphilic molecules may be
polymerizable or non-polymerizable. It is to be understood that a
"non-polymerizable" amphiphile is non-polymerizable under the
reaction conditions in which the nanofilm is prepared.
[0088] A nanofilm may be prepared with mixtures of different
modules, or with mixtures of macrocyclic modules, amphiphilic
molecules, and/or polymeric components. In these variations, the
polymeric component may be intermixed, aggregated, or phase
separated from the macrocyclic modules and amphiphilic molecules,
as described herein. Nanofilms having one or more polymeric
components made with mixtures of different modules and/or
amphiphilic molecules may also have interspersed arrays of pores of
various sizes.
[0089] These materials may have regions in which unique structures
exist. The unique structures may repeat at regular intervals to
provide a lattice of pores having substantially uniform dimensions.
The unique structures may have a variety of shapes and sizes,
thereby providing pores of various shapes and sizes. Because the
unique structures may be formed in a monolayer of molecular
thickness, the pores defined by the unique structures may include a
cavity, opening, or chamber-like structure of molecular size. In
general, pores of atomic to molecular size defined by those unique
structures may be used for selective permeation or molecular
sieving functions. Some aspects of nanotechnology are given in
Nanostructured Materials, J. Ying, ed., Academic Press, San Diego,
2001.
[0090] The nanofilm may have one or more polymeric components.
These nanofilms may have regions composed primarily of one or more
polymeric components. In some cases, the polymeric components act
as a plasticizer. In some cases, regions composed primarily of one
or more polymeric components may form a barrier to permeation by
fluids, small molecules, biomolecules, solvent molecules, or ions.
In other cases, the porosity of the nanofilm is controlled by the
type and degree of cross-linking of the polymeric components.
[0091] A wide variety of structural features and properties such as
amorphous, glassy, semicrystalline or crystalline structures, and
elastomeric, pliable, thermoplastic, or deformation properties may
be exhibited by the nanofilms.
[0092] The various components, such as, for example, modules and
polymeric components, may be deposited on a surface to form a
nanofilm. Macrocyclic modules can be oriented on a surface by
providing functional groups on the modules which impart amphiphilic
character to the modules. For example, when the module is deposited
on a hydrophilic surface, hydrophobic substituent groups or
hydrophobic tails attached to the module may cause the module to
reorient on the surface so that the hydrophobic substituents are
oriented away from the surface, leaving a more hydrophilic facet of
the module oriented toward the surface. Other components may also
optionally similarly be oriented on the surface by providing
amphiphilic groups in the component.
[0093] The conformation of a molecule on a surface may depend on
the loading, density, or state of the phase or layer in which the
molecule resides on the surface. Surfaces which may be used to
orient modules or other molecules include interfaces such as
gas-liquid, air-water, immiscible liquid-liquid, liquid-solid, or
gas-solid interfaces. The thickness of the oriented layer may, in
some cases, be substantially a monomolecular layer thickness.
[0094] The composition of the nanofilm may be solid, gel, or
liquid. The modules of the nanofilm may be in an expanded state, a
liquid state, or a liquid-expanded state. The state of the modules
of the nanofilm may be condensed, liquid-condensed, collapsed, or
may be a solid phase or close-packed state. The modules and/or
other components of the nanofilm may interact with each other by
weak forces of attraction. Alternatively, they may be coupled
through, for example, covalent bonds. For example, the modules of a
nanofilm prepared from surface-oriented macrocyclic modules need
not be linked by any strong interaction or coupling. Alternatively,
for example, the modules of the nanofilm may be linked through, for
example, covalent bonds.
[0095] This invention further includes the rational design of
molecules or macrocyclic modules that may be assembled as "building
blocks" for further assembly into larger species. Standardized
molecular subunits or modules may be used from which hierarchical
molecules of predicted properties can be assembled. Coupling
reactions can be employed to combine or attach modules in directed
syntheses.
[0096] The preparation of macrocyclic modules beginning with a set
of synthons is described in U.S. patent application Ser. Nos.
10/071,377 and 10/226,400, and in the PCT Application entitled
"Macrocyclic module compositions" filed Feb. 7, 2003, incorporated
by reference herein in their entirety. The assembly of molecular
building blocks, beginning with a set of synthons assembled to make
macrocyclic modules, which, in turn, are combined to form a
nanofilm are described in U.S. Serial No. 60/383,236, filed May 22,
2002, and in U.S. patent application entitled "Nanofilm and
Membrane Compositions" filed Feb. 7, 2003, incorporated by
reference herein in their entirety. Examples and syntheses of
synthons, macrocyclic modules, and amphiphilic macrocyclic modules
are further described hereinbelow.
[0097] Examples of modules useful as molecular building blocks are
shown in Table 1.
3 Examples of macrocyclic modules MODULE STRUCTURE Hexamer 1a 3
Hexamer 1dh 4 Hexamer 3j- amine 5 Hexamer 1jh-AC 6 Hexamer 1jh- 7
Hexamer 2j- amine/ester 8 Hexamer 1dh- 9 Octamer 5jh- 10 Octamer
4jh- acryl 11
[0098] Nanofilm Polymeric Components
[0099] In one aspect, this invention relates variously to nanofilm
compositions having polymeric components. Polymeric components may
be introduced into nanofilm compositions which contain macrocyclic
modules. Nanofilm compositions may also be made from polymeric
components coupled by linker molecules. Nanofilm compositions may
also be made from polymeric components and amphiphilic molecules,
wherein the amphiphilic molecules may optionally be
polymerizable.
[0100] A polymeric component is a polymerizable species, or a
polymer or macromolecule of any molecular weight which is made of
monomers. Polymerizable species include monomers, which are
molecules that can be repeated in a polymer, and polymers, wherein
the monomers or polymers have polymerizable or crosslinkable
groups. Any polymeric component, polymerizable species, polymer, or
monomer may also be amphiphilic. Examples of polymeric components
include organic polymers, thermoplastics, synthetic and natural
elastomers, conducting polymers, synthetic and natural biopolymers,
and inorganic polymers. Examples of polymeric components of this
invention include organic polymers containing atoms selected from
H, C, N, O, S. F, and Cl.
[0101] The polymeric component may be a homopolymer, or a mixed,
block, or graft copolymer. Mixed polymers, block polymers, and
copolymers include macromolecules having two, three, or more
different monomers. The polymeric component may have any
combination of the monomers or polymers which make up any of the
example polymers described herein, or may be a blend of polymers.
Mixtures of polymeric components may be used in variations of this
invention. Examples of polymers include linear or branched,
side-chain branched, or branched comb polymers. A polymer may be a
star or dendrimeric form, or forms including microtubules,
cylinders, or nanotubes of various compositions. Polymer branches
may be long-chain branches or short-chain branches. The polymers
may be made by synthetic methods, or may be obtained from
naturally-occurring sources.
[0102] A polymeric component may be in the form of a polymer when
introduced into the mixture used to form a nanofilm. In some
variations, a polymeric component which is already in the form of a
polymer when introduced into the mixture used to form a nanofilm
may have amphiphilic character. A polymer having amphiphilic
character may be more soluble in water than organic solvent, or
vice-versa. In some variations, a polymeric component may be a
water soluble polymer having polar groups and amphiphilic
character.
[0103] In further variations, the polymeric component may be in the
form of a polymerizable molecule when introduced into the mixture
used to form a nanofilm. Polymerizable molecules used to prepare a
nanofilm include monomers. In some variations, polymerizable
molecules used to prepare a nanofilm may have amphiphilic
character. The polymeric component of a nanofilm may be formed
in-situ during preparation of the nanofilm from macrocyclic modules
and/or other components. In-situ formation of the polymeric
component of a nanofilm may be carried out by polymerization of a
monomer or polymerizable amphiphile in a multicomponent
mixture.
[0104] Examples of a polymeric component include poly(maleic
anhydrides), a copolymer of maleic anhydride,
poly(ethylene-co-maleic anhydride), poly(maleic anhydride-co-alpha
olefin), polyacrylates, a polymer or copolymer having acrylate side
groups, a polymer or copolymer having oxacyclopropane side groups,
polyethyleneimides, polyetherimides, polyethylene oxides,
polypropylene oxides, polystyrenes, poly(vinyl acetate)s,
polytetrafluoroethylenes, polyolefins, polyethylenes,
polypropylenes, ethylene-propylene copolymers, polyisoprenes,
neopropenes, polyanilines, polyacetylenes, polyvinylchlorides,
polyvinylidene chlorides, polyvinylidene fluorides,
polyvinylalcohols, polyurethanes, polyamides, polyimides,
polysulfones, polyethersulfones, polysulfonamides, polysulfoxides,
polyglycolic acids, polyacrylamides, polyvinylalcohols, polyesters,
polyester ionomers, polyethylene terephthalates, polybutylene
terephthalates, polycarbonates, polysorbates, polylysines,
polypeptides, poly(amino acids), polyvinylpyrrolidones, polylactic
acids, gels, hydrogels, carbohydrates, polysaccharides, agarose,
amylose, amylopectin, glycogen, dextran, cellulose, cellulose
acetates, chitin, chitosan, peptidoglycan, and glycosaminoglycan.
Examples of a polymeric component also include amino-branched,
amino-substituted, and amino-terminal derivatives of the preceding
example polymers. Other examples of a polymeric component include
polynucleotides, synthetic or naturally-occurring polynucleotides,
for example, poly(T) and poly(A), nucleic acids, as well as
proteoglycans, glycoproteins, and glycolipids.
[0105] Examples of polymeric components which are polymerizable
monomers include vinyl halide compounds such as vinyl chloride;
vinylidene monomers such as vinylidene chloride; unsaturated
carboxylic acids such as acrylic acid, methacrylic acid, maleic
acid, itaconic acid, and salts thereof; acrylates such as methyl
acrylate, ethyl acrylate, butyl acrylate, octyl acrylate,
methoxyethyl acrylate, phenyl acrylate and cyclohexyl acrylate;
methacrylates such as methyl methacrylate, ethyl methacrylate,
butyl methacrylate, octyl methacrylate, phenyl methacrylate and
cyclohexyl methacrylate; unsaturated ketones such as methyl vinyl
ketone, ethyl vinyl ketone, phenyl vinyl ketone, methyl isobutenyl
ketone and methyl isopropenyl ketone; vinyl esters such as vinyl
formate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl
benzoate, vinyl monochloroacetate, vinyl dichloroacetate, vinyl
trichloroacetate, vinyl monofluoroacetate, vinyl difluoroacetate
and vinyl trifluoroacetate; vinyl ethers such as methyl vinyl ether
and ethyl vinyl ether; acrylamide and alkyl substituted compounds
thereof; acid compounds containing a vinyl group and salts,
anhydrides and derivatives thereof such as vinylsulfonic acid,
allylsulfonic acid, methallylsulfonic acid, styrenesulfonic acid,
2-acrylamido-2-methylpropanesulfonic acid, sulfopropyl
methacrylate, vinylstearic acid and vinylsulfinic acid; styrene or
alkyl- or halogen-substituted compounds thereof such as styrene,
methylstyrene and chlorostyrene; allyl alcohol or esters or ethers
thereof; vinylimides such as N-vinylphthalimide and
N-vinylsuccinoimide; basic vinyl compounds such as vinylpyridine,
vinylimidazole, dimethylaminoethyl methacrylate,
N-vinylpyrrolidone, N-vinylcarbazole and vinylpyridine; unsaturated
aldehydes such as acrolein and methacrolein; and cross-linking
vinyl compounds such as glycidyl methacrylate,
N-methylolacrylamide, hydroxyethyl methacrylate, triallyl
isocyanurate, triallyl cyanurate, divinylbenzene, ethylene glycol
di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene
glycol di (meth)acrylate, trimethylolpropane tri (meth)acrylate and
methylene bisacrylamide.
[0106] Examples of polymeric components which are polymerizable
amphiphiles include long chain alkyl derivatives of vinyl halides,
vinylidene halides, unsaturated carboxylic acids and salts thereof,
acrylates, methacrylates, unsaturated ketones, vinyl esters, vinyl
ethers, acrylamides, acid compounds containing a vinyl group,
anhydrides, styrenes, allyl alcohol or esters or ethers thereof,
vinylimides, vinyl compounds, unsaturated aldehydes, and vinyl
compounds. Examples of polymeric components which are polymerizable
amphiphiles generally include amphiphilic acrylates, amphiphilic
acrylamides, amphiphilic vinyl esters, amphiphilic anilines,
amphiphilic diynes, amphiphilic dienes, amphiphilic acrylic acids,
amphiphilic enes, amphiphilic cinnamic acids, amphiphilic
amino-esters, and amphiphilic oxiranes. Further examples of
polymeric components which are polymerizable amphiphiles include
amphiphilic amines, amphiphilic diesters, amphiphilic diacids,
amphiphilic diols, amphiphilic polyols, and amphiphilic diepoxides,
any of which may be coupled with linker molecules.
[0107] Preferred polymeric components include poly(maleic
anhydride-co-alpha olefin), PMAOD, PMMA, poly(2-hydroxyethyl
methacrylate) (PHEMA), PGM, polyethylene imine (PEI) and
CH.sub.2.dbd.CHC(O)OCH.sub.2CH.sub.2OH. Further preferred polymeric
components which may be used in the nanofilms of the invention
include those described in Tables 5-9 hereinbelow. In some
embodiments, the polymeric component is poly(maleic
anhydride-co-alpha olefin). In some embodiments, the polymeric
component is PMAOD. In some embodiments, the polymeric component is
PMMA. In some embodiments, the polymeric component is PHEMA. In
some embodiments, the polymeric component is PGM. In some
embodiments, the polymeric component is PEI. In some embodiments,
the polymeric component is
CH.sub.2.dbd.CHC(O)OCH.sub.2CH.sub.2OH.
[0108] A polymeric component may have an atom or a group of atoms
which couple to other species or components of a nanofilm. Coupling
of the polymeric component to other species in a nanofilm may be
complete or incomplete. The polymeric component may couple to
macrocyclic modules or linker molecules, or to other polymeric
components, or to other species such as amphiphiles or monomers.
Coupling of macrocyclic modules, linker molecules, or other species
may be to domains of the polymeric component, occurring at the
interface or surface of the domains.
[0109] Nanoflims of Amphiphilic Molecules
[0110] Amphiphilic molecules may be oriented on a surface such as
an air-water interface in a Langmuir trough, and may be compressed
to form a Langmuir thin film. The amphiphilic molecules of the
Langmuir thin film may be coupled to each other or to other
components, and may form a substantially monomolecular layer thin
film material.
[0111] Non-limiting examples of polar groups of the amphiphilic
molecules include amide, amino, ester, --SH, acrylate, acrylamide,
epoxy, --OH, --OCH.sub.3, --NH.sub.2, --CN, --NO.sub.2,
--N.sup.+RR'R", --SO.sub.3.sup.-, --OPO.sub.2.sup.2-,
--OC(O)CH.dbd.CH.sub.2, --SO.sub.2NH.sub.2, --SO.sub.2NRR',
--OP(O)(OCH.sub.2CH.sub.2N.sup.+RR'R"- )O.sup.-, --C(O)OH,
--C(O)O.sup.-, guanidinium, aminate, pyridinium, --C(O)OCH.sub.3,
--C(O)OCH.sub.2CH.sub.3, 12
[0112] where w is 1-6, --C(O)OCH.dbd.CH.sub.2,
--O(CH.sub.2).sub.xC(O)NH.s- ub.2, where x is 1-6,
--O(CH.sub.2).sub.yC(O)NHR, where y is 1-6, and
--O(CH.sub.2CH.sub.2O).sub.zR, where z is 1-6, and hydrophilic
groups. The polar groups may be coupled together by coupling
reactions to form a thin film material. The polar groups of the
amphiphilic molecules may be linked directly to each other. For
example, sulfhydryl groups may be coupled to form disulfide link,
or polar groups having ester and amino groups may couple to attach
the amphiphilic molecules through amide linkages. The coupling may
attach more than two amphiphilic molecules, for example, by
extended amide linkages. The polar groups of the amphiphilic
molecules may also be linked to each other with a linker molecule.
For example, amino may be coupled by the Mannich reaction with
formaldehyde. A portion of the amphiphilic molecules of the
nanofilm may be coupled, while the rest are not coupled. The
amphiphilic molecules of the nanofilm, both those which are coupled
and those which are not coupled, may also interact through weak
non-bonding or bonding interactions such as hydrogen bonding and
other interactions.
[0113] The hydrophobic tails of the amphiphilic molecules may be
any length, and are sometimes from about 1 to 28 carbon atoms.
Examples of hydrophobic tails of the amphiphilic molecules include
the hydrophobic groups which may be attached to macrocyclic modules
to impart amphiphilic character to the modules.
[0114] Preferred polymerizable amphiphiles include amphiphilic
acrylates, amphiphilic acrylamides, amphiphilic vinyl esters,
amphiphilic anilines, amphiphilic diynes, amphiphilic dienes,
amphiphilic acrylic acids, amphiphilic enes, amphiphilic cinnamic
acids, amphiphilic amino-esters, amphiphilic oxiranes, amphiphilic
amines, amphiphilic diesters, amphiphilic diacids, amphiphilic
diols, amphiphilic polyols, and amphiphilic diepoxides.
[0115] Preferred non-polymerizable amphiphiles include decylamine
and stearic acid. It is to be understood that these are
"non-polymerizable amphiphiles" when they are non-polymerizable
under the conditions in which the nanofilm is prepared. These may
be considered polymerizable amphiphiles when included in other
nanofilms, wherein the conditions of the preparation of those
nanofilms could cause the amphiphiles to be polymerized.
[0116] In some embodiments, the amphiphile may be octadecylamine
(ODA). In some embodiments, the amphiphile may be
methylheptadecanoate (MHD). In some embodiments, the amphiphile may
be N-octadecylacrylamide (ODAA). In some embodiments, the
amphiphile may be decylamine. In some embodiments, the amphiphile
may be stearic acid. In some embodiments, the amphiphile may be a
methyl ester of stearic acid. In some embodiments, the amphiphile
may be icosanol, or other long chain alkanol. Further examples of
preferred amphiphiles may be found in the Examples, and in Tables
5-9.
[0117] Pores and barrier properties are found in the structure of
the nanofilm made by coupling amphiphilic molecules. The pores and
barrier properties may be modified by the degree or extent of
coupling or interaction of the amphiphilic molecules, and for
example, by the length of the linker molecules.
[0118] Coupling of Macrocyclic Modules and other Components
[0119] Macrocyclic modules and/or other components oriented on a
surface may be coupled to form a thin layer composition or
nanofilm. For example, surface-oriented modules may be coupled in a
two-dimensional array to form a substantially monomolecular layer
nanofilm. The two-dimensional array is generally one molecule thick
throughout the thin layer composition, and may vary locally due to
physical and chemical forces. Coupling of modules and/or other
components may be done to form a substantially two-dimensional thin
film by orienting the modules and/or other components on a surface
before or during the process of coupling. In general, amphiphilic
components may be oriented on an interface. In general, water
soluble components may be added to the subphase for the formation
of a nanofilm. Components may also be mixed prior to orienting on
an interface.
[0120] Macrocyclic modules can be prepared to possess functional
groups which permit coupling of the modules. The nature of the
products formed by coupling modules depends, in one variation, on
the relative orientations of the functional groups with respect to
the module structure, and in other variations on the arrangement of
complementary functional groups on different modules which can form
covalent, non-covalent or other binding attachments with each
other.
[0121] In some variations, a macrocyclic module includes functional
groups which couple directly to complementary functional groups of
other macrocyclic modules to form linkages between macrocyclic
modules. The functional groups may in some cases contribute to the
amphiphilic character of the module before or after coupling, and
may be covalently or non-covalently attached to the modules. In
some embodiments, the functional groups are covalently attached to
the modules. The functional groups may be attached to the modules
before, during, or after orientation of the modules on the
surface.
[0122] In other variations, a macrocyclic module includes
functional groups which couple to polymeric components and/or other
components. Macrocyclic modules may be prepared with functional
groups which couple to complementary functional groups of polymeric
and/or other components to form linkages. The coupling between
macrocyclic modules and these other components may be direct, or
may occur through linker molecules.
[0123] In other variations, components such as polymeric components
and amphiphiles may also comprise functional groups for coupling to
themselves or to other components, such as coupling a polymeric
component to another polymeric component, or coupling a polymeric
component to an amphiphilic component. The functional groups may be
attached to the components before, during, or after orientation of
the components on a surface or subphase. In some cases, the
functional groups impart amphiphilic character to the component,
either before or after coupling.
[0124] In making nanofllms from macrocyclic modules and/or other
components, one or more coupling linkages may be formed between
macrocyclic modules, and coupling may occur between macrocyclic
modules and other components. In some variations, coupling may also
occur between other components, for example, between amphiphilic
groups and polymeric components. The linkage formed between, e.g.,
macrocyclic modules or between a macrocyclic module and another
component may be the product of the coupling of one functional
group from each molecule. For example, a hydroxyl group of a first
macrocyclic module may couple with an acid group or acid halide
group of a second macrocyclic module to form an ester linkage
between the two macrocyclic modules. Another example is an imine
linkage, --CH.dbd.N--, resulting from the reaction of an aldehyde,
--CH.dbd.O, on one macrocyclic module with an amine, --NH.sub.2, on
another macrocyclic module. Examples of linkages between
macrocyclic modules or between macrocyclic modules and other
components are shown in Table 2.
4TABLE 2 Examples of functional groups and linkages formed
Functional Group A Functional Group B Linkage Formed --NH.sub.2
--C(O)H --N.dbd.CH-- --NH.sub.2 --CO.sub.2H --NHC(O)-- --NHR
--CO.sub.2H --NRC(O)-- --OH --CO.sub.2H --OC(O)-- -X --O Na --O--
--SH --SH --S--S-- -X --(NR)Li --NR- -X --S Na --S-- -X --NHR --NR-
-X --CH.sub.2CuLi --CH.sub.2-- -X --(CRR ").sub.n=1-6CuLi --(CRR
").sub.n-- module-X module-X module-module --CH.sub.2X --CH.sub.2X
--CH.sub.2CH.sub.2-- --ONa --C(O)OR --C(O)O-- --SNa --C(O)OR
--C(O)S-- -X --C.ident.CH --C.ident.C-- --C.ident.CH --C.ident.CH
--C.ident.C--C.ident.C-- --MgX --C(O)H --CH(OH)-- module-NH.sub.2
13 14 module-MgX 15 16 17 module-X 18 --C(O)H --C(O)H --HC.dbd.CH--
(CH.sub.3).sub.2C.ident.CH-module module-C(O)Cl 19 --N.dbd.C.dbd.O
--NH.sub.2 --NHC(O)NH-- --N.dbd.C.dbd.O HO-- --NHC(O)O-- --C(O)H
--NHNH.sub.2 --CH.dbd.N--NH-- --OH --OC(O)X --OC(O)O--
(CH.sub.3).sub.2C.dbd.CH-module module-SH 20
(CH.sub.3).sub.2CHC(O)O-module module-CH(O) 21
module-CH.sub.2C(O)OH module-CH.sub.2C(O)OH 22 23 R.sub.2SiH-module
24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 --NH.sub.2
65 66 67 68 69 70 71
[0125] In Table 2, R and R' represent hydrogen or alkyl groups, and
X is halogen or other good leaving group. It is to be understood
that the functional groups included in Table 2 may also be used to
link a module with another component, such as a polymeric
component, and may also be used to link non-module components
together, such as a polymeric component to another polymeric
component, or a polymeric component to an amphiphilic
component.
[0126] In another variation, a macrocyclic module may have
functional groups for coupling to other macrocyclic modules wherein
the functional groups are coupled to the macrocyclic module after
initial preparation of the closed ring of the module. For example,
an amine linkage between the synthons of a macrocyclic module may
be substituted with one of various functional groups to produce a
substituted linkage. Examples of such linkages between synthons of
a macrocyclic module having functional groups for coupling other
macrocyclic modules are shown in Table 3.
5TABLE 3 Examples of macrocyclic module linkages Macrocyclic Module
Linkage Reagent Substituted Linkage 72 73 74 75 76 77 78 79 80 81
82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98
[0127] In Table 3, X is halogen, and Q represents a synthon in a
macrocyclic module.
[0128] Referring to Table 3, the substituted linkage of a
macrocyclic module may couple to a substituted linkage of another
module. In some variations, the coupling of these linkages is done
by initiating 2+2 cycloaddition. For example, acrylamide linkages
may couple to produce 99
[0129] by 2+2 cycloaddition. In other variations, coupling of these
reactive substituted linkages may be initiated by other chemical,
thermal, photochemical, electrochemical, and irradiative methods to
provide a variety of coupled structures. It is to be understood
that the functional groups and substituted linkages formed included
in Table 3 may also be used to link a module with another
component, such as a polymeric component, and may also be used to
link non-module components together, such as a polymeric component
to an amphiphilic component.
[0130] The functional groups used to form linkages between
macrocyclic modules and/or other components may be separated from
the module or component by a spacer. A spacer can be any atom or
group of atoms which couples the functional group to the
macrocyclic module or other component, and does not interfere with
the linkage-forming reaction. A spacer is part of the functional
group, and becomes part of the linkage between macrocyclic modules
and/or other components. An example of a spacer is a polymethylene
group, --(CH2)n-, where n is 1-6. The spacer may be said to extend
the linkage between macrocyclic modules and/or other components.
Other examples of spacer groups are alkylene, aryl, acyl, alkoxy,
saturated or unsaturated cyclic hydrocarbon, heteroaryl,
heteroarylalkyl, heterocyclic, and corresponding substituted
groups. Further examples of spacer groups are polymer, copolymer,
or oligomer chains, for example, polyethylene oxides, polypropylene
oxides, polysaccharides, polylysines, polypeptides, poly(amino
acids), polyvinylpyrrolidones, polyesters, polyacrylates,
polyamines, polyimines, polystyrenes, poly(vinyl acetate)s,
polytetrafluoroethylenes, polyisoprenes, neopropene, polycarbonate,
polyvinylchlorides, polyvinylidene fluorides, polyvinylalcohols,
polyurethanes, polyamides, polyimides, polysulfones,
polyethersulfones, polysulfonamides, polysulfoxides, and copolymers
thereof. Examples of polymer chain spacer structures include
linear, branched, comb and dendrimeric polymers, random and block
copolymers, homo- and heteropolymers, flexible and rigid chains.
The spacer may be any group which does not interfere with formation
of the linkage. A spacer group may be substantially longer or
shorter than the functional group to which it is attached.
[0131] Coupling of macrocyclic modules and/or other components to
each other may occur through coupling of functional groups of the
macrocyclic modules and/or other components to linker molecules.
The functional groups involved may be, for example, those
exemplified in Table 2. For example, modules may couple to at least
one other module through a linker molecule. A linker molecule is a
discrete molecular species used to couple at least two modules.
Each module may have 1 to 30 or more functional groups which may
couple to a linker molecule. Linker molecules may have 1 to 20 or
more functional groups which may couple to, for example, a
module.
[0132] In one variation, a linker molecule has at least two
functional groups, each of which can couple to a module and/or
other component. In these variations, linker molecules may include
a variety of functional groups for coupling modules and/or other
components. Non-limiting examples of functional groups of modules
and linker molecules are illustrated in Table 4.
6TABLE 4 Examples of functional groups of modules and linker
molecules Functional Functional Group of Group of Module A Module B
Linker Molecule Linkage --NHR or --NH.sub.2 --NHR or --NH.sub.2 100
101 --NHR or NH.sub.2 --NHR or --NH.sub.2 102 103 --NHR or
--NH.sub.2 --NHR or --NH.sub.2 104 105 --NHR or --NH.sub.2 --NHR or
--NH.sub.2 106 107 --OH --OH 108 109 --OH --OH 110 111 --OH --OH
(RO).sub.2BR 'B(OR).sub.2 --O(HO)BR '(OH)O-- --NHR or --NHR or
(RO).sub.2BR 'B(OR).sub.2 --NH(HO)BR 'B(OH)NH-- --NH.sub.2
--NH.sub.2 --OH --OH X-(CH.sub.2).sub.n-X
--O--(CH.sub.2).sub.n--O-- --OH --OH
ClC(O)--(CH.sub.2).sub.n--C(O)Cl 112 --NHR or --NH.sub.2 --NHR or
--NH.sub.2 113 114 --NHR or --NH.sub.2 --NHR or --NH.sub.2 115 116
117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
--OH --OH 133 --OCH.sub.2CH(OH)CH.sub.- 2O-- --OH --NH.sub.2 134
--OCH.sub.2CH(OH)CH.sub.2NH-- --NH.sub.2 --NH.sub.2 135
--NHCH.sub.2CH(OH)CH.sub.2NH-- --NRH --NRH 136
--NHCH.sub.2CH(OH)CH.sub.2NR--
[0133] In Table 4, n is 1-6, m is 1-10, R is --CH.sub.3 or --H, R'
is --(CH.sub.2).sub.n-- or phenyl, R" is --(CH.sub.2)--,
polyethylene glycol (PEG), or polypropylene glycol (PPG), and X is
Br, Cl, I, or other good leaving groups which are organic groups
containing atoms selected from the group of carbon, oxygen,
nitrogen, halogen, silicon, phosphorous, sulfur, and hydrogen. A
module may have a combination of the various functional groups
exemplified in Table 4. It is to be understood that the functional
groups and linkers included in Table 4 may also be used to link a
module with another component, such as a polymeric component, and
may also be used to link nonmodule components together, such as a
polymeric component to an amphiphilic component. Preferred linkers
include DEM and ethylene diamine. Further examples of suitable
linkers are found in the Examples, and in Tables 5-9.
[0134] Methods of initiating coupling of the modules and/or
components to linker molecules include chemical, thermal,
photochemical, electrochemical, and irradiative methods.
[0135] A nanofilm comprising coupled modules and/or other
components can be made by coupling together one or more members of
the collection of modules and/or other components, perhaps with
other bulky or flexible components, to form a thin layer nanofilm
material or composition. Coupling of modules and/or other
components may be complete or incomplete, providing a variety of
structural variations useful as nanoflim membranes.
[0136] In general, the coupling of polymeric components to
macrocyclic modules to prepare a nanofilm may be done with myriad
combinations of complementary functional groups. For example, as
shown herein, macrocyclic modules which may couple to other
macrocyclic modules through linker molecules may also couple to
polymeric components and other components having complementary
functional groups. In the various schemes for the preparation of
nanofilm with linker molecules illustrated in Table 5 hereinbelow,
a polymeric component having amino functional groups, for example,
may couple to linker molecules and compete with the macrocyclic
modules for coupling to other macrocyclic modules. In another
example, a macrocyclic module having amino functional groups may
couple to poly(ethylene-co-maleic anhydride) to form a maleimide
group in the polymer. The various types and degrees of coupling
depend on the identity of the functional groups of the polymeric
components.
[0137] When mixtures of polymerizable species are used to prepare a
nanofilm, the species may copolymerize. Copolymerization may
involve coupling to functional groups of macrocyclic modules.
[0138] The coupling of modules in a nanofilm may attach two or more
components by a linkage or linkages. The coupling may attach more
than two modules, for example, by an array of linkages each formed
between two modules. Each module may form more than one linkage to
another module, and each module may form several types of linkages,
including those exemplified in Tables 2-4. A module may have direct
linkages, linkages through a linker molecule, and linkages which
include spacers, in any combination. A linkage may connect any
portion of a module to any portion of another module. An array of
linkages and an array of modules may be described in terms of the
theory of Bravais lattices and theories of symmetry.
[0139] A portion of each of the components of aznanofilm may be
coupled, while the remainder of each is not coupled. The components
of the nanofilm may interact through, for example, hydrogen
bonding, van der Waals, and other interactions. The arrangement of
linkages formed in a nanofilm may be represented by a type of
symmetry, or may be substantially unordered.
[0140] Nanofilms of Macrocyclic Modules and Polymeric
Components
[0141] A nanofilm may be prepared from mixtures of macrocyclic
modules and other components. The types of coupling between the
components and the phase and domain behavior of the mixture, as
described herein, may influence the composition and properties of
the product nanofilm. Multicomponent mixtures of these types
sometimes result in phase separated or aggregated compositions. A
macrocyclic module may participate in more than one type of
coupling, and the product nanofilm may have a wide variety of
compositions.
[0142] In one aspect, this invention relates to the introduction of
polymeric components into nanofilms comprising macrocyclic modules.
Various types of coupling may be used to prepare a nanofilm with
macrocyclic modules and polymeric components. In one type of
coupling, a macrocyclic module may have functional groups which
couple to a linker molecule which, in turn, couples to another
macrocyclic module or other species, but may not effectively couple
to a polymeric component. In this type of coupling, the macrocyclic
module may couple much more rapidly to another macrocyclic module
than to the polymeric component, and form a nanofilm in which the
degree of coupling between macrocyclic modules and the polymeric
component is limited. For example, a macrocyclic module having
amino functional groups may couple readily with a linker molecule
such as ClC(O)CH2C(O)Cl, but not as readily with some polymeric
components.
[0143] In another mode of coupling, a macrocyclic module may not
have functional groups which readily couple to other components. An
example of this type is a macrocyclic module having imine linkages
and only alkyl substituents which may not readily couple to other
macrocyclic modules, polymeric components, or other species. A
macrocyclic module which does not readily couple to other species
may form a nanofilm with polymeric components without substantial
coupling between macrocyclic modules and polymeric components.
[0144] In one aspect, this invention involves the formation of a
nanofilm using multicomponent mixtures of macrocyclic modules and
polymeric components, wherein the macrocyclic modules may not
directly couple to other macrocyclic modules or to polymeric
components in forming the nanofilm, and wherein the macrocyclic
modules may be coupled through linker molecules.
[0145] Various schemes for the preparation of nanofilms with linker
molecules are illustrated in Table 5.
7TABLE 5 Schemes to prepare nanoflims from macrocyclic modules with
linker molecules and polymeric components Reagents Scheme
macrocyclic module linker molecule polymer 137 138 macrocyclic
module linker molecule amphiphilic polymer 139 140 macrocyclic
module linker molecule polymerizable amphiphile 141 142 macrocyclic
module linker molecuel polymerizable monomer 143 144 Macrocyclic
module linker molecule polymer amphiphile 145 146 macrocyclic
module linker molecule polymer polymerizable amphiphile 147 148
macrocyclic module linker molecule polymer amphiphilic polymer 149
150 macrocyclic module linker molecule amphiphilic polymer
polymerizable amphiphile 151 152 macrocyclic module linker molecule
amphiphile polymerizable amphiphile 153 154 macrocyclic module
linker molecule polymerizable amphiphile polymerizable monomer 155
156
[0146] In Table 5, R is alkyl, and n is about 3 to 1,000,000.
Referring to Table 5, in some schemes the multicomponent mixture of
macrocyclic modules may include a polymer, or an amphiphilic
polymer, or mixtures thereof. In one scheme, for example,
macrocyclic modules having amino functional groups are mixed with
polymethylmethacrylate (PMMA), which is immiscible with water. The
macrocyclic modules are then coupled with linker molecules
ClC(O)CH2C(O)Cl. In schemes with such mixtures, the macrocyclic
modules may not couple directly to polymeric components, except at
interfaces between phases. Even where the macrocyclic modules and
polymeric components form a single continuous phase, the
macrocyclic modules may be coupled predominantly to other
macrocyclic modules. In nanofilms where macrocyclic modules and
polymeric components are phase separated, surface coupling and
other adhesion of various domains may occur.
[0147] In other schemes illustrated in Table 5, multicomponent
mixtures of macrocyclic modules used to prepare nanofilm may
include a polymer and/or an amphiphilic polymer, and may further
include a molecule which is amphiphilic which may or may not be
polymerizable, or a monomer which is polymerizable, or mixtures
thereof.
[0148] In other schemes illustrated in Table 5, multicomponent
mixtures of macrocyclic modules used to prepare nanofilms may
include a polymerizable amphiphile or a polymerizable monomer
species, or mixtures thereof. These nanofilms may optionally
include a non-polymerizable amphiphilic species.
[0149] In the schemes illustrated in Table 5, multicomponent
mixtures of macrocyclic modules used to prepare nanofilm may
optionally include amphiphilic molecules which may have a
functional group that can couple to macrocyclic modules or to
polymeric components.
[0150] In another aspect, this invention involves formation of
nanofilm using multicomponent mixtures of macrocyclic modules and
polymeric components, where the macrocyclic modules may not readily
couple to the polymeric components or to other macrocyclic modules.
Various schemes for the preparation of such nanofilms are
illustrated in Table 6.
8TABLE 6 Schemes to prepare nanoflim from macrocyclic modules which
may not readily couple Reagents Scheme macrocyclic module polymer
157 158 macrocyclic module amphiphilic polymer 159 160 macrocyclic
module polymerizable amphiphile 161 162 macrocyclic module
polymerizable monomer 163 164 macrocyclic module polymer amphiphile
165 166 macrocyclic module polymer polymerizable amphiphile 167 168
macrocyclic module amphiphilic polymer polymerizable amphiphile 169
170 macrocyclic module amphiphile polymerizable amphiphile 171 172
macrocyclic module polymerizable amphiphile polymerizable monomer
173 174
[0151] In Table 6, n is about 3 to about 1,000,000. Referring to
Table 6, in some schemes the multicomponent mixture of macrocyclic
modules may include a polymer, or an amphiphilic polymer, or
mixtures thereof. In these schemes, the macrocyclic modules may not
readily couple to polymeric components or to other modules, but may
undergo some degree of coupling to either the polymeric components
or other modules. In the schemes illustrated in Table 6,
multicomponent mixtures of macrocyclic modules used to prepare
nanofilm may include a polymer and/or an amphiphilic polymer, and
may further include a molecule which is amphiphilic and may be
polymerizable, or a monomer which is polymerizable, or mixtures
thereof.
[0152] In other schemes illustrated in Table 6, multicomponent
mixtures of macrocyclic modules used to prepare nanofilms may
include a polymerizable amphiphile or a polymerizable monomer
species, or mixtures thereof. These nanofilms may optionally
include a non-polymerizable amphiphilic species.
[0153] In the schemes illustrated in Table 6, multicomponent
mixtures of macrocyclic modules used to prepare nanofilm may
further include amphiphilic molecules which may have a functional
group that can couple to macrocyclic modules or to polymeric
components.
[0154] In another aspect, this invention relates to the formation
of nanofilms using multicomponent mixtures of macrocyclic modules
and polymeric components, wherein the macrocyclic modules may
directly couple to the polymeric components, or to other
macrocyclic modules. Various schemes for the preparation of such
nanofilms are illustrated in Table 7.
9TABLE 7 Schemes to prepare nanoflim with macrocyclic modules which
may undergo direct coupling Reagents Scheme macrocyclic module
polymer 175 176 macrocyclic module and amphiphilic polyer: (a)
prepare nanofilm layer of components (b) couple components 177 178
macrocyclic module polymerizable amphiphile 179 180 macrocyclic
module polymerizable monomer 181 182 macrocyclic module polymer
amphiphile 183 184 macrocyclic module polymer polymerizable
amphiphile 185 186 macrocyclic module polymer amphiphilic polymer
187 188 macrocyclic module amphiphilic polymer polymerizable
amphiphile 189 190 macrocyclic module polymerizable amphiphile
amphiphile 191 192 macrocyclic module polymerizable amphiphile
polymerizable monomer 193 194 macrocyclic module polymerizable
monomer amphiphile 195 196 macrocyclic module and amphiphilic
polymer: (a) couple in solution (b) prepare nanofilm 197 198
[0155] In Table 7, R is alkyl, and n is about 3 to about 1,000,000.
Referring to Table 7, in some schemes the multicomponent mixture of
macrocyclic modules may include a polymer, or an amphiphilic
polymer, or mixtures thereof In these schemes, the macrocyclic
modules may in some cases couple directly to polymeric components,
and may form a single phase.
[0156] In other schemes illustrated in Table 7, multicomponent
mixtures of macrocyclic modules used to prepare nanofilm may
include a polymer and/or an amphiphilic polymer, and may further
include a molecule which is amphiphilic which may or may not be
polymerizable, or a monomer which is polymerizable, or mixtures
thereof.
[0157] In other schemes illustrated in Table 7, multicomponent
mixtures of macrocyclic modules used to prepare nanofilms may
include a polymerizable amphiphile or a polymerizable monomer
species, or mixtures thereof These nanofilms may optionally include
a non-polymerizable amphiphilic species.
[0158] In the schemes illustrated in Table 7, multicomponent
mixtures of macrocyclic modules used to prepare nanofilm may also
include amphiphilic molecules which may have a functional group
that can couple to macrocyclic modules or to polymeric
components.
[0159] The type of coupling in which a macrocyclic module
participates to form a nanofilm may depend on the presence of other
components of the nanofilm. For example, a macrocyclic module with
acrylate functional groups may couple much more rapidly to itself
than to a polymeric component with less reactive groups.
[0160] A macrocyclic module may participate in more than one type
of coupling. For example, a macrocyclic module which may couple
directly to another macrocyclic module may also couple through a
linker molecule to another macrocyclic module. Both types of
coupling may occur in the same multicomponent mixture used to
prepare a nanofilm.
[0161] In one type of coupling, a macrocyclic module may have
functional groups which couple directly to complementary functional
groups of another macrocyclic module. An example of this form is a
macrocyclic module having acrylamide functional groups. In this
type of coupling, the macrocyclic module may couple much more
rapidly to another macrocyclic module than to any polymeric
component, and form a nanofilm in which the degree of coupling
between macrocyclic modules and the polymeric component is
limited.
[0162] In some variations, the polymeric component may have
complementary functional groups which effectively compete for the
coupling groups of macrocyclic modules. In these variations, the
macrocyclic module may couple as rapidly to another macrocyclic
module as it does to the polymeric component, and may form a
nanofilm in which the degree of coupling between the macrocyclic
modules themselves is comparable to that between the macrocyclic
modules and the polymeric component. In other variations, the
degree of coupling between the macrocyclic modules and the
polymeric component may exceed that between the macrocyclic modules
themselves.
[0163] A nanofilm may be prepared by various methods where the
macrocyclic modules couple directly to a polymeric component. For
example, as shown in Table 7, the macrocyclic modules and polymeric
component may be dissolved in organic solvent and coupled together
before preparation of a nanofilm. This scheme may result in a
substantially single continuous phase within the nanofilm. In
another variation shown in Table 7, the macrocyclic modules may be
coupled to the polymeric component during or after preparation of
the nanofilm layer.
[0164] In another aspect, a nanofilm of this invention may be
formed from macrocyclic modules having functional groups which may
couple directly to complementary fuinctional groups of a polymeric
component. In these variations, the macrocyclic modules may not
readily couple to other macrocyclic modules. Schemes for the
preparation of such nanofilms are illustrated in Table 8.
10TABLE 8 Schemes to prepare nanoflim from macrocyclic modules
which couple to polymeric components Reagents Scheme macrocyclic
module polymer 199 200 macrocyclic module amphiphilic polymer 201
202
[0165] Referring to Table 8, in some schemes the multicomponent
mixture of macrocyclic modules may include a polymer, or an
amphiphilic polymer, or mixtures thereof. In these schemes, the
macrocyclic modules directly couple to polymeric components, but
may not readily couple to other modules.
[0166] In general, for a nanofilm prepared from macrocyclic modules
which directly couple to polymeric components, a discrete product
is formed from the coupling of macrocyclic modules to a polymeric
component. The discrete module-polymer product may be similar in
molecular architecture to a side-group branched polymer, or a graft
polymer. The discrete product may have a predominantly single
continuous phase.
[0167] In one example in Table 8, secondary amine linkages between
synthons of a macrocyclic module may couple to a carboxylic acid
side group of a copolymer such as the diacid form of
poly(ethylene-co-maleic anhydride). In these schemes, macrocyclic
modules couple to polymeric components, and both may be miscible in
water. The coupling between the macrocyclic module and the
polymeric component may also be indirect, and involve a linker
molecule.
[0168] In the schemes illustrated in Table 8, multicomponent
mixtures of macrocyclic modules used to prepare nanofilm may also
include amphiphilic molecules which may have a functional group
that can couple to macrocyclic modules or to polymeric
components.
[0169] Nanofilms of Amphiphiles and Polymeric Components
[0170] In one aspect, this invention relates to the introduction of
polymeric components into nanofilms comprising amphiphiles. Various
types of coupling may be used to prepare a nanofilm comprising
amphiphiles and polymeric components.
[0171] In some variations, an amphiphile may contain a
polymerizable functional group, such as an acrylate group. In these
variations, a polymeric component of a nanofilm may be formed
in-situ with the nanofilm by using a multicomponent mixture which
includes a polymerizable amphiphile, and which may also optionally
include a polymerizable monomer.
[0172] In other variations, an amphiphilic molecule which does not
have a polymerizable functional group may be used. In these
variations, amphiphiles may be mixed with polymer, amphiphilic
polymer, polymerizable monomer, polymerization amphiphile, or
mixtures thereof to form a nanofilm having polymeric
components.
[0173] In forming a nanofilm from multicomponent mixtures of
amphiphiles, the phase and domain behavior of the mixture may
influence the composition and properties of the nanofilm. Various
schemes for the preparation of nanofilms with polymeric components
and amphiphiles are illustrated in Table 9.
11TABLE 9 Schemes to prepare nanofilm with amphiphiles Reagents
Scheme polymerizable amphiphile polymer 203 204 polymerizable
amphiphile amphiphilic polymer 205 206 polymerizable amphiphile
polymerizable monomer 207 208 polymerizable amphiphile polymer
amphiphilic polymer 209 210 polymerizable amphiphile amphiphilic
polymer polymerizable monomer 211 212 amphiphile polymerizable
amphiphile 213 214 amphiphile polymer polymerizable amphiphile 215
amphiphile amphiphilic polymer polymerizable amphilphile 216
amphiphile polymerizable monomer polymerizable amphiphile 217
polymer amphiphile 218 219 amphiphilic polymer amphiphile 220 221
amphiphile polymerizable monomer 222 223
[0174] Referring to Table 9, in some schemes a nanofilm is prepared
with polymerizable amphiphiles. In forming a nanofilm from
polymerizable amphiphiles, a polymeric component may be formed
in-situ from the polymerizable amphiphiles. The mixtures used to
fonn such nanofilms may further include a polymer, or an
amphiphilic polymer, a polymerizable monomer, an amphiphile, or
mixtures thereof.
[0175] In some schemes illustrated in Table 9, a nanofilm may be
prepared from a polymer, an amphiphilic polymer, or a polymerizable
monomer. The nanofilms may optionally include an amphiphile.
[0176] Nanofilms of Polymieric Components
[0177] In one aspect, this invention relates variously to nanofilms
prepared from polymeric components. The polymeric components may be
directly linked to each other, or may be linked via linker
molecules.
[0178] In a non-limiting example, a LB film of PGM may be
crosslinked with ethylene diamine to form a nanofllm. In another
example, a LB film of polyethylene imine (PEI) may be crosslinked
with diethylene glycol diglycidyl ether: 224
[0179] to form a nanofilm. Other possible combinations of the
polymeric components included herein with appropriate linkers will
be apparent to those of skill in the art.
[0180] Nanoflim Composition and Characteristics
[0181] The characteristics of a nanofilm having one or more
polymeric components may be substantially different than those of
nanofilm prepared from macrocyclic modules alone. A nanofilm having
polymeric components may be advantageously flexible and pliable
compared to nanofilm prepared from modules alone, making it easier
to fabricate articles such as membranes for filtration and other
separation processes. Various domains of a nanofilm having
polymeric components may undergo plastic deformation in response to
stress, while other regions may be elastomeric. Nanofilms having
polymeric components may be deposited on a substrate to form a
continuous, substantially unbroken supported nanofilm or
membrane.
[0182] Because the physical, chemical, and physico-chemical
properties of nanofilm having one or more polymeric components may
be dependent, in part, on the fraction of polymeric component
relative to macrocyclic modules or other components, these
properties can be varied by changing the fraction of polymeric
component in the nanofilm.
[0183] In general, components which are polymerizable may be used
to prepare a polymeric component of a nanofilm in-situ during
formation of the nanofilm. In-situ formation of a nanofilm
polymeric component provides an alternative scheme in which phase
and domain behavior of the multicomponent mixture may be modified.
Schemes involving polymerizable species in a multicomponent mixture
may be used to prepare, among other compositions, nanofilm having
smaller domains of phase separated polymeric components as compared
to nanofilm prepared with polymer or amphiphilic polymer components
alone. Multicomponent mixtures involving a polymerizable amphiphile
may be used to prepare nanofilm with fewer openings of micrometer
dimension through which transport of species can occur, as compared
to nanofilm prepared with polymer or amphiphilic polymer components
alone.
[0184] In further variations of a nanofilm having one or more
polymeric components, the polymeric molecules may not be coupled to
other components of the nanofilm. The ability of a polymeric
component to make a nanofilm flexible or pliable may not require
coupling to macrocyclic modules or other components.
[0185] The area fraction of a component of a nanofilm is the
fraction of the total nanofilm area that the individual component
represents. The nanofilm area fraction of a component is calculated
from the mole fraction (Mf) of the component in the initial mixture
of components used to form the nanofilm, and the mean molecular
area (MMA) of the component obtained by extrapolation of the
high-surface pressure region of the pressure-area Langmuir isotherm
of the pure component to zero surface pressure. The area fraction
of a component in the nanofilm is the product (Mf)(MMA) for the
component, divided by the sum of the products (Mf)(MMA) for all
components: area fraction=(Mf.sub.1)(MMA.sub.1)/[(Mf).sub.1(MMA).-
sub.1+(Mf).sub.2(MMA).sub.2+ . . . (Mf).sub.n(MMA).sub.n], where n
is the number of components.
[0186] In general, area fraction can be measured where all nanofilm
components are immiscible in water or are amphiphilic, and all
nanofilm components are found in the initial mixture of components.
The uncertainty in measurement of area fraction may be up to about
20%, which includes uncertainty due to extrapolation of Langmuir
isotherms, and for polymeric components which are polymers in the
initial mixture of components, uncertainty due to molecular weight
polydispersity of the polymer.
[0187] In some variations, the nanofilm area fraction of a
component may not always be measured by the above formula. For
example, the area fraction of a component which was not in the
initial mixture of components used to form the nanofilm, but
entered the nanofilm later, would not be measured by the formula
above. The area fraction of a component may also not be measured by
the formula above when the component does not form a stable
Langmuir film for which MMA can be measured, or when a
polymerizable component is used in the initial mixture which may
have an MMA different from the polymer it produces.
[0188] A nanofilm may have any area fraction of polymeric
components. In some variations, a nanofilm may have an area
fraction of polymeric components from about 0.005 (0.5%) to about
0.98 (98%). In other variations, a nanofilm may have an area
fraction of polymeric components from about 0.005 to about 0.7,
often from about 0.005 to about 0.5, sometimes from about 0.005 to
about 0.3, sometimes from about 0.005 to about 0.2, sometimes from
about 0.005 to about 0.1, sometimes from about 0.005 to about 0.05,
sometimes from about 0.005 to about 0.02, sometimes from about 0.50
to about 0.98.
[0189] A nanofilm may have an area fraction or weight percent of
polymeric components sufficient to make it flexible and pliable so
that it may be deposited on a substrate as a homogeneous film with
little mechanical breakage, or to reduce the surface modulus of the
nanofilm. Flexibility of a nanofilm having polymeric components may
be demonstrated by depositing the nanofilm on various substrates to
form a continuous, substantially unbroken film on the substrate, or
by reducing surface modulus of the nanofilm.
[0190] A nanofilm may have any molar ratio of polymeric components,
as measured against the other components. In some variations, the
molar ratio of polymeric components may be, for example, about
0.005 to about 0.995, for example about 0.010 to about 0.990, for
example, about 0.01 to about 0.50, for example about 0.01 to about
0.20, for example, about 0.20 to about 0.50, for example about 0.50
to about 0.99, for example, about 0.1 to about 0.9, as measured
against the other components. In certain embodiments, the molar
ratio of polymeric component: module is about 0.1:0.9, about
0.2:0.8, about 0.5:0.5, about 0.25:0.75, or about 0.90:0.10.
[0191] The thickness of nanofilms described herein, whether through
coupled or non coupled components, is exceptionally small, often
being less than about 30 nanometers, sometimes less than about 20
nanometers, and sometimes from about 1-15 nanometers. The thickness
of a nanofilm depends partly on the structure and nature of the
groups on the modules or other species which impart amphiphilic
character to the modules, and partly on the nature of the polymeric
or other components. The thickness may be dependent on temperature,
and the presence of solvent on the surface or located within the
nanofilm. The thickness may be modified if the groups on the
modules or other components which impart amphiphilic character, in
particular the lipophilic moiety, to the component are removed or
modified after the components have been coupled, or at other points
during or after the process of preparation of a nanofilm. The
thickness of a nanofilm may also depend on the structure and nature
of the surface attachment groups on the components. The thickness
of nanofilms may be less than about 300, 250, 200, 150, 100, 90,
80, 70, 60, 50, 40, 30, 20, 10 or 5 .ANG..
[0192] The nanofilm composition may include uniquely structured
regions in which modules and/or other components are coupled.
Coupling of modules and/or other components provides a nanofilm in
which unique structures may be formed. Nanofilm structures define
pores through which atoms, molecules, or particles of only up to a
certain size and composition may pass. One variation of a nanofilm
structure includes an area of nanofilm able to face a fluid medium,
either liquid or gaseous, and provide pores or openings through
which atoms, ions, small molecules, biomolecules, or other species
are able to pass. The dimensions of the pores defined by nanofilm
structures may be exemplified by quantum mechanical calculations
and evaluations, and physical tests, as further described in the
following Examples.
[0193] The dimensions of the pores defined by nanofilm structures
are described by actual atomic and chemical structural features of
the nanofilm. The approximate diameters of pores formed in the
structure of a nanofilm are from about 1-150 .ANG., or more. In
some embodiments, the dimensions of the pores are about 1-10 .ANG.,
about 3-15 .ANG., about 10-15 .ANG., about 15-20 .ANG., about 20-30
.ANG., about 30-40 .ANG., about 40-50 .ANG., about 50-75 .ANG.,
about 75-100 .ANG., about 100-125 .ANG., about 125-150 .ANG., about
150-300 .ANG., about 600-1000 .ANG.. The approximate dimensions of
pores formed in the structure of a nanofilm are useful to
understand the porosity of the nanofilm. On the other hand, the
porosity of conventional membranes is normally quantified by
empirical results such as molecular weight cut-off, which reflects
complex diffusive and other transport characteristics.
[0194] In one variation, a nanofilm structure may comprise an array
of coupled modules which provides an array of pores of
substantially uniform size. The pores of uniform size may be
defined by the individual modules themselves. Each module defines a
pore of a particular size, depending on the conformation and state
of the module. For example, the conformation of the coupled module
of the nanofilm may be different from the nascent, pure macrocyclic
module in a solvent, and both may be different from the
conformation of the amphiphilic module oriented on a surface before
coupling. A nanofilm structure including an array of coupled
modules can provide a matrix or lattice of pores of substantially
uniform dimension based on the structure and conformation of the
coupled modules.
[0195] Modules of various composition and structure may be prepared
which define pores of different sizes. A nanofilm prepared from
coupled modules may be made from any one of a variety of modules.
Thus, nanofilms having pores of various dimensions are provided,
depending on the particular module used to prepare the
nanofilm.
[0196] In other instances, nanofilm structures define pores in the
matrix of coupled modules or other components. Pores defined by
nanofilm structures may have a wide range of dimensions, for
example, dimensions capable of selectively blocking the passage of
small molecules or large molecules. For example, nanofilm
structures may be formed from the coupling of two or more modules,
in which an interstitial pore is defined by the combined structure
of the linked modules. A nanofilm may have an extended matrix of
pores of various dimensions and characteristics. Interstitial pores
may be, for example, less than about 5 .ANG., less than about 10
.ANG., about 3-15 .ANG., about 10-15 .ANG., about 15-20 .ANG.,
about 20-30 .ANG., about 30-40 .ANG., about 40-50 .ANG., about
50-75 .ANG., about 75-100 .ANG., about 100-125 .ANG., about 125-150
.ANG., about 150-300 .ANG., about 300-600 .ANG., about 600-1000
.ANG.. In some variations, the other components may act as a
"filler" to limit the porosity of the nanofilm. In other
variations, the other components will provide porosity to the
nanofilm, depending on the type and extent of cross-linking between
the components.
[0197] The coupling process may result in a nanofilm in which
regions of the nanofilm are not precisely monomolecular layers.
Various types of local structures are possible which do not prevent
use of the nanofilm in a variety of applications. Local structural
features may include amphiphilic components or species, including
polymeric species, which are flipped over relative to their
neighbors, or turned in a different orientation, having their
hydrophobic and hydrophilic facets oriented differently than
neighboring species. Local structural features may also include
overlaying or stacking of molecules in which the nanofilm is two or
more molecular layers thick, local regions in which the
interlinking of the modules or other components is not complete so
that some of the available coupling groups are not coupled to other
species, or local regions in which there is an absence of a
particular molecule or component. Other local structural features
may include grain boundaries and orientational faults. In one
variation, the nanofilm has a thickness of up to 30 nanometers due
to the layering of nanofilm structures.
[0198] The nanofilms disclosed herein may be substantially uniform
with respect to the orientation of their amphiphilic components,
but may in some embodiments comprise regions of local structural
features as indicated hereinabove. Local structural features may
comprise, for example, greater than about 30%, less than about 30%,
less than about 20%, less than about 15%, less than about 10%, less
than about 5%, less than about 3%, less than about 1% of the
surface area of the nanofilm.
[0199] Phase and Domain Behavior of Nanofilm
[0200] In some variations of a nanofilm having one or more
polymeric components, the nanofilm may have domains in which a
polymeric component or components are intermixed at the atomic
level with macrocyclic modules or other species, and solubilized
with each other. In these variations, the macrocyclic modules or
other species may be miscible with the polymeric component.
[0201] In other variations of a nanofilm having one or more
polymeric components, the polymeric molecules, macrocyclic modules,
or other components may be located in finite-sized aggregates.
Above some critical concentration in a particular solvent,
polymeric molecules, macrocyclic modules, or other components may
collect into finite-sized aggregates. These finite-sized aggregates
may persist at the air-water interface in formation of a nanofilm.
The structure of the aggregates may be affected by the geometry and
shape of the molecules, among other factors, or the capability of
the molecules to couple in particular orientations with other
species. The structure of the aggregates may be highly dynamic with
motion and exchange of the molecules at various rates. In these
variations, the self assembled aggregates of one species may be
interspersed in a continuous phase of another species, where the
other species is not aggregated. Different molecules or components
may form separate aggregates, or be combined in an aggregate
structure. Coupling between macrocyclic modules or other components
and the polymeric molecules may occur at a surface, edge, or point
of the self assembled aggregates.
[0202] In further variations of a nanofilm having one or more
polymeric components, the polymeric molecules may reside in domains
that are substantially polymeric, which may be interspersed with
domains composed substantially of other species. In these
variations, a polymeric component may be immiscible or phase
separated from macrocyclic modules or other components. Phase
separation may occur when the aggregation of polymeric molecules is
not limited to a small finite size, but may continue until regions
of polymeric molecules are separated from regions of other
molecules. The form of a polymeric component in these variations
may be a solid, gel, or liquid-like polymer melt, or an amorphous
composition, in the form of layers, beads, discs or mixtures
thereof, and can be homogeneous or heterogeneous in structure or
composition. Polymeric components of such nanofilms may form hard
and soft domains typical of thermoplastic elastomers, or a
polymeric component may form a soft domain relative to a hard
domain of macrocyclic modules. A polymeric component may form
regions which are amorphous, glassy, semicrystalline, or
crystalline, or have subregions with those characteristics. A
region of a polymeric component may exhibit rubberlike elasticity
or viscoelastic states. Different polymeric components may form
separate phases, or may be miscible with each other while remaining
immiscible with macrocyclic modules or other components. Coupling
between macrocyclic modules or other components and polymeric
molecules may occur at or near the interface between the phases,
and may contribute to adhesion of the phases.
[0203] A nanofilm may also be prepared with mixtures of different
macrocyclic modules, or with mixtures of macrocyclic modules,
polymeric components, and other species. A nanofilm may have an
array of coupled modules and other species in which the positional
ordering of the modules and other species is random, or is
non-random with regions in which one type of species is
predominant. In these variations, the polymeric component maybe
intermixed, aggregated, or phase separated from the macrocyclic
modules and other species, as described above. Nanofilms made from
mixtures of different modules, or with mixtures of macrocyclic
modules and other amphiphilic molecules may also have interspersed
arrays of pores of various sizes.
[0204] Methods of Preparing Nanofilms
[0205] In Langmuir film methods, a monolayer of oriented
amphiphilic species, for example amphiphilic modules, amphiphilic
polymers, and/or amphiphiles, is formed on the surface of a liquid
subphase. In one example, the amphiphilic components may be
dissolved in a solvent and deposited on an air-subphase interface
in a Langmuir trough to form the monolayer. Typically, movable
plates or barriers are used to compress the monolayer and decrease
its surface area to form a more dense monolayer. At various degrees
of compression, having corresponding surface pressures, the
monolayer may reach various condensed states. Surfaces which may be
used to orient amphiphiles include interfaces such as gas-liquid,
air-water, immiscible liquid-liquid, liquid-solid, or gas-solid
interfaces. The thickness of the oriented layer may be
substantially a monomolecular layer thickness.
[0206] Surface pressure versus film area isotherms are obtained by
the Wilhelmy balance method to monitor the state of the film.
Extrapolation of the isotherm to zero surface pressure reveals the
average surface area per component, or mean molecular area, before
the components are coupled. The isotherm gives an empirical
indication of the state of the thin film. Surface-oriented
macrocyclic modules and/or other components in a nanofilm layer may
be in an expanded state, a liquid state, or a liquid-expanded
state, or may be condensed, collapsed, or a solid phase or
closepacked state.
[0207] Nanofilms may be prepared by various alternative methods.
For example, linker molecules may be added to the solution
containing the modules and/or other components, which is
subsequently deposited on the surface of the Langmuir subphase.
Alternatively, the linker molecules may be added to the water
subphase of the Langmuir trough, and subsequently transfer to the
layer phase containing macrocyclic module and/or other components
for coupling.
[0208] In one variation of this invention, a water-soluble
polymeric component may be added to the subphase of a Langmuir
trough. In other variations, a polymeric component may be dissolved
in water or solvent and spread on an interface. One or more
polymeric components may be co-spread on an interface with
macrocyclic modules, and optionally with linker molecules. In other
variations, one or more polymeric components may be co-spread on an
interface with macrocyclic modules and/or linker molecules, and/or
other amphiphilic molecules.
[0209] In some instances, macrocyclic modules and/or other
components may be added to the subphase of the Langmuir trough, and
subsequently transfer to the interface.
[0210] Other variations will be apparent to those of skill in the
art.
[0211] In general, coupling of the components of a nanofilm may be
initiated by chemical, thermal, photochemical, electrochemical, and
irradiative methods. In some variations of this invention, the type
of coupling of the components of a nanofilm may depend on the type
of initiation and the chemical process involved. For example, in
forming a nanofilm from a multicomponent mixture, species in the
mixture which are polymerizable may produce polymeric components by
non-selective chain or addition polymerization. The type of the
coupling of macrocyclic modules to polymerizable species or
polymeric components depends on the functional groups of the
modules. For example, free radical polymerization of unsaturated
polymeric components, amphiphiles, or monomers may couple polymeric
components to benzene synthons of macrocyclic modules, or to other
reactive or unsaturated sites.
[0212] Functional groups added to the modules or other components
to impart amphiphilic character may in some embodiments be removed
during or after formation of the nanofilm. In one embodiment,
groups which impart amphiphilic character to a polymeric component
may be removed after formation of the nanofilm. In another
embodiment, groups which impart amphiphilic character to
macrocyclic modules may be removed after formation of the nanofilm.
The method of removal depends on the functional group. The groups
attached to the modules which impart amphiphilic character to the
component may include functional groups which can be used to remove
the groups at some point during or after the process of formation
of a nanofilm. Acid or base hydrolysis may be used to remove groups
attached to the component via a carboxylate or amide linkage. An
unsaturated group located in the functional group which imparts
amphiphilic character to the module may be oxidized and cleaved by
hydrolysis. Photolytic cleavage of the functional group which
imparts amphiphilic character to the module may also be done.
Examples of cleavable functional groups include 225
[0213] where n is zero to four, which is cleavable by light
activation, and 226
[0214] where n is zero to four, and m is 7 to 27, which is
cleavable by acid or base catalyzed hydrolysis.
[0215] Examples of functional groups added to the components to
impart amphiphilic character to the modules include alkyl groups,
alkoxy groups, --NHR, --OC(O)R, --C(O)OR, --NHC(O)R, --C(O)NHR,
--CH.dbd.CHR, and --C.ident.CR, where the carbon atoms of an alkyl
group may be interrupted by one or more --S--, double bond, triple
bond or --SiRR'-- group(s), or substituted with one or more
fluorine atoms, or any combination thereof, where R and R' are
independently hydrogen or alkyl.
[0216] In alternative variations, the multicomponent mixtures of
macrocyclic modules and/or other components may include additives,
dispersants, surfactants, excipients, compatiblizers, emulsifiers,
suspension agents, plasticizers, or other species which modify the
properties of the components. For example, compatiblizers may be
used to reduce domain sizes and form more continuous phase
dispersion of the components of a nanofilm.
[0217] In some instances, the nanofilm may be derivatized to
provide biocompatability or reduce fouling of the nanofilm by
attachment or adsorption of biomolecules.
[0218] Nanofilms may be deposited on a substrate by various
methods, such as Langmuir-Schaefer, Langmuir-Blodgett, or other
methods used with Langmuir systems. In one variation, a nanofilm is
deposited on a substrate in a Langmuir tank by locating the
substrate in the subphase beneath the air-water interface, and
lowering the level of the subphase until the nanofilm lands gently
on the substrate and is therefore deposited. A description of
Langmuir films and substrates is given in U.S. Pat. Nos. 6,036,778,
4,722,856, 4,554,076, and 5,102,798, and in R. A. Hendel et al.,
Vol. 119, J. Am. Chem. Soc. 6909-18 (1997). A description of films
on substrates is given in Munir Cheryan, Ultrafiltration and
Microfiltration Handbook (1998). A description of polymers on
surfaces is given in Jacob N. Israelachvili, Intermolecular and
Surface Forces (1991).
[0219] Other methods to prepare a nanofilm having polymeric
components include forced removal of solvent to prepare a film,
such as spin coating methods and spray coating methods, as well as
coating and deposition methods including interfacial, dip coating,
knife-edge coating, grafting, casting, phase inversion, or
electroplating or other plating methods.
[0220] Nanofilms deposited on a substrate may be cured or annealed
by chemical, thermal, photochemical, electrochemical, irradiative
or drying methods during or after deposition on a substrate. For
example, chemical methods include reactions with vapor phase
reagents such as ethylenediamine or solution phase reagents. A
nanofilm treated by any method to attach or couple it to a
substrate may be said to be cured.
[0221] The deposition may result in non-covalent or weak attachment
of the nanofilm to the substrate through physical interactions and
weak chemical forces such as van der Waals forces and weak hydrogen
bonding. The nanofilm may in some embodiments be bound to the
substrate through ionic or covalent interaction, or other type of
interaction.
[0222] The substrate may be any surface of any material. Substrates
may be porous or non-porous, and may be made from polymeric and
inorganic substances. Examples of porous substrates are plastics or
polymers, track-etch polycarbonate, track-etch polyester,
polyethersulfone, polysulfone, gels, hydrogels, cellulose acetate,
polyamide, PVDF, polyethylene terephthalate or polybutylene
terephthalate, polyvinyl chloride, polyvinylidene chloride,
polytetrafluoroethylene, polyethylene or polypropylene, ceramics,
anodic alumina, laser ablated and other porous polyimides, and UV
etched polyacrylate. Examples of non-porous substrates are silicon,
germanium, glass, metals such as platinum, nickel, palladium,
aluminum, chromium, niobium, tantalum, titanium, steel, or gold,
glass, silicates, aluminosilicates, non-porous polymers, and mica.
Further examples of substrates include diamond and indium tin
oxide. Preferred substrates include silicon, gold, SiO.sub.2,
polyethersulfone, and track etch polycarbonate. In some
embodiments, the substrate is SiO.sub.2. In other embodiments, the
substrate is polycarbonate track etch membrane.
[0223] Substrates may have any physical shape or form including
films, sheets, plates, or cylinders, and may be particles of any
shape or size.
[0224] A nanofilm deposited on a substrate may serve as a membrane.
Any number of layers of nanofilm may be deposited on the substrate
to form a membrane. In some variations, nanofilm is deposited on
both sides of a substrate.
[0225] A layer or layers of various spacing materials may be
deposited or attached in between layers of a nanofilm, and a
spacing layer may also be used in between the substrate and the
first deposited layer of nanofilm. Examples of spacing layer
compositions include polymeric compositions, hydrogels (acrylates,
poly vinyl alcohols, polyurethanes, silicones), thermoplastic
polymers (polyolefins, polyacetals, polycarbonates, polyesters,
cellulose esters), polymeric foams, thermosetting polymers,
hyperbranched polymers, biodegradable polymers such as
polylactides, liquid crystalline polymers, polymers made by atom
transfer radical polymerization (ATRP), polymers made by ring
opening metathesis polymerization (ROMP), polyisobutylenes and
polyisobutylene star polymers, and amphiphilic polymers. Other
examples of spacing layer compositions include inorganics, such as
inorganic particles such as inorganic microspheres, colloidal
inorganics, inorganic minerals, silica spheres or particles, silica
sols or gels, clays or clay particles, and the like. Examples of
amphiphilic molecules include amphiphiles containing polymerizable
groups such as diynes, enes, or amino-esters. The spacing layers
may serve to modify barrier properties of the nanofilm, or may
serve to modify transport, flux, or flow characteristics of the
membrane or nanofilm. Spacing layers may serve to modify functional
characteristics of the membrane or nanofilm, such as strength,
modulus, or other properties. In some variations, the polymeric
components of a nanofilm may provide a spacing layer between the
nanofilm and a substrate.
[0226] In some variations, a nanofilm having polymeric components
may be deposited on a surface and adhere to the surface to a degree
sufficient for many applications, such as filtration and membrane
separations, without coupling to the surface. Nanofilm having
polymeric components may be advantageously cohesive to a substrate,
which may include some coupling interactions.
[0227] In other variations, a nanofilm may be coupled to a
substrate surface. Surface attachment groups may be provided on a
polymeric component of a nanofilm, which may be used to couple the
nanofilm to the substrate. Coupling of some, but not all of the
surface attachment groups may be done to attach the nanofilm to the
substrate. Optionally, surface attachment groups may be provided on
the macrocyclic modules and/or other components of a nanofilm.
[0228] Examples of functional groups which may be used as surface
attachment groups to couple a nanofilm to a substrate include amine
groups, carboxylic acid groups, carboxylic ester groups, alcohol
groups, glycol groups, vinyl groups, styrene groups, epoxide
groups, thiol groups, magnesium halo or Grignard groups, acrylate
groups, acrylamide groups, diene groups, aldehyde groups, and
mixtures thereof.
[0229] A substrate may have functional groups which couple to the
functional groups of a nanofilm. The functional groups of the
substrate may be surface groups or linking groups bound to the
substrate, which may be formed by reactions which bind the surface
groups or linking groups to the substrate. Surface groups may also
be created on the substrate by a variety of treatments such as cold
plasma treatment, surface etching methods, solid abrasion methods,
or chemical treatments. Some methods of plasma treatment are given
in Inagaki, Plasma Surface Modification and Plasma Polymerization,
Technomic, Lancaster, Pa., 1996. In some embodiments, the substrate
is derivatized with APTES. In other embodiments, the substrate is
derivatized with methylacryloxymethyltrimet- hoxysilane (MAOMTMOS).
In other embodiments, the substrate is derivatized with
acryloxypropyltrimethoxysilane (AOPTMOS).
[0230] Surface attachment groups of the nanofilm and the surface
may be blocked with protecting groups until needed. Non-limiting
examples of suitable functional groups for coupling the nanofilm to
the substrate and the resulting linkages may be found in Tables 2
and 4. The functional groups on the nanoflim may be from any
component of the nanofilm, for example, the macrocyclic modules,
the polymer component, or the amphiphilic component.
[0231] Surface attachment groups may be connected to a nanofilm by
spacer groups. Likewise, substrate functional groups may be
connected to the substrate by spacer groups. Spacer groups for
surface attachment groups may be polymeric. Examples of polymeric
spacers include polyethylene oxides, polypropylene oxides,
polysaccharides, polylysines, polypeptides, poly(amino acids),
polyvinylpyrrolidones, polyesters, polyvinylchlorides,
polyvinylidene fluorides, polyvinylalcohols, polyurethanes,
polyamides, polyimides, polysulfones, polyethersulfones,
polysulfonamides, and polysulfoxides. Examples of polymeric spacer
structures include linear, branched, comb and dendrimeric polymers,
random and block copolymers, homo- and heteropolymers, flexible and
rigid chains. Spacer groups for surface attachment groups may also
include bifunctional linker groups or heterobifunctional linker
groups used to couple biomolecules and other chemical species.
[0232] In one variation, a photoreactive group such as a
benzophenone is bound to the substrate. The photoreactive group may
be activated with light, for example, ultraviolet light, to provide
a reactive species which couples to a nanofilm. The photoreactive
species may couple to any atom or group of atoms of the
nanofilm.
[0233] Surface attachment of modules may also be achieved through
ligand-receptor mediated interactions, such as biotin-streptavidin.
For example, the substrate may be coated with streptavidin, and
biotin may be attached to the modules, for example, through linker
groups such as PEG or alkyl groups.
[0234] Memnbranes and Filtration Function
[0235] The nanofilms described herein may be useful, for example,
as membranes. The membrane may be brought into contact with a fluid
or solution, separating a species or component from that fluid or
solution, for example, for purposes of filtration. Normally, a
membrane is a substance which acts as a barrier to block the
passage of some species, while allowing restricted or regulated
passage of other species. In general, permeants may traverse the
membrane if they are smaller than a cut-off size, or have a
molecular weight smaller than a so-called cut-off molecular weight.
The membrane may be called impermeable to species which are larger
than the cut-off molecular weight. The cut-off size or molecular
weight is a characteristic property of the membrane. Selective
permeation is the ability of the membrane to cut-off, restrict, or
regulate passage of some species, while allowing smaller species to
pass. Thus, the selective permeation of a membrane may be described
functionally in terms of the largest species able to pass the
membrane under given conditions. The size or molecular weight of
various species may also be dependent on the conditions in the
fluid to be separated, which may determine the form of the species.
For example, species may have a sphere of hydration or solvation in
a fluid, and the size of the species in relation to membrane
applications may or may not include the water of hydration or the
solvent molecules. Thus, a membrane is permeable to a species of a
fluid if the species can traverse the membrane in the form in which
it normally would be found in the fluid. Permeation and
permeability may be affected by interaction between the species of
a fluid and the membrane itself. While various theories may
describe these interactions, the empirical measurement of
pass/no-pass information relating to a nanofilm, membrane, or
module is a useful tool to describe permeation properties. A
membrane is impermeable to a species if the species cannot pass
through the membrane.
[0236] Pores may be provided in the nanofilms described herein, for
example, pores may be supplied in the structure of the nanofilm.
Pores may be supplied in the structure of the macrocyclic modules.
Pores may in some cases be supplied from the packing of the
macrocyclic modules and the polymeric components. The type and
degree of crosslinking between components may influence pore size.
The nanofilms described herein comprising one or more polymeric
components may advantageously have reduced numbers of
micrometer-sized or macroscopic openings which affect use in
filtration and selective permeation.
[0237] The nanofilms may have molecular weight species cut offs of,
for example, greater than about 15 kDa, greater than about 10 kDa,
greater than about 5 kDa, greater that about 1 kDa, greater than
about 800 Da, greater than about 600 Da, greater than about 400 Da,
greater than about 200 Da, greater than about 100 Da, greater than
about 50 Da, greater than about 20 Da, less than about 15 kDa, less
than about 10 kDa, less than about 5 kDa, less that about 1 kDa,
less than about 800 Da, less than about 600 Da, less than about 400
Da, less than about 200 Da, less than about 100 Da, less than about
50 Da, less than about 20 Da, about 13 kDa, about 190 Da, about 100
Da, about 45 Da, about 20 Da.
[0238] "High permeability" indicates a clearance of, for example,
greater than about 70%, greater than about 80%, greater than about
90% of the solute. "Medium permeability" indicates a clearance of,
for example, less than about 50%, less than about 60%, less than
about 70% of the solute. "Low permeability" indicates a clearance
of less than, for example, about 10%, less than about 20%, less
than about 30% of the solute. A membrane is impermeable to a
species if it has a very low clearance (for example, less than
about 5%, less than about 3%) for the species, or if it has very
high rejection for the species (for example, greater than about
95%, greater than about 98%). The passage or exclusion of a solute
is measured by its clearance, which reflects the portion of solute
that actually passes through the membrane. For example, the no pass
symbol in Tables 16-17 indicates that the solute is partly excluded
by the module, sometimes less than 90% rejection, often at least
90% rejection, sometimes at least 98% rejection. The pass symbol
indicates that the solute is partly cleared by the module,
sometimes less than 90% clearance, often at least 90% clearance,
sometimes at least 98% clearance.
[0239] Examples of processes in which nanofilms may be useful
include processes involving liquid or gas as a continuous fluid
phase, filtration, clarification, fractionation, pervaporation,
reverse osmosis, dialysis, hemodialysis, affinity separation,
oxygenation, and other processes. Filtration applications may
include ion separation, desalinization, gas separation, small
molecule separation, separation of enantiomers, ultrafiltration,
microfiltration, hyperfiltration, water purification, sewage
treatment, removal of toxins, removal of biological species such as
bacteria, viruses, or fungus.
[0240] Synthons and Macrocyclic Modules
[0241] Synthons
[0242] As used herein, the term "synthon" refers to a molecule used
to make a macrocyclic module. A synthon may be substantially one
isomeric configuration, for example, a single enantiomer. A synthon
may be substituted with functional groups which are used to couple
a synthon to another synthon or synthons, and which are part of the
synthon. A synthon may be substituted with an atom or group of
atoms which are used to impart hydrophilic, lipophilic, or
amphiphilic character to the synthon or to species made from the
synthon. The synthon before being substituted with functional
groups or groups used to impart hydrophilic, lipophilic, or
amphiphilic character may be called the core synthon. As used
herein, the term "synthon" refers to a core synthon, and also
refers to a synthon substituted with functional groups or groups
used to impart hydrophilic, lipophilic, or amphiphilic
character.
[0243] As used herein, the term "cyclic synthon" refers to a
synthon having one or more ring structures. Examples of ring
structures include aryl, heteroaryl, and cyclic hydrocarbon
structures including bicyclic ring structures and multicyclic ring
structures. Examples of core cyclic synthons include, but are not
limited to, benzene, cyclohexadiene, cyclopentadiene, naphthalene,
anthracene, phenylene, phenanthracene, pyrene, triphenylene,
phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl,
bipyridyl, cyclohexane, cyclohexene, decalin, piperidine,
pyrrolidine, morpholine, piperazine, pyrazolidine, quinuclidine,
tetrahydropyran, dioxane, tetrahydrothiophene, tetrahydrofuran,
pyrrole, cyclopentane, cyclopentene, triptycene, adamantane,
bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octane,
bicyclo[2.2.2]octene, bicyclo[3.3.0]octane, bicyclo[3.3.0]octene,
bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene, bicyclo[3.2.2]nonane,
bicyclo[3.2.2]nonene, bicyclo[4.2.2]decane,
7-azabicyclo[2.2.1]heptane, 1,3-diazabicyclo[2.2.1]heptane, and
spiro[4.4]nonane. A core synthon comprises all isomers or
arrangements of coupling the core synthon to other synthons. For
example, the core synthon benzene includes synthons such as 1,2-
and 1,3-substituted benzenes, where the linkages between synthons
are formed at the 1,2- and 1,3-positions of the benzene ring,
respectively. For example, the core synthon benzene includes
1,3-substituted synthons such as 227
[0244] where L is a linkage between synthons and the 2,4,5,6
positions of the benzene ring may also have substituents. A
condensed linkage between synthons involves a direct coupling
between a ring atom of one cyclic synthon to a ring atom of another
cyclic synthon, for example, where synthons M--X and M--X couple to
form M--M, where M is a cyclic synthon and X is halogen; as for
example when M is phenyl resulting in the condensed linkage 228
[0245] Macrocyclic Modules
[0246] A macrocyclic module is a closed ring of coupled synthons.
To make a macrocyclic module, synthons may be substituted with
functional groups to couple the synthons to form a macrocyclic
module. Synthons may also be substituted with functional groups
which will remain in the structure of the macrocyclic module.
Functional groups which remain in the macrocyclic module may be
used to couple the macrocyclic module to other macrocyclic modules
or other components.
[0247] A macrocyclic module may contain from three to about
twenty-four cyclic synthons. In the closed ring of a macrocyclic
module, a first cyclic synthon may be coupled to a second cyclic
synthon, the second cyclic synthon may be coupled to a third cyclic
synthon, the third cyclic synthon may be coupled to a fourth cyclic
synthon, if four cyclic synthons are present in the macrocyclic
module, the fourth to a fifth, and so on, until an nth cyclic
synthon may be coupled to its predecessor, and the nth cyclic
synthon may be coupled to the first cyclic synthon to form a closed
ring of cyclic synthons. In one variation, the closed ring of the
macrocyclic module may be formed with a linker molecule.
[0248] A macrocyclic module may be an amphiphilic macrocyclic
module when hydrophilic and lipophilic functional groups exist in
the structure. The amphiphilic character of a macrocyclic module
may arise from atoms in the synthons, in the linkages between
synthons, or in functional groups coupled to the synthons or
linkages.
[0249] In some variations, one or more of the synthons of a
macrocyclic module may be substituted with one or more lipophilic
moieties, while one or more of the synthons may be substituted with
one or more hydrophilic moieties, thereby forming an amphiphilic
macrocyclic module. Lipophilic and hydrophilic moieties may be
coupled to the same synthon or linkage in an amphiphilic
macrocyclic module. Lipophilic and hydrophilic moieties may be
coupled to the macrocyclic module before or after formation of the
closed ring of the macrocyclic module. For example, lipophilic or
hydrophilic moieties may be added to the macrocyclic module after
formation of the closed ring by substitution of a synthon or
linkage.
[0250] The amphiphilicity of a macrocyclic module may be
characterized in part by its ability to form a stable Langmuir
film. A Langmuir film may be formed on a Langmuir trough at a
particular surface pressure measured in milliNewtons per meter
(mN/m) with a particular barrier speed measured in millimeters per
minute (mm/min), and the isobaric creep or change in film area at
constant surface pressure can be measured to characterize stability
of the film. For example, a stable Langmuir film of macrocyclic
modules on a water subphase may have an isobaric creep at 5-15 mN/m
such that the majority of the film area is retained over a period
of time of about one hour. Examples of stable Langmuir films of
macrocyclic modules on a water subphase may have isobaric creep at
5-15 mN/m such that about 70% of the film area is retained over a
period of time of about 30 minutes, sometimes about 70% of the film
area is retained over a period of time of about 40 minutes,
sometimes about 70% of the film area is retained over a period of
time of about 60 minutes, and sometimes about 70% of the film area
is retained over a period of time of about 120 minutes. Other
examples of stable Langmuir films of macrocyclic modules on a water
subphase may have isobaric creep at 5-15 mN/m such that about 80%
of the film area is retained over a period of time of about thirty
minutes, sometimes about 85% of the film area is retained over a
period of time of about thirty minutes, sometimes about 90% of the
film area is retained over a period of time of about thirty
minutes, sometimes about 95% of the film area is retained over a
period of time of about thirty minutes, and sometimes about 98% of
the film area is retained over a period of time of about thirty
minutes.
[0251] In one aspect, an individual macrocyclic module may include
a pore in its structure. Each macrocyclic module may define a pore
of a particular size, depending on the conformation and state of
the module. Various macrocyclic modules may be prepared which
define pores of different sizes.
[0252] A macrocyclic module may have flexibility in its structure.
Flexibility may permit a macrocyclic module to more easily form
linkages with other macrocyclic modules and/or other components by
coupling reactions. Flexibility of a macrocyclic module may also
play a role in regulating passage of species through the pore of
the macrocyclic module. For example, flexibility may affect the
dimension of the pore of an individual macrocyclic module since
various conformations may be available to the structure. For
example, the macrocyclic module may have a certain pore dimension.
in one conformation when no substituents are located at the pore,
and the same macrocyclic module may have a different pore dimension
in another conformnation when one or more substituents of that
macrocycle are located at the pore. Likewise, a macrocyclic module
may have a certain pore dimension in one conformation when one
group of substituents are located at the pore, and have a different
pore dimension in a different conformation when a different group
of substituents are located at the pore. For example, the "one
group" of substituents located at the pore may be three alkoxy
groups arranged in one regioisomer, while the "different group" of
substituents may be two alkoxy groups arranged in another
regioisomer. The effect of the "one group" of substituents located
at the pore and the "different group" of substituents located at
the pore is to provide a macrocyclic module composition which may
regulate transport and filtration, in conjunction with other
regulating factors.
[0253] In making macrocyclic modules from synthons, the synthons
may be used as a substantially pure single isomer, for example, as
a pure single enantiomer.
[0254] In making macrocyclic modules from synthons, one or more
coupling linkages are formed between adjacent synthons. The linkage
formed between synthons may be the product of the coupling of one
functional group on one synthon to a complementary functional group
on a second synthon. For example, a hydroxyl group of a first
synthon may couple with an acid group or acid halide group of a
second synthon to form an ester linkage between the two synthons.
Another example is an imine linkage, --CH.dbd.N--, resulting from
the reaction of an aldehyde, --CH.dbd.O, on one synthon with an
amine, --NH.sub.2, on another synthon. Examples of suitable
complementary functional groups and linkages between synthons are
shown in Table 2, wherein "synthon" may substitute for
"module".
[0255] The functional groups of synthons used to form linkages
between synthons or other macrocyclic modules may be separated from
the synthon by a spacer. A spacer can be any atom or group of atoms
which couples the functional group to the synthon, and does not
interfere with the linkage-formning reaction. A spacer is part of
the functional group, and becomes part of the linkage between
synthons. An example of a spacer is a methylene group,
--CH.sub.2--. The spacer may be said to extend the linkage between
synthons. For example, if one methylene spacer were inserted in an
imine linkage, --CH.dbd.N--, the resulting imine linkage may be
--CH.sub.2CH.dbd.N--.
[0256] A linkage between synthons may also contain one or more
atoms provided by an external moiety other than the two functional
groups of the synthons. An external moiety may be a linker molecule
which may couple with the functional group of one synthon to form
an intermediate which couples with a finctional group on another
synthon to form a linkage between the synthons, such as, for
example, to form a closed ring of synthons from a series of coupled
synthons. An example of a linker molecule is formaldehyde. For
example, amino groups on two synthons may undergo Mannich reaction
in the presence of formaldehyde as the linker molecule to produce
the linkage --NHCH.sub.2NH--. Examples of suitable functional
groups and linker molecules are shown in Table 4, wherein "synthon"
may substitute for "module."
[0257] A macrocyclic module may include functional groups for
coupling the macrocyclic module to a solid surface, substrate, or
support. Examples of functional groups of macrocyclic modules which
can be used to couple to a substrate or surface include amine,
carboxylic acid, carboxylic ester, benzophenone and other light
activated crosslinkers, alcohol, glycol, vinyl, styryl, olefin
styryl, epoxide, thiol, magnesium halo or Grignard, acrylate,
acrylamide, diene, aldehyde, and mixtures thereof. These functional
groups may be coupled to the closed ring of the macrocyclic module,
and may optionally be attached by a spacer group. Examples of solid
surfaces include metal surfaces, ceramic surfaces, polymer
surfaces, semiconductor surfaces, silicon wafer surfaces, alumina
surfaces, and so on. Examples of functional groups of macrocyclic
modules which can be used to couple to a substrate or surface
further include those described in the left hand column of Tables
2-4. Methods of initiating coupling of the modules to the substrate
include chemical, thermal, photochemical, electrochemical, and
irradiative methods.
[0258] Examples of spacer groups include polyethylene oxides,
polypropylene oxides, polysaccharides, polylysines, polypeptides,
poly(amino acids), polyvinylpyrrolidones, polyesters,
polyvinylchlorides, polyvinylidene fluorides, polyvinylalcohols,
polyurethanes, polyamides, polyimides, polysulfones,
polyethersulfones, polysulfonamides, and polysulfoxides.
[0259] In one embodiment, the macrocyclic module composition
comprises: from three to about twenty-four cyclic synthons coupled
to form a closed ring; at least two functional groups for coupling
the closed ring to complementary functional groups on at least two
other closed rings; wherein each functional group and each
complementary functional group comprises a functional group
containing atoms selected from the group consisting of C, H, N, O,
Si, P, S, B, Al, halogens, and metals from the alkali and alkaline
earth groups. The composition may comprise at least two closed
rings coupled through said functional groups. The composition may
comprise at least three closed rings coupled through said
functional groups.
[0260] In another embodiment, the macrocyclic module composition
comprises: from three to about twenty-four cyclic synthons coupled
to form a closed ring defining a pore; the closed ring having a
first pore dimension in a first conformation when a first group of
substituents is located at the pore and a second pore dimension in
a second conformation when a second group of substituents is
located at the pore; wherein each substituent of each group
comprises a functional group containing atoms selected from the
group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and
metals from the alkali and alkaline earth groups.
[0261] In another embodiment, the macrocyclic module composition
comprises: (a) from three to about twenty-four cyclic synthons
coupled to form a closed ring defining a pore; (b) at least one
functional group coupled to the closed ring at the pore and
selected to transport a selected species through the pore, wherein
the at least one functional group comprises a functional group
containing atoms selected from the group consisting of C, H, N, O,
Si, P, S, B, Al, halogens, and metals from the alkali and alkaline
earth groups; (c) a selected species to be transported through the
pore. The selected species may, in one example, be selected from
the group of ovalbumin, glucose, creatinine, H.sub.2PO.sub.4.sup.-,
HPO.sub.4.sup.-2, HCO.sub.3.sup.-, urea, Na.sup.+, Li.sup.+, and
K.sup.+.
[0262] In some embodiments, the cyclic synthons are each
independently selected from the group consisting of benzene,
cyclohexadiene, cyclohexene, cyclohexane, cyclopentadiene,
cyclopentene, cyclopentane, cycloheptane, cycloheptene,
cycloheptadiene, cycloheptatriene, cyclooctane, cyclooctene,
cyclooctadiene, cyclooctatriene, cyclooctatetraene, naphthalene,
anthracene, phenylene, phenanthracene, pyrene, triphenylene,
phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl,
bipyridyl, decalin, piperidine, pyrrolidine, morpholine,
piperazine, pyrazolidine, quinuclidine, tetrahydropyran, dioxane,
tetrahydrothiophene, tetrahydrofuran, pyrrole, triptycene,
adamantane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene,
bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, bicyclo[3.3.0]octane,
bicyclo[3.3.0]octene, bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene,
bicyclo[3.2.2]nonane, bicyclo[3.2.2]nonene, bicyclo[4.2.2]decane,
7-azabicyclo[2.2.1]heptane, 1,3-diazabicyclo[2.2.1]heptane, and
spiro[4.4]nonane.
[0263] In some embodiments, each coupled cyclic synthon is
independently coupled to two adjacent synthons by a linkage
selected from the group consisting of (a) a condensed linkage, and
(b) a linkage selected from the group consisting of --NRC(O)--,
--OC(O)--, --O--, --S--S--, --S--, --NR--, --(CRR').sub.p--,
--CH.sub.2NH--, --C(O)S--, --C(O)O--, --C.ident.C--,
--C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--, --NHC(O)NH--,
--NHC(O)O--, --NHCH.sub.2NH--, --NHCH.sub.2CH(OH)CH.sub.2NH- --,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 229
[0264] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein the linkage
is independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures; wherein Q is one of the synthons connected by the
linkage.
[0265] In one variation, a macrocyclic module may be a closed ring
composition of the formula: 230
[0266] wherein: the closed ring comprises a total of from three to
twenty-four synthons Q; J is 2-23; Q.sup.1 are synthons each
independently selected from the group consisting of (a) aryl
synthons, (b) heteroaryl synthons, (c) saturated cyclic hydrocarbon
synthons, (d) unsaturated cyclic hydrocarbon synthons, (e)
saturated bicyclic hydrocarbon synthons, (f) unsaturated bicyclic
hydrocarbon synthons, (g) saturated multicyclic hydrocarbon
synthons, and (h) unsaturated multicyclic hydrocarbon synthons;
wherein ring positions of each Q.sup.1 which are not coupled to a
linkage L are independently substituted with hydrogen or a
functional group containing atoms selected from the group of C, H,
N, O, Si, P, S, B, Al, halogens, and metals from the alkali and
alkaline earth groups; Q.sup.2 is a synthon independently selected
from the group consisting of (a) aryl synthons, (b) heteroaryl
synthons, (c) saturated cyclic hydrocarbon synthons, (d)
unsaturated cyclic hydrocarbon synthons, (e) saturated bicyclic
hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon
synthons, (g) saturated multicyclic hydrocarbon synthons, and (h)
unsaturated multicyclic hydrocarbon synthons; wherein ring
positions of Q.sup.2 which are not coupled to an L are
independently substituted with hydrogen or a functional group
containing atoms selected from the group consisting of C, H, N, O,
Si, P, S, B, Al, halogens, and metals from the alkali and alkaline
earth groups; L are linkages between the synthons each
independently selected from the group consisting of
synthon-synthon, --NRC(O)--, --OC(O)--, --O--, --S--S--, --S--,
--NR--, --(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --H.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 231232
[0267] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein the linkages
L are each independently configured with respect to the Q.sup.1 and
Q.sup.2 synthons, each L having either of its two possible
configurations with respect to the synthons it couples together,
the forward and reverse configurations of the linkage with respect
to the immediately adjacent synthons to which it couples, for
example, Q.sup.1.sub.a--NHC(O)--Q.sup.1- .sub.b and
Q.sup.1.sub.a--C(O)NH--Q.sup.1.sub.b, if the two configurations are
isomerically different structures. Synthons Q.sup.1, when
independently selected, may be any cyclic synthon as described, so
that the J synthons Q.sup.1 may be found in the closed ring in any
order, for example,
cyclohexyl--1,2-phenyl--piperidinyl--1,2-phenyl--1,2-phenyl--cyc-
lohexyl, and so on, and the J linkages L may also be independently
selected and configured in the closed ring. The macrocyclic modules
represented and encompassed by the formula include all
stereoisomers of the synthons involved, so that a wide variety of
stereoisomers of the macrocyclic module are included for each
closed ring composition of synthons.
[0268] In other embodiments, the macrocyclic module may comprise a
closed ring composition of the formula: 233
[0269] wherein: J is 2-23; Q.sup.1 are synthons each independently
selected from the group consisting of (a) phenyl synthons coupled
to linkages L at 1,2-phenyl positions, (b) phenyl synthons coupled
to linkages L at 1,3-phenyl positions, (c) aryl synthons other than
phenyl synthons, (d) heteroaryl synthons other than pyridinium
synthons, (e) saturated cyclic hydrocarbon synthons, (f)
unsaturated cyclic hydrocarbon synthons, (g) saturated bicyclic
hydrocarbon synthons, (h) unsaturated bicyclic hydrocarbon
synthons, (i) saturated multicyclic hydrocarbon synthons, and (j)
unsaturated multicyclic hydrocarbon synthons; wherein ring
positions of each Q.sup.1 which are not coupled to a linkage L are
independently substituted with hydrogen or a functional group
containing atoms selected from the group of C, H, N, O, Si, P, S,
B, Al, halogens, and metals from the alkali and alkaline earth
groups; Q.sup.2 is a synthon independently selected from the group
consisting of (a) aryl synthons other than phenyl synthons and
naphthalene synthons coupled to linkages L at 2,7-naphthyl
positions, (b) heteroaryl synthons other than pyridine synthons
coupled to linkages L at 2,6-pyridino positions, (c) saturated
cyclic hydrocarbon synthons other than cyclohexane synthons coupled
to linkages L at 1,2-cyclohexyl positions, (d) unsaturated cyclic
hydrocarbon synthons other than pyrrole synthons coupled to
linkages L at 2,5-pyrrole positions, (e) saturated bicyclic
hydrocarbon synthons, (f) unsaturated bicyclic hydrocarbon
synthons, (g) saturated multicyclic hydrocarbon synthons, and (h)
unsaturated multicyclic hydrocarbon synthons; wherein ring
positions of Q.sup.2 which are not coupled to an L are
independently substituted with hydrogen or a functional group
containing atoms selected from the group consisting of C, H, N, O,
Si, P, S, B, Al, halogens, and metals from the alkali and alkaline
earth groups; L are linkages between the synthons each
independently selected from the group consisting of (a) a condensed
linkage, and (b) a linkage selected from the group consisting of
--NRC(O)--, --OC(O)--, --O--, --S--S--, --S--, --NR--,
--(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH- --,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 234
[0270] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures; wherein y is 1 or 2, and Q.sup.y are each independently
one of the Q.sup.1 or Q.sup.2 synthons connected by the
linkage.
[0271] In another embodiment, the macrocyclic module may comprise a
closed ring composition of the formula: 235
[0272] wherein: J is 2-23; Q.sup.1 are synthons each independently
selected from the group consisting of (a) phenyl synthons coupled
to linkages L at 1,2-phenyl positions, (b) phenyl synthons coupled
to linkages L at 1,3-phenyl positions, and (c) cyclohexane synthons
coupled to linkages L at 1,2-cyclohexyl positions; wherein ring
positions of each Q.sup.1 which are not coupled to a linkage L are
independently substituted with hydrogen or a functional group
containing atoms selected from the group of C, H, N, O, Si, P, S,
B, Al, halogens, and metals from the alkali and alkaline earth
groups; Q.sup.2 is a cyclohexane synthon coupled to linkages L at
1,2-cyclohexyl positions; wherein ring positions of Q.sup.2 which
are not coupled to an L are independently substituted with hydrogen
or a functional group containing atoms selected from the group
consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals
from the alkali and alkaline earth groups; L are linkages between
the synthons each independently selected from the group consisting
of (a) a condensed linkage, and (b) a linkage selected from the
group consisting of --NRC(O)--, --OC(O)--, --O--, --S--S--, --S--,
--NR--, --(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 236
[0273] wherein p is 1-6;
[0274] wherein R and R' are each independently selected from the
group of hydrogen and alkyl; wherein linkages L are each
independently configured in either of two possible configurations,
forward and reverse, with respect to the synthons, it couples
together, if the two configurations are different structures;
wherein y is 1 or 2, and Q.sup.y are each independently one of the
Q.sup.1 or Q.sup.2 synthons connected by the linkage.
[0275] In another embodiment, the macrocyclic module comprises a
closed ring composition of the formula: 237
[0276] wherein: J is 2-23; Q.sup.1 are synthons each independently
selected from the group consisting of (a) phenyl synthons coupled
to linkages L at 1,4-phenyl positions, (b) aryl synthons other than
phenyl synthons, (c) heteroaryl synthons, (d) saturated cyclic
hydrocarbon synthons, (e) unsaturated cyclic hydrocarbon synthons,
(f) saturated bicyclic hydrocarbon synthons, (g) unsaturated
bicyclic hydrocarbon synthons, (h) saturated multicyclic
hydrocarbon synthons, and (i) unsaturated multicyclic hydrocarbon
synthons; wherein at least one of Q.sup.1 is a phenyl synthon
coupled to linkages L at 1,4-phenyl positions, and wherein ring
positions of each Q.sup.1 which are not coupled to a linkage L are
independently substituted with hydrogen or a functional group
containing atoms selected from the group of C, H, N, O, Si, P, S,
B, Al, halogens, and metals from the alkali and alkaline earth
groups; Q.sup.2 is a synthon independently selected from the group
consisting of (a) aryl synthons other than phenyl synthons and
naphthalene synthons coupled to linkages L at 2,7-naphthyl
positions, (b) heteroaryl synthons, (c) saturated cyclic
hydrocarbon synthons other than cyclohexane synthons coupled to
linkages L at 1,2-cyclohexyl positions, (d) unsaturated cyclic
hydrocarbon synthons, (e) saturated bicyclic hydrocarbon synthons,
(f) unsaturated bicyclic hydrocarbon synthons, (g) saturated
multicyclic hydrocarbon synthons, and (h) unsaturated multicyclic
hydrocarbon synthons; wherein ring positions of Q.sup.2 which are
not coupled to an L are independently substituted with hydrogen or
a functional group containing atoms selected from the group
consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals
from the alkali and alkaline earth groups; L are linkages between
the synthons each independently selected from the group consisting
of (a) a condensed linkage, and (b) a linkage selected from the
group consisting of --NRC(O)--, --OC(O)--, --O--, --S--S--, --S--,
--NR--, --(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 238
[0277] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures; wherein y is 1 or 2, and Q.sup.y are each independently
one of the Q.sup.1 or Q.sup.2 synthons connected by the
linkage.
[0278] In some embodiments, the functional groups are each
independently selected from the group consisting of hydrogen, an
activated acid, --OH, --C(O)OH, --C(O)H, --C(O)OCH.sub.3, --C(O)Cl,
--NRR, --NRRR.sup.+, --MgX, --Li, --OLi, --OK, --ONa, --SH,
--C(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--NH-alkyl-C(O)CH.sub.2CH(NH.sub.2)CO.sub.2-alkyl,
--CH.dbd.CH.sub.2, --CH.dbd.CHR, --CH.dbd.CR.sub.2, 4-vinylaryl,
--C(O)CH.dbd.CH.sub.2, --NHC(O)CH.dbd.CH.sub.2,
--C(O)CH.dbd.CH(C.sub.6H.sub.5), 239
[0279] --OH, --OC(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--OC(O)CH.dbd.CH.sub.2, 240
[0280] --P(O)(OH)(OX),
--P(.dbd.O)(O.sup.-)O(CH.sub.2).sub.sNR.sub.3.sup.+- ; wherein R
are each independently selected from the group consisting of
hydrogen and 1-6C alkyl; X is selected from the group consisting of
Cl, Br, and I; r is 1-50; and s is 1-4.
[0281] In other embodiments, the macrocylic module may comprise a
closed ring composition of the formula: 241
[0282] wherein:
[0283] Q is 242
[0284] J is from 1-22, and n is from 1-24; X and R.sup.n are each
independently selected from the group consisting of hydrogen or a
functional group containing atoms selected from the group
consisting of C, H, N, O, Si, P, S, B, Al, halogens, and metals
from the alkali and alkaline earth groups; Z are each independently
hydrogen or a lipophilic group; L are linkages between synthons
each independently selected from the group consisting of (a) a
condensed linkage, and (b) a linkage selected from the group
consisting of --N.dbd.CR--, --NRC(O)--, --OC(O)--, --O--, --S--S--,
--S--, --NR--, --(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--,
--C(O)O--, --C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--,
--HC.dbd.CH--, --NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH--, --N.dbd.CHCH.sub.2CH.dbd.N--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --P(O)(OH).sub.2O--,
--CH(OH)CH.sub.2NH--, --CH(OH)CH.sub.2--,
--CH(OH)C(CH.sub.3).sub.2C(O)O-- -, 243
[0285] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in eitherof two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures.
[0286] In another embodiment, the macrocyclic module may comprise a
closed ring composition of the formula: 244
[0287] wherein:
[0288] Q is 245
[0289] J is from 1-22, and n is from 1-48; X and R.sup.n are each
independently selected from the group consisting of functional
groups containing atoms selected from the group consisting of C, H,
N, O, Si, P, S, B, Al, halogens, and metals from the alkali and
alkaline earth groups; Z are each independently hydrogen or a
lipophilic group; L are linkages between the synthons each
independently selected from the group consisting of (a) a condensed
linkage, and (b) a linkage selected from the group consisting of
--NRC(O)--, --OC(O)--, --O--, --S--S--, --S--, --NR--,
--(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH- --,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.nCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 246
[0290] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures.
[0291] In some embodiments, X and R.sup.n are each independently
selected from the group consisting of hydrogen, an activated acid,
--OH, --C(O)OH, --C(O)H, --C(O)OCH.sub.3, --C(O)Cl, --NRR,
--NRRR.sup.+, --MgX, --Li, --OLi, --OK, --ONa, --SH,
--C(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--NH-alkyl-C(O)CH.sub.2CH(NH.sub.2)CO.sub.2-alkyl,
--CH.dbd.CH.sub.2, --CH.dbd.CHR, --CH.dbd.CR.sub.2, 4-vinylaryl,
--C(O)CH.dbd.CH.sub.2, --NHC(O)CH.dbd.CH.sub.2,
--C(O)CH.dbd.CH(C.sub.6H.sub.5), 247
[0292] --OH, --OC(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--OC(O)CH.dbd.CH.sub.2, 248
[0293] --P(O)(OH)(OX),
--P(.dbd.O)(O.sup.-)O(CH.sub.2).sub.sNR.sub.3.sup.+- ;
[0294] wherein R are each independently selected from the group
consisting of hydrogen and 1-6C alkyl; X is selected from the group
consisting of Cl, Br, and I; r is 1-50; and s is 1-4.
[0295] In another embodiment, the macrocyclic module comprises the
formula: 249
[0296] wherein:
[0297] Q is 250
[0298] J is from 1-11, and n is from 1-12; X and R.sup.n are each
independently selected from the group consisting of hydrogen, an
activated acid, --OH, --C(O)OH, --C(O)H, --C(O)OCH.sub.3, --C(O)Cl,
--NRR, --NRRR.sup.+, --MgX, --Li, --OLi, --OK, --ONa, --SH,
--C(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--NH-alkyl-C(O)CH.sub.2CH(NH.sub.2)C- O.sub.2-alkyl,
--CH.dbd.CH.sub.2, --CH.dbd.CHR, --CH.dbd.CR.sub.2, 4-vinylaryl,
--C(O)CH.dbd.CH.sub.2, --NHC(O)CH.dbd.CH.sub.2,
--C(O)CH.dbd.CH(C.sub.6H.sub.5), 251
[0299] --OH, --OC(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--OC(O)CH.dbd.CH.sub.2, 252
[0300] --P(O)(OH)(OX),
--P(.dbd.O)(O.sup.-)O(CH.sub.2),NR.sub.3.sup.+; wherein R are each
independently selected from thegroup consisting of hydrogen and
1-6C alkyl; X is selected from the group consisting of Cl, Br, and
1; r is 1-50; and s is 1-4; Z are each independently hydrogen or a
lipophilic group; L are linkages between synthons each
independently selected from the group consisting of (a) a condensed
linkage, and (b) a linkage selected from the group consisting of
--NRC(O)--, --OC(O)--, --O--, --S--S--, --S--, --NR--,
--(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O-- -, 253
[0301] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures.
[0302] In another embodiment, the macrocyclic module has the
formula: 254
[0303] wherein:
[0304] Q is 255
[0305] J is from 1-11, and n is from 1-12; X and R.sup.n are each
independently selected from the group consisting of hydrogen, an
activated acid, --OH, --C(O)OH, --C(O)H, --C(O)OCH.sub.3, --C(O)Cl,
--NRR, --NRRR.sup.+, --MgX, --Li, --OLi, --OK, --ONa, --SH,
--C(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--NH-alkyl-C(O)CH.sub.2CH(NH.sub.2)C- O.sub.2-alkyl,
--CH.dbd.CH.sub.2, --CH.dbd.CHR, --CH.dbd.CR.sub.2, 4-vinylaryl,
--C(O)CH.dbd.CH.sub.2, --NHC(O)CH.dbd.CH.sub.2,
--C(O)CH.dbd.CH(C.sub.6H.sub.5), 256
[0306] --OH, --OC(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--OC(O)CH.dbd.CH.sub.2, 257
[0307] --P(O)(OH)(OX),
--P(.dbd.O)(O.sup.-)O(CH.sub.2).sub.sNR.sub.3.sup.- +; wherein R
are each independently selected from the group consisting of
hydrogen and 1-6C alkyl; X is selected from the group consisting of
Cl, Br, and I; r is 1-50; and s is 1-4; Z are each independently
hydrogen or a lipophilic group; L are linkages between the synthons
each independently selected from the group consisting of (a) a
condensed linkage, and (b) a linkage selected from the group
consisting of --NRC(O)--, --OC(O)--, --O--, --S--S--, --S--,
--NR--, --(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 258
[0308] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures.
[0309] In another embodiment, the macrocyclic module comprises the
formula: 259
[0310] wherein:
[0311] Q is 260
[0312] J is from 1-11, and n is from 1-12; X is --NX.sup.1-- or
--CX.sup.2X.sup.3, where X.sup.1 is selected from the group
consisting of an amino acid residue,
--CH.sub.2C(O)CH.sub.2CH(NH.sub.2)CO.sub.2-alkyl, and
--C(O)CH.dbd.CH.sub.2; X.sup.2 and X.sup.3 are each independently
selected from the group consisting of hydrogen, --OH, --NH.sub.2,
--SH, --(CH.sub.2).sub.tOH, --(CH.sub.2).sub.tNH.sub.2 and
--(CH.sub.2).sub.tSH, wherein t is 1-4, and X.sup.2 and X.sup.3 are
not both hydrogen; R.sup.n are each independently selected from the
group consisting of hydrogen, an activated acid, --OH, --C(O)OH,
--C(O)H, --C(O)OCH.sub.3, --C(O)Cl, --NRR, --NRRR.sup.+, --MgX,
--Li, --OLi, --OK, --ONa, --SH,
--C(O)(CH.sub.2).sub.2C(O)OCH.sub.3, --NH-alkyl-C(O)CH.sub.2-
CH(NH.sub.2)CO.sub.2-alkyl, --CH.dbd.CH.sub.2, --CH.dbd.CHR,
--CH.dbd.CR.sub.2, 4-vinylaryl, --C(O)CH.dbd.CH.sub.2,
--NHC(O)CH.dbd.CH.sub.2, --C(O)CH.dbd.CH(C.sub.6H.sub.5), 261
[0313] --OH, --OC(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--OC(O)CH.dbd.CH.sub.2, 262
[0314] --P(O)(OH)(OX),
--P(.dbd.O)(O.sup.-)O(CH.sub.2).sub.sNR.sub.3.sup.- +; wherein R
are each independently selected from the group consisting of
hydrogen and 1-6C alkyl; X is selected from the group consisting of
Cl, Br, and I; r is 1-50; and s is 1-4; Z are each independently
hydrogen or a lipophilic group; L are linkages between synthons
each independently selected from the group consisting of (a) a
condensed linkage, and (b) a linkage selected from the group
consisting of --NRC(O)--, --OC(O)--, --O--, --S--S--, --S--,
--NR--, --(CRR').sub.p--, --CH.sub.2NH--, --C(O)S--, --C(O)O--,
--C.ident.C--, --C.ident.C--C.ident.C--, --CH(OH)--, --HC.dbd.CH--,
--NHC(O)NH--, --NHC(O)O--, --NHCH.sub.2NH--,
--NHCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O-- -, 263
[0315] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures.
[0316] In another embodiment, the macrocyclic module has the
formula: 264
[0317] wherein:
[0318] Q is 265
[0319] J is from 1-11, and n is from 1-12; X and R.sup.n are each
independently selected from the group consisting of hydrogen, an
activated acid, --OH, --C(O)OH, --C(O)H, --C(O)OCH.sub.3, --C(O)Cl,
--NRR, --NRRR.sup.+, --MgX, --Li, --OLi, --OK, --ONa, --SH,
--C(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--NH-alkyl-C(O)CH.sub.2CH(NH.sub.2)C- O.sub.2-alkyl,
--CH.dbd.CH.sub.2, --CH.dbd.CHR, --CH.dbd.CR.sub.2, 4-vinylaryl,
--C(O)CH.dbd.CH.sub.2, --NHC(O)CH.dbd.CH.sub.2,
--C(O)CH.dbd.CH(C.sub.6H.sub.5), 266
[0320] --OH, --OC(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--OC(O)CH.dbd.CH.sub.2, 267
[0321] --P(O)(OH)(OX),
--P(.dbd.O)(O.sup.-)O(CH.sub.2).sub.sNR.sub.3.sup.- +; wherein R
are each independently selected from the group consisting of
hydrogen and 1-6C alkyl; X is selected from the group consisting of
Cl, Br, and I; r is 1-50; and s is 1-4; Z and Y are each
independently hydrogen or a lipophilic group; L are linkages
between the synthons each independently selected from the group
consisting of (a) a condensed linkage, and (b) a linkage selected
from the group consisting of --NRC(O)--, --OC(O)--, --O--,
--S--S--, --S--, --NR--, --(CRR').sub.p--, --CH.sub.2NH--,
--C(O)S--, --C(O)O--, --C.ident.C--, --C.ident.C--C.ident.C--,
--CH(OH)--, --HC.dbd.CH--, --NHC(O)NH--, --NHC(O)O--,
--NHCH.sub.2NH--, --NHCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 268
[0322] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures.
[0323] In another embodiment, the macrocyclic module has the
fonnula: 269
[0324] wherein:
[0325] Q is 270
[0326] J is from 1-11, and n is from 1-12; X and R.sup.n are each
independently selected from the group consisting of hydrogen, an
activated acid, --OH, --C(O)OH, --C(O)H, --C(O)OCH.sub.3, --C(O)Cl,
--NRR, --NRRR.sup.+, --MgX, --Li, --OLi, --OK, --ONa, --SH,
--C(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--NH-alkyl-C(O)CH.sub.2CH(NH.sub.2)C- O.sub.2-alkyl,
--CH.dbd.CH.sub.2, --CH.dbd.CHR, --CH.dbd.CR.sub.2, 4-vinylaryl,
--C(O)CH.dbd.CH.sub.2, --NHC(O)CH.dbd.CH.sub.2,
--C(O)CH.dbd.CH(C.sub.6H.sub.5), 271
[0327] --OH, --OC(O)(CH.sub.2).sub.2C(O)OCH.sub.3,
--OC(O)CH.dbd.CH.sub.2, 272
[0328] --P(O)(OH)(OX),
--P(.dbd.O)(O.sup.-)O(CH.sub.2).sub.sNR.sub.3.sup.- +; wherein R
are each independently selected from the group consisting of
hydrogen and 1-6C alkyl; X is selected from the group consisting of
Cl, Br, and I; r is 1-50; and s is 1-4; Z and Y are each
independently hydrogen or a lipophilic group; L are linkages
between synthons each independently selected from the group
consisting of (a) a condensed linkage, and (b) a linkage selected
from the group consisting of --NRC(O)--, --OC(O)--, --O--,
--S--S--, --S--, --NR--, --(CRR').sub.p--, --CH.sub.2NH--,
--C(O)S--, --C(O)O--, --C.ident.C--, --C.ident.C--C.ident.C--,
--CH(OH)--, --HC.dbd.CH--, --NHC(O)NH--, --NHC(O)O--,
--NHCH.sub.2NH--, --NHCH.sub.2CH(OH)CH.sub.2NH--,
--N.dbd.CH(CH.sub.2).sub.pCH.dbd.N--, --CH.sub.2CH(OH)CH.sub.2--,
--N.dbd.CH(CH.sub.2).sub.hCH.dbd.N-- where h is 1-4,
--CH.dbd.N--NH--, --OC(O)O--, --OP(O)(OH)O--, --CH(OH)CH.sub.2NH--,
--CH(OH)CH.sub.2--, --CH(OH)C(CH.sub.3).sub.2C(O)O--, 273
[0329] wherein p is 1-6; wherein R and R' are each independently
selected from the group of hydrogen and alkyl; wherein linkages L
are each independently configured in either of two possible
configurations, forward and reverse, with respect to the synthons
it couples together, if the two configurations are different
structures.
[0330] In some embodiments, the nanofilm may be coupled to a solid
support selected from the group of Wang resins, hydrogels,
aluminas, metals, ceramics, polymers, silica gels, sepharose,
sephadex, agarose, inorganic solids, semiconductors, and silicon
wafers.
[0331] In one embodiment, the nanofilm retains at least 85% of film
area after thirty minutes on a Langmuir trough at 5-15 mN/m. In
other embodiments, the nanofilm retains at least 95% of film area
after thirty minutes on a Langmuir trough at 5-15 mN/m. In another
embodiment, the nanofilm retains at least 98% of film area after
thirty minutes on a Langmuir trough at 5-15 mN/m.
[0332] In one embodiment, a method for making a macrocyclic module
composition comprises: (a) providing a plurality of a first cyclic
synthon; (b) contacting a plurality of a second cyclic synthon with
the first cyclic synthons; (c) isolating the macrocyclic module
composition. The method may further comprise contacting a linker
molecule with the mixture in (a) or (b).
[0333] In another embodiment, a method for making a macrocyclic
module composition comprises: (a) providing a plurality of a first
cyclic synthon; (b) contacting a plurality of a second cyclic
synthon with the first cyclic synthons; (c) contacting a plurality
of the first cyclic synthon with the mixture from (b).
[0334] In another embodiment, a method for making a macrocyclic
module composition comprises: (a) providing a plurality of a first
cyclic synthon; (b) contacting a plurality of a second cyclic
synthon with the first cyclic synthons; (c) contacting a plurality
of a third cyclic synthon with the mixture from (b).
[0335] The method may further comprise contacting a linker molecule
with the mixture in (a) or (b) or (c). The method may further
comprise supporting a cyclic synthon or coupled synthons on a solid
phase.
[0336] In another embodiment, a method for making a macrocyclic
module composition comprises: (a) contacting a plurality of cyclic
synthons with a metal complex template; and (b) isolating the
macrocyclic module composition.
[0337] In another embodiment, a method of preparing a composition
for transporting a selected species through the composition
comprises: selecting a first cyclic synthon, wherein the first
cyclic synthon is substituted with at least one functional group
comprising a functional group containing atoms selected from the
group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and
metals from the alkali and alkaline earth groups; selecting from
two to about twenty-three additional cyclic synthons; incorporating
the first cyclic synthon and the additional cyclic synthons into a
macrocyclic module composition comprising: from three to about
twenty-four cyclic synthons coupled to form a closed ring defining
a pore; wherein the at least one functional group of the first
cyclic synthonhis located at the pore of the macrocyclic module
composition and is selected to transport the selected species
through the pore.
[0338] Macrocyclic Module Pores
[0339] An individual macrocyclic module may include a pore in its
structure. The size of the pore may determine the size of molecules
or other species which can pass through the macrocyclic module. The
size of a pore in a macrocyclic module may depend on the structure
of the synthons used to make the macrocyclic module, the linkages
between synthons, the number of synthons in a module, the structure
of any linker molecules used to make the macrocyclic module, and
other structural features of the macrocyclic module whether
inherent in the preparation of the macrocyclic module or added in
later steps or modifications. Stereoisomerism of macrocyclic
modules may also be used to regulate the size of a pore of a
macrocyclic module by variation of the stereoisomer of each synthon
used to prepare the closed ring of the macrocyclic module.
[0340] The dimension of a pore in a macrocyclic module may be
varied by changing the combination of synthons used to form the
macrocyclic module, or by varying the number of synthons in the
closed ring. The dimension of a pore may also be varied by
substituents on the synthons or linkages. The pore may therefore be
made large enough or small enough to achieve an effect on transport
of species through the pore. Species which may be transported
through the pore of a macrocyclic module include atoms, molecules,
biomolecules, ions, charged particles, and photons.
[0341] The size of a species may not be the sole determinant of
whether it will be able to pass through a pore of a macrocyclic
module. Groups or moieties located in or near the pore structure of
a macrocyclic module may regulate or affect transport of a species
through the pore by various mechanisms. For example, transport of a
species through the pore may be affected by groups of the
macrocyclic module which interact with the species, by ionic or
other interaction, such as chelating groups, or by complexing the
species. For example, a charged group such as a carboxylate anion
or ammonium group may couple an oppositely-charged species and
affect its transport. Substituents of synthons in a macrocyclic
module may affect the passage of a species through the pore of the
macrocyclic module. Groups of atoms which render the pore of a
macrocyclic module more or less hydrophilic or lipophilic may
affect transport of a species through the pore. An atom or group of
atoms may be located within or proximate to a pore to sterically
slow or block the passage of a species through the pore. For
example, hydroxyl or alkoxy groups may be coupled to a cyclic
synthon and located in the pore of the structure of the macrocyclic
module, or may be coupled to a linkage between synthons and located
in the pore. A wide range of functional groups may be used to
sterically slow or block the passage of a species through the pore,
including functional groups containing atoms selected from the
group consisting of C, H, N, O, Si, P, S, B, Al, halogens, and
metals from the alkali and alkaline earth groups. Blocking and
slowing passage of a species through the pore may involve reducing
the dimension of the pore by steric blocking, as well as slowing
the passage of species by creating a path through the pore which is
not linear, and providing interaction between the functional group
and the species to slow transport. The stereochemical structure of
the portion of the macrocyclic module which defines the pore and
its interior may also affect transport. Any groups or moieties
which affect transport of a species through the pore of a
macrocyclic module may be introduced as part of the synthons used
to prepare the macrocyclic module, or may be added later by various
means. For example, S7-1 could be reacted with
ClC(O)(CH.sub.2).sub.2C(O)- OCH.sub.2CH.sub.3 to convert the phenol
groups to succinyl ester groups. Further, molecular dynamical
motion of the synthons and linkages of a partly flexible
macrocyclic module may affect transport of a species through the
pore of the module. Transport behavior may not be described solely
by the structure of the macrocyclic module itself since the
presence of the species which is to be transported through the pore
affects the flexibility, conformation, and dynamical motions of a
macrocyclic module. In general, solvent may also affect transport
of solutes through a pore.
[0342] The following examples further describe and demonstrate
variations within the scope of the present invention. All examples
described in this specification, both in the description above and
the examples below, are given solely for the purpose of
illustration and are not to be construed as limiting the present
invention. While there have been described illustrative variations
of this invention, those skilled in the art will recognize that
they may be changed or modified without departing from the spirit
and scope of this invention, and it is intended to cover all such
changes, modifications, and equivalent arrangements that fall
within the true scope of the invention as set forth in the appended
claims.
[0343] All documents referenced herein, including applications for
patent, patent references, publications, articles, books, and
treatises, are specifically incorporated by reference herein in
their entirety.
EXAMPLES
[0344] Reagents were obtained from Aldrich Chemical Company and VWR
Scientific Products. The Langmuir trough used was a KSV minitrough
(KSV Instruments, Trumbull, Conn.). Interfacial rheometry was
performed using a CIR-100 Interfacial Rheometer (Rheometric
Scientific, Piscataway N.J.) with a KSV Langmuir two-barrier
rheology microtrough having a width of 85 mm (KSV Instruments,
Trumbull, Conn.). Rates of surface compression are reported as the
linear rate of barrier movement. Atomic force microscopy (AFM)
images were obtained with a PicoSPM (Molecular Imaging, Pheonix
Ariz.). Contact Mode images were typically recorded under flowing
nitrogen with an Si point probe tip.
Example 1
[0345] Derivatization of SiO.sub.2 Substrates with
(3-aminopropyl)triethox- ysilane (APTES): SiO.sub.2 substrates were
first sonicated in a piranha solution (3:1 ratio of
H.sub.2SO.sub.4:30% H.sub.2O.sub.2) for 15 minutes. This was
followed by a 15 min sonication in Milli-Q water (>18
M.OMEGA.-cm). The derivatization step was done in a glove bag under
a N.sub.2 atmosphere. 0.05 mL APTES and 0.05 mL pyridine were added
to 9 mL of toluene. Immediately following mixing, the freshly
cleaned SiO.sub.2 substrates were immersed in the APTES solution
for 10 min. Substrates were washed with copious amounts of toluene
and then dried with N.sub.2. Deposited APTES films showed a range
of thickness values from 0.8 to 1.3 nm.
Example 2
[0346] Deposition of Hexamer 1dh/PMAOD nanofilm on APTES modified
SiO.sub.2 substrate: A 50%:50% area fraction solution of Hexamer
1dh:poly(maleic anhydride-alt-1-octadecene) (PMAOD) (Aldrich,
30,000-50,000 MW) was spread onto a pH 9 water subphase. After 10
minutes the film was compressed to 12 mN/m at a rate of 3 mm/min.
Upon compression a layer of nanofilm was deposited onto an
APTES-modified substrate on the upstroke using a vertical dip. The
deposition rate was typically 0.25 or 0.5 mm/min. Following
deposition, the nanofilm was heated at 70.degree. C. under N.sub.2
for about 6 hours.
[0347] Imaging ellipsometry, illustrated in FIG. 1A, revealed an
APTES coating on the substrate having a thickness of 0.94 nm. The
thickness of the coating and deposited nanofilm, illustrated on the
left in FIG. 1B, was 1.94 nm, while the thickness of the APTES
coating of the substrate, illustrated on the right in FIG. 1B, was
0.82 nm. Thus, the thickness of the uncured nanofilm itself was 1.1
nm. A smooth, physically homogeneous, continuous and unbroken
nanofilm was deposited. After heating, the thickness of the coating
and cured nanofilm was 1.57 nm, illustrated on the left in FIG. 1C,
while the APTES coating of the substrate, illustrated on the right
in FIG. 1C, was 0.53 nm. Thus, the thickness of the nanofilm itself
was virtually unchanged at 1.0 nm. After sonication in CHCl.sub.3
(FIG. 2A), acetone (FIG. 2B), and water (FIG. 2C), each for five
minutes, the thickness of the nanofilm itself was virtually
unchanged at 0.9 nm, 1.0 nm, and 1.0 nm, respectively. Thus,
ellipsometric measurements determined that the loss of nanofilm
material from the substrate upon sonication was minimal.
Example 3
[0348] Deposition of Hexamer 1dh/PMAOD/DEM nanofilm on APTES
modified SiO.sub.2 substrate: A 0.1:0.9 mole fraction solution of
Hexamer 1dh:PMAOD was spread onto a pH 9 diethyl malonimidate (DEM)
subphase (0.5 mg/mL in aqueous solution). After 10 minutes the film
was compressed to 12 mN/m at a rate of 2 mm/min. Upon compression a
layer of nanofilm was deposited onto the APTES modified substrate
on the upstroke using a vertical dip. The deposition rate was
typically 0.5 or 1.0 mm/min. Following deposition, the nanofilm was
cured at 80.degree. C. under N.sub.2 for 14-19 hours to attach the
nanofilm to the surface. A nanofilm thickness of 1.1 nm was
measured by ellipsometry before curing the nanofilm, and 0.9-1.0 nm
after curing. A smooth, physically homogeneous, continuous and
unbroken nanofilm was deposited. After sonication in CHCl.sub.3 at
room temperature a nanofilm thickness of 0.7-0.9 nm was measured by
ellipsometry.
Example 4
[0349] Deposition of Hexamer 1dh/PMAOD/DEM nanofilm on APTES
modified SiO.sub.2 substrate: A nanofilm of Hexamer 1dh and PMAOD
was prepared as in Example 3, except at deposition surface pressure
of 25 mN/m. A smooth, physically homogeneous, continuous and
unbroken nanofilm was deposited for DEM subphase concentrations of
0.5 mg/mL and 2.0 mg/mL. After sonication in CHCl.sub.3 at room
temperature a thickness of 1.2 nm was measured by ellipsometry for
nanofilm on bare SiO.sub.2 substrate, and a thickness of 1.4-1.6 nm
was measured by ellipsometry for nanofilm on APTES modified
SiO.sub.2 substrate.
Example 5
[0350] Surface rheology of a sample of nanofilm of Hexamer 1dh and
DEM having polymeric component PMAOD is shown in Table 10.
Referring to Table 10, as the area fraction of Hexamer 1dh
decreased, corresponding to an increase in polymeric component
PMAOD, the surface moduli of the nanofilm substantially decreased.
G' indicates storage modulus and G" indicates loss modulus.
12TABLE 10 Rheology of nanoflim of Hexamer 1dh and DEM having
polymeric component PMAOD SURFACE MODULI AREA FRACTION OF HEXAMER
(.phi.) G', G" 0.0 0.6 0.8 0.9 0.95 1.0 G' @ 10 mN/m 0.2 5.9 15.1
5.0 6.1 13.3 G" @ 10 mN/m 7.5 88.2 163.1 97.3 151.4 257.4 G' @ 20
mN/m 6.6 45.3 65.8 58.8 57.5 147.4 G" @ 20 mN/m 154.7 412.8 474.6
501.7 570.7 1269.9 G' @ 30 mN/m 35.05 -- -- -- 153.5 418.5 G" @ 30
mN/m 391.1 -- -- -- 859.6 2707.2
[0351] As shown in Table 10, G" typically exceeds G' in the viscous
nanofilm. The data in Table 10 indicate that for a nanofilm of
Hexamer 1dh and DEM, introducing an area fraction of polymeric
component PMAOD of about 5% into the nanofilm reduced the moduli of
thle nanofilm by more than 50%. The polymeric component makes the
nanofilm more flexible and less brittle. In other words, the data
in Table 10 indicate that for a nanofilm having an area fraction of
polymeric component PMAOD of about 5%, the surface loss modulus of
the nanofilm at a surface pressure from 5-30 mN/m is less than
about 50% of the surface loss modulus of the same nanofilm
composition made without the polymeric components.
[0352] To prepare the nanofilms used in Table 10, chloroform
solutions of Hexamer 1dh and PMAOD were mixed in proportions
corresponding to Table 10, and allowed to equilibrate at room
temperature for approximately one hour. Subsequently, 10 .mu.l of
the chloroform mixture were spread at the liquid-air interface of a
50 mM NaHCO.sub.3 buffer (pH 9) containing 0.5 mg/ml DEM. After
allowing 15 minutes for evaporation of the spreading solvent, the
nanofilm was compressed to a surface pressure of 10 mN/m. The
viscoelastic properties of the nanofilm were then measured using a
CIR-100 interfacial rheometer (Camtel Ltd, Herts, UK). A sinusoidal
torque of amplitude 0.02 .mu.N*m and frequency 1 Hz was applied to
the nanofilm, and the in-phase and out-of-phase components of the
resulting strain were measured, giving the elastic and viscous
components, respectively. For the data in Table 10, the response
was averaged over about 40 minutes.
[0353] Surface rheology of a sample of nanofilm of Hexamer 1dh and
DEM having polymeric component PMAOD is shown in FIG. 3A. Nanofilms
used in FIG. 3A were prepared with a 2.0 mg/ml DEM subphase. The
dashed line curves in FIG. 3A were obtained with a subphase heated
to 33.degree. C., while the solid line curves were obtained with a
subphase at room temperature 22.degree. C. The data in FIG. 3A
indicate that for a nanofilm of Hexamer 1dh and DEM, introducing an
area fraction of PMAOD of about 20% into the nanofilm reduced the
loss modulus (G") of the nanofilm by about one-half at 10 mN/m
surface pressure. The data in FIG. 3A also indicate that the
modulus of the nanofilm is generally higher for the higher subphase
temperature.
[0354] Surface rheology of a sample of nanofilm of Hexamer 1dh and
DEM having polymeric component PMAOD is shown in FIGS. 3B-D.
Nanofilms used in FIGS. 3B-D were prepared with a 2.0 mg/ml DEM
subphase at room temperature. The data in FIGS. 3B-D indicate that
for a nanofilm of Hexamer 1dh and DEM, introducing an area fraction
of polymeric component PMAOD of about 5% into the nanofilm reduced
the storage and loss moduli of the nanofilm by more than one-half
at 20 mN/m surface pressure or greater.
Example 6
[0355] Hexamer 1dh, PMAOD and DEM on polycarbonate track etch
membrane (PCTE): A nanofilm of Hexamer 1dh, PMAOD, and DEM can be
made to span the pores of a 0.01 .mu.m PCTE. A solution of Hexamer
1dh and PMAOD having 0.1 mole fraction hexamer: 0.9 mole fraction
PMAOD was spread onto a subphase of 0.5 mg/ml DEM. One layer of the
resulting nanofilm was deposited by vertical dip at 2 mm/min at a
surface pressure of 12 mN/m and deposition rate 1 mm/min onto a
PCTE having holes of 10 nm diameter. The sample was not heated. The
PCTE substrates were not plasma treated, and the attachment of the
nanofilm to the PCTE was not necessarily by covalent binding, but
may have been by weaker types of binding or coupling.
[0356] The scanning electron micrographs of this nanofilm are shown
in FIG. 4. FIG. 4A shows an area in the center of the nanofilm in
which no holes in the nanofilm were visible. FIG. 4B shows an area
far from the edge of the nanofilm in which no holes in the nanofilm
were visible. FIG. 4C shows an area next to that in FIG. 4D which
was near the edge of the nanofilm and in which a few holes of
various sizes may have been visible in the nanofilm. In FIG. 4D is
shown an area near the edge of the nanofilm in which a few holes of
various sizes may have been visible in the nanofilm. The holes
observed in the nanofilm in FIGS. 4A-4D may have been as large as
30 nm in diameter.
[0357] By comparison, the scanning electron micrograph of a PCTE
substrate having holes of 10 nm diameter is shown in FIG. 5A, which
illustrates the pattern of holes in the substrate. The scanning
electron micrograph of the same PCTE substrate after plasma
treatment is shown in FIG. 5B, which illustrates that the holes may
be widened as compared to the PCTE substrate used in FIG. 5A.
Example 7
[0358] The FTIR-ATR spectrum of CHCl.sub.3 rinsings from PMAOD
Langmuir thin film deposited on a SiO.sub.2 substrate from an
aqueous subphase is shown in FIG. 6. The absorbance at 1737
cm.sup.-1 (acid carbonyl) resulted from the hydrolysis of the
anhydride group to form a diacid.
Example 8
[0359] The FTIR-ATR spectrum of Hexamer 1dh is shown in FIG. 7. The
dominant absorbance at 1450 cm.sup.-1 was from the --CH.sub.2--
stretching of the alkyl chains of the hexamer.
Example 9
[0360] The FTIR-ATR spectrum of CHCl.sub.3 rinsings from a nanofilm
of Hexamer 1dh and PMAOD deposited on a SiO.sub.2 substrate from a
pH 9 aqueous subphase is shown in FIG. 8. The peak at 1737
cm.sup.-1 revealed that the diacid form was present. The broadening
of this peak and the formation of a shoulder at 1713 cm.sup.-showed
that ester and amide bond formation occurred. Ester formation
(shoulder at 1713 cm.sup.-1) appeared to be favored over an amide
carbonyl absorbance (1630-1680 cm.sup.-1). In the PMAOD spectrum
(FIG. 6), the ratio of the areas of the peak appearing at 1450
cm.sup.-1 to the peak at 1737 cm.sup.-1 was about 3:1. The ratio
for the same peaks observed in FIG. 8 was less than one, and
indicated ester or amide formation because of the increase in
absorbance in the carbonyl region. This indicated coupling of the
module via the phenol and secondary amine groups to the PMAOD
polymer.
Example 10
[0361] The FTIR-ATR spectrum of CHCl.sub.3 rinsings from a Hexamer
1dh Langmuir film deposited on a SiO.sub.2 substrate from a pH 9
DEM subphase is shown in FIG. 9. Absorbances at 1737 cm.sup.-1 and
1713 cm.sup.-1 were observed. The carbonyl absorbance showed that
amide linkages may have formed, indicating coupling of between the
module and the cross-linker.
Example 11
[0362] The FTIR-ATR spectrum of CHCl.sub.3 rinsings from a nanofilm
made from Hexamer 1dh and PMAOD deposited on a SiO.sub.2 substrate
from a pH 9 DEM subphase is shown in FIG. 10. The carbonyl region
resembles that in FIG. 8, which would be expected as the DEM can
react with the amine functionality of the hexamer to form amide
cross-links. In addition, ester formation is possible between PMAOD
and the hexamer. This indicated coupling between the module and the
polymer, and between the module and the cross-linker.
Example 12
[0363] Contact Mode AFM images of plasma treated PCTE are shown in
FIG. 11. The surface of this substrate was partially smoothed using
the AFM tip, as shown in the bottom panel of FIG. 11.
Example 13
[0364] A nanofilm of 0.8:0.2 mole fraction Hexamer 1dh:PMAOD which
were pre-mixed in solution was prepared, and deposited by vertical
dip onto APTES coated SiO.sub.2 substrate. The nanofilm was cured
at 70.degree. C. under N.sub.2 for 15 hours. The Contact Mode AFM
images of the nanofilm obtained under flowing N.sub.2 are shown in
FIG. 12A. Referring to FIG. 12A, the top panels show the images of
a continuous nanofilm, while the bottom panels show the images of
the same nanofilm after a piece of the nanofilm about 250 nm.sup.2
in area was removed by scraping with the AFM tip. The thickness of
the film observed at the edge of the hole created by the tip was
2-3 mm. A second nanofilm of the same composition was cured at
70.degree. C. under N.sub.2 for 39 hours. The Contact Mode AFM
images of the second nanofilm obtained under flowing N.sub.2 are
shown in FIG. 12B. Referring to FIG. 12B, the top panels show the
images of a continuous nanofilm, while the bottom panels show the
images of the same nanofilm after an attempt to scrape away a piece
of the nanofilm with the AFM tip. The nanofilm could not be scraped
away, showing that the longer-cured nanofilm was more strongly
attached to the substrate by annealing.
Example 14
[0365] The Contact Mode AFM image of a nanofilm made from Hexamer
1dh and PMAOD and DEM, having 0.10 mole fraction of Hexamer
1dh:0.90 mole fraction PMAOD is shown in FIG. 13. The nanofilm was
deposited by vertical dip onto PCTE having a random array of holes
0.01 .mu.m in diameter. A depression in the nanofilm made with the
AFM tip is clearly visible.
Example 15
[0366] A nanofilm was made from an amphiphile, octadecylamine
(ODA), and an amphiphilic polymer, polymethylmethacrylate (PMMA)
(Polysciences, Warrington Pa., MW 100,000, polydispersity 1.1),
from a chloroform solution of the two components heated to
55.degree. C. for 18 hours, then spread at the liquid-air interface
of a 100 mM NaH.sub.2PO.sub.4 buffer (pH 7.3) at room temperature.
Isotherms of this nanofilm and its components made with a 1:1
mixture of ODA:PMMA, illustrated in FIG. 14, showed that the
isotherms of ODA and PMMA each retained substantially the same
shape in the nanofilm. In general, the isotherms of FIG. 14
indicate that ODA and PMMA were immiscible in the nanofilm.
Example 16
[0367] A nanofilm was made from an amphiphile, ODA, and an
amphiphilic polymer, PMAOD, by spreading a 1:1 molar ratio of
ODA:PMAOD in chloroform at the liquid-air interface. The isotherm
of this nanofilm, illustrated in FIG. 15, exhibited a different
shape than either of the components alone, and a much higher mean
molecular area than either of the components alone. In general, the
isotherm of FIG. 15 indicates that ODA and PMAOD were miscible in
the nanofilm.
Example 17
[0368] A solution of Hexamer 1dh and PMMA was spread at the
liquid-air interface over a water subphase to form a nanofilm
having 0.6 area fraction Hexamer 1dh. One layer of the resulting
nanofilm was deposited by vertical dip at a surface pressure of 20
mN/m onto an APTES coated silicon substrate. The Contact Mode AFM
image of the deposited nanofilm is shown in FIG. 16 and illustrates
a phase separated nanofilm composition, which confirms that the
Hexamer 1dh/PMMA mixture is immiscible. The height of the
continuous phase was about 1 nm above the discontinuous phase.
Deformations were made with the AFM probe tip in each of the
continuous phase and the discontinuous phase to confirm that the
two phases are composed of nanofilm and were not part of the
substrate. By comparison, the ellipsometric image of a
Langmuir-Blodgett deposition of PMMA alone showed a homogeneous,
continuous and unbroken film of about 0.6-1.0 nm thickness.
Example 18
[0369] A solution of Hexamer 1dh and PMAOD was spread at the
liquid-air interface over a water subphase containing 2 mg/ml DEM
to form a nanofilm. Surface rheology of this nanofilm is shown in
FIG. 17. Referring to FIG. 17, storage and loss surface moduli of
the nanofilm are illustrated over time as the temperature of the
subphase was raised. T.sub.bath indicates the temperature of the
surrounding circulation bath, and T.degree. C. indicates the
temperature of the subphase.
Example 19
[0370] A solution of Hexamer 1dh and poly(2-hydroxyethyl
methacrylate) (PHEMA) was spread at the liquid-air interface over a
water subphase containing 2 mg/ml DEM to form a nanofilm. 274
[0371] Surface rheology of this nanofilm is shown in Table 11.
Referring to Table 11, storage and loss surface moduli of the
nanofilm are illustrated as the mole fraction of the components was
varied.
13TABLE 11 Rheology of nanofilm of Hexamer 1dh and DEM having
polymeric component PHEMA mol fraction 10 mN/m 20 mN/m 30 mN/m
Hexamer 1dh G' G" G' G" G' G" 0 0.07* 14* -- -- -- -- 0.5 32 649
138 1233 291 1660 0.75 5.8 172 64 660 172 1206 100 13.3 257 147
1297 419 2707 *Obtained at 5 mN/m.
[0372] The data in Table 11 indicate that for a nanofilm of Hexamer
1dh, PHEMA and DEM, introducing a mole fraction of polymeric
component PHEMA of about 25% into the nanofilm reduced the loss
modulus (G") of the nanofilm by more than 50% at 30 mN/m surface
pressure. In Table 11, the increase of both loss and storage
surface moduli of the nanofilm as the mole fraction of PHEMA
increases from 0.25 to 0.5 indicates coupling of PHEMA to the
cross-linker.
Example 20
[0373] Rheological characterization of polyglycidyl methacrylate
(PGM) monolayers on a subphase containing 1% (by volume) ethylene
diamine was performed according to the following protocol. 10 .mu.l
of a chloroform solution of PGM (1 mg/mL) was spread at the
liquid-air interface of a 1% ethylene diamine subphase. After
allowing 15 minutes for evaporation of the spreading solvent, the
film was compressed to a surface pressure of 10 mN/m. The
viscoelastic properties of the film were then measured at
30.degree. C. using the CIR-100 interfacial rheometer (Camtel LTD,
Herts, UK). Briefly, a sinusoidal torque of amplitude 0.02
.mu.N.multidot.m and frequency 1 Hz was applied to the film, and
the in-phase and out-of-phase components of the resulting strain
were measured, giving the elastic and viscous components,
respectively. The response was measured for approximately 70
minutes, and the data were then averaged. Subsequently, a control
experiment was performed with PGM on basic subphases (pH=10.5 and
12) to determine whether pH played any roll in the high viscosities
observed for experiments performed on the ethylene diamine
subphases. The Rheology data in FIG. 18 indicates that the PGM
films made on an ethylene diamine subphase have an almost 2 orders
of magnitude increase in surface moduli, as compared to PGM on a
basic subphase. Therefore, ethylene diamine appears to be
cross-linking the PGM into a nanofilm. When spread on a pure
H.sub.2O subphase, PGM makes a Langmuir film with a collapse
pressure of approximately 10 mN/m (data not shown).
Example 21
[0374] Without intending to be bound by any one particular theory,
one method to approximate pore size of a macrocyclic module is
quantum mechanical (QM) and molecular mechanical (MM) computations.
In this example, macrocyclic modules having two types of synthons,
"A" and "B," were used and all linkages between synthons were
assumed to be the same. For the purposes of QM and MM computations,
the root mean square deviations in the pore areas were computed
over dynamic runs.
[0375] For QM, each module was first optimized using the MM+ force
field approach of Allinger (JACS, 1977, 99:8127) and Burkert, et
al., (Molecular Mechanics, ACS Monograph 177, 1982). They were then
re-optimized using the AM1 Hamiltonian (Dewar, et al., JACS, 1985,
107:3903; Dewar, et al., JACS, 1986, 108:8075; Stewart, J. Comp.
Aided Mol. Design, 1990, 4:1). To verify the nature of the
potential energy surface in the vicinity of the optimized
structures, the associated Hessian matrices were computed using
numerical double-differencing.
[0376] For MM, the OPLS-AA force field approach (Jorgensen, et al.,
JACS, 1996, 118:11225) was used. For imine linkages, the dihedral
angle was confined to 180.degree..+-.10.degree.. The structures
were minimized and equilibrated for one picosecond using 0.5
femtosecond time steps. Then a 5 nanosecond dynamics run was
carried out with a 1.5 femtosecond time step. Structures were saved
every picosecond. The results are shown in Tables 12 and 13.
[0377] Macrocyclic module pore areas derived from QM and MM
computations for various linkages and macrocyclic module pore size
are shown in Table 12. In Table 12, the macrocyclic modules had
alternating synthons "A" and "B." Synthon "A" is a benzene synthon
coupled to linkages L at 1,3-phenyl positions, and Synthon "B" is
shown in the left-hand column of the table.
14TABLE 12 Pore areas for various macrocyclic modules (.ANG..sup.2)
TETRAMER TETRAMER HEXAMER HEXAMER OCTAMER OCTAMER SYNTHON B QM MM
QM MM QM MM trans-1,2- imine (trans) Imine (trans) cyclohexane 14.3
.ANG..sup.2 13.2 .+-. 1.4 .ANG..sup.2 trans-1,2- Acetylene
cyclohexane 14.3 .ANG..sup.2 trans-1,2- Amine Amine cyclohexane
23.1 .ANG..sup.2 13.9 .+-. 1.9 .ANG..sup.2 trans-1,2- Amide Amide
cyclohexane 19.7 .ANG..sup.2 17.5 .+-. 2.0 .ANG..sup.2 trans-1,2-
Ester Ester cyclohexane 18.9 .ANG..sup.2 19.6 .+-. 2.0 .ANG..sup.2
Equatorial-1,3- imine (trans) Imine (trans) imine (trans) Imine
(trans) cyclohexane 18.1 .ANG..sup.2 21.8 .+-. 1.6 .ANG..sup.2 66.2
.ANG..sup.2 74.5 .+-. 7.7 .ANG..sup.2 Equatorial-1,3- Amine Amine
cyclohexane 14.7 .ANG..sup.2 19.9 .+-. 2.6 .ANG..sup.2
Equatorial-1,3- Amide Amide cyclohexane 24.8 .ANG..sup.2 21.7 .+-.
1.8 .ANG..sup.2 Equatorial-1,3- Ester Ester cyclohexane 22.9
.ANG..sup.2 22.8 .+-. 2.4 .ANG..sup.2 Equatorial-3- imine (trans)
imine (trans) imine (trans) Imine (trans) imine (trans) Imine
(trans) amino- oxygen- oxygen-oxygen 18.4 .ANG..sup.2 21.0 .+-. 1.5
.ANG..sup.2 56.7 .ANG..sup.2 60.5.sup.+ - 8.3 .ANG..sup.2
cyclohexene oxygen distance distance 3.7 .+-. .3 .ANG. 2.481 .ANG.
trans-1,2- imine (trans) Imine (trans) pyrrolidine 10.4 .ANG..sup.2
9.2 .+-. 1.4 .ANG..sup.2 Equatorial-1,3- imine (trans) Imine
(trans) piperidene 19.2 .ANG..sup.2 20.9 .+-. 1.1 .ANG..sup.2
Endo-exo-1,2- imine (trans) Imine (trans) bicycloheptane 11.1
.ANG..sup.2 14.1 .+-. + - 11 .ANG..sup.2 Endo-endo-1,3- imine
(trans) Imine (trans) bicycloheptane 18.8 .ANG..sup.2 20.7 .+-. 1.4
.ANG..sup.2 Endo-exo-1,3- Imine Imine bicycloheptane 19.5
.ANG..sup.2 10.1 .+-. + 4.9 .ANG..sup.2 Equatorial-1,3- Amine Amine
cyclohexane 9.8 .ANG..sup.2 9.9 .+-. 2.4 .ANG..sup.2 Endo-endo-1,3-
imine (trans) Imine (trans) bicyclooctene 18.9 .ANG..sup.2 21.6
.+-. 1.5 .ANG..sup.2 Endo-exo-1,3- imine (trans) Imine (trans)
bicyclooctene 15.6 .ANG..sup.2 18.7 .+-. 1.6 .ANG..sup.2
Equatorial-3,9- imine (trans) Imine (trans) decalin 35.4
.ANG..sup.2 40.0 .+-. 2.2 .ANG..sup.2
[0378] Further macrocyclic module pore areas derived from QM and MM
computations for various linkages and macrocyclic module pore size
are shown in Table 13. In Table 13, the macrocyclic modules had
alternating synthons "A" and "B." In Table 13, Synthon "A" is a
naphthalene synthon coupled to linkages L at 2,7-naphthyl
positions, and Synthon "B" is shown in the left-hand column of the
table.
15TABLE 13 Pore areas for various macrocyclic modules (.ANG..sup.2)
HEXAMER HEXAMER SYNTHON B QM MM Trans-1,2- imine (trans) imine
(trans) cyclohexane 23.5 .ANG..sup.2 25.4 .+-. 4.9 .ANG..sup.2
Endo-endo-1,3- imine (trans) imine (trans) bicycloheptane 30.1
.ANG..sup.2 30.0 .+-. 3.6 .ANG..sup.2
[0379] An example of the energy-minimized conformations of some
hexamer macrocyclic modules having groups of substituents are shown
in FIGS. 19A and 19B. Referring to FIG. 19A, a Hexamer
1-h-(OH).sub.3 is shown having a group of --OH substituents.
Referring to FIG. 19B, a Hexamer 1-h-(OEt).sub.3 is shown having a
group of --OEt substituents. The differences in pore structure and
area between these two examples, which also reflect conformational
and flexibility differences, are evident. This macrocyclic module
results in a composition which may be used to regulate pores.
Selection of ethoxy synthon substituents over hydroxy synthon
substituents for this hexamer composition is a method which may be
used for transporting selected species. 275
[0380] The pore size of macrocyclic modules was determined
experimentally using a voltage-clamped bilayer procedure. A
quantity of a macrocyclic module was inserted into a lipid bilayer
formed by phosphatidylcholine and phosphatidylethanolamine. On one
side of the bilayer was placed a solution containing the cationic
species to be tested. On the other side was a solution containing a
reference cationic species known to be able to pass through the
pore of the macrocyclic module. Anions required for charge balance
were selected which could not pass through the pores of the
macrocyclic module. When a positive electrical potential was
applied to the solution on the side of the lipid bilayer containing
the test species, if the test species passed through the pores in
the macrocyclic modules, a current was detected. The voltage was
then reversed to detect current due to transport of the reference
species through the pores, thereby confirming that the bilayer is a
barrier to transport and that the pores of the macrocyclic modules
provide transport of species.
[0381] Using the above technique, a hexameric macrocyclic module
comprised of 1R,2R-(-)-transdiaminocyclohexane and
2,6-diformal-4-(1-dodec-1-ynyl)p- henol synthons, having imine
groups as the linkages (the first module in Table 1) was tested for
transport of various ionic species. The results are shown in Table
14.
16TABLE 14 Voltage-clamped bilayer test for macrocyclic module pore
size Calculated Calculated van der van der Waals Waals Does ionic
radius of radius of ionic species ionic species with one pass
through Ionic species species (.ANG.) water shell (.ANG.) pore?
Na.sup.+ 1.0 2.2 Yes K.sup.+ 1.3 2.7 Yes Ca.sup.2+ 1.0 2.7 Yes
NH.sub.4.sup.+ 1.9 2.9 Yes Cs.sup.+ 1.7 3.0 Yes MeNH.sub.3.sup.+
2.0 3.0 Yes EtNH.sub.3.sup.+ 2.6 3.6 No NMe.sub.4.sup.+ 2.6 3.6 No
Aminoguanidinium 3.1 4.1 No NEt.sub.4.sup.+ 3.9 4.4 No Choline 3.8
4.8 No Glucosamine 4.2 5.2 No
[0382] The results in Table 14 show that the cut-off for passage
through the pore in the selected module is a van der Waals radius
of between 2.0 and 2.6 .ANG.. In Table 12, the QM and MM computed
pore sizes are given as areas. Using the equation for area of a
circle, A=.pi.r.sup.2, the computed area of the pore in the first
module of Table 12, 14.3 .ANG..sup.2, gives a value for r of 2.13
.ANG.. Ions having van der Waals radii of less than 2.13 .ANG.would
be expected to traverse the pore and those with larger radii would
not, and that is what was observed. CH.sub.3NH.sub.3.sup.+, having
a radius of 2.0 .ANG., passed through the pore while
CH.sub.3CH.sub.2NH.sub.3.sup.+, with a radius of 2.6 .ANG., did
not. Without being held to a particular theory, and recognizing
that several factors influence pore transport, the observed ability
of hydrated ions to pass through the pore may be due to partial
dehydration of the species to enter the pore, transport of water
molecules and ions through the pore separately or with reduced
interaction during transport, and recoordination of water molecules
and ions after transport. The details of pore structure,
composition, and chemistry, the flexibility of the macrocyclic
module, and other interactions may affect the transport
process.
Example 23
[0383] Pore properties of 1,2-imine-linked and 1,2-amine-linked
hexamer macrocyclic modules are illustrated in Table 15. Referring
to Table 15, the bilayer clamp data indicates that the passage and
exclusion of certain species through the pore of the modules
correlates with the computational size of the pores. Further, these
surprising data show that a very small change in the placement of
atoms and/or structural features can lead to a discrete change in
transport properties and allow regulation of transport through the
pore by variation of synthons and linkages, among other
factors.
17TABLE 15 Voltage-clamped bilayer test for macrocyclic module pore
size Radius of solute with H.sub.2O (radius of 2.sup.nd hydration
Hexamer 1a Hexamer 1jh Solute Radius of shell in (1,2-imine)
(1,2-amine) species Solute parentheses) Radius = 3.3 .ANG. Radius =
3.9 .ANG. Li.sup.+ 0.6 2.0 (5.6) No Yes Na.sup.+ 1.0 2.2 Yes Yes
K.sup.+ 1.3 2.7 Yes Yes Ca.sup.+ 1.0 2.7 Yes Yes Mg.sup.2+ 0.7 2.8
(5.5) No Yes NH.sub.4.sup.+ 1.9 2.9 Yes Yes Cs.sup.+ 1.7 3 Yes Yes
MeNH.sub.3.sup.+ 2 3 Yes Yes EtNH.sub.3.sup.+ 2.6 3.6 No Yes
NMe.sub.4.sup.+ 2.6 3.6 No Yes Aminoguanidine 3.1 4.1 No Yes
Choline 3.8 4.8 No Yes NEt.sub.4.sup.+ 3.9 4.4 No No Glucosamine
4.2 5.2 No No NPr.sub.4.sup.+ -- -- -- No 276 277
Example 24
[0384] The filtration function of a membrane may be described in
terms of its solute rejection profile. The filtration function of
some nanofilm membranes is exemplified in Tables 16-17.
18TABLE 16 Example filtration function of a G-membrane MOLECULAR
SOLUTE WEIGHT PASS/NO PASS Albumin 68 kDa NP Ovalbumin 44 kDa P
Myoglobin 17 kDa P .beta..sub.2-Microglobulin 12 kDa P Insulin 5.2
kDa P Vitamin B.sub.12 1350 Da P Urea, H.sub.2O, ions <1000 Da
P
[0385]
19TABLE 17 Example filtration function of a T-membrane MOLECULAR
SOLUTE WEIGHT PASS/NO PASS .beta..sub.2-Microglobulin 12 kDa NP
Insulin 5.2 kDa NP Vitamin B.sub.12 1350 Da NP Glucose 180 Da NP
Creatinine 131 Da NP H.sub.2PO.sub.4.sup.-, HPO.sub.4.sup.2-
.apprxeq.97 Da NP HCO.sub.3 61 Da NP Urea 60 Da NP K+ 39 Da P Na+
23 Da P
[0386] The passage or exclusion of a solute is measured by its
clearance, which reflects the portion of solute that actually
passes through the membrane. The no pass symbol in Tables 16-17
indicates that the solute is partly excluded by the nanofilm,
sometimes less than 90% rejection, often at least 90% rejection,
sometimes at least 98% rejection. The pass symbol indicates that
the solute is partly cleared by the nanofilm, sometimes less than
90% clearance, often at least 90% clearance, sometimes at least 98%
clearance.
Example 25
[0387] Selective filtration and relative clearance of solutes is
exemplified in Table 18. In Table 18, the heading "high
permeability" indicates a clearance of greater than about 70-90% of
the solute. The heading "medium permeability" indicates a clearance
of less than about 50-70% of the solute. The heading "low
permeability" indicates a clearance of less than about 10-30% of
the solute.
20TABLE 18 Clearance of solutes by nanofilms Nanofilm high
permeability medium permeability low permeability Hexamer 1a
H.sub.2O, Na.sup.+, K.sup.+, Cs.sup.+ Ca.sup.2+, Mg.sup.2+,
phosphate Glucose, Li.sup.+, urea, creatinine water H.sub.2O
Glucose, Na.sup.+, K.sup.+, Ca.sup.2+, Mg.sup.2+, Li.sup.+, urea,
nanofilm phosphate creatinine ion H.sub.2O, Na.sup.+, K.sup.+,
phosphate Glucose Ca.sup.2+, Mg.sup.2+, Li.sup.+, urea, nanofilm
creatinine glucose H.sub.2O, Na.sup.+, K.sup.+, Glucose Phosphate
Ca.sup.2+, Mg.sup.2+, Li.sup.+, urea, nanofilm creatinine G
H.sub.2O, Na.sup.+, K.sup.+, phosphate, Vitamin B.sub.12, Insulin,
.beta..sub.2 Myglobin, Ovalbumin, nanofilm Glucose, Ca.sup.2+,
Mg.sup.2+, Li.sup.+, Microglobulin Albumin, urea, creatinine gas
He, H.sub.2 -- H.sub.2O and larger, liquids in nanofilm general
anion Cl.sup.- HCO.sub.3.sup.-, Phosphate -- nanofilm
Example 26
[0388] The approximate diameter of various species to be considered
in a filtration process are illustrated in Table 19:
21 solute molecular weight (Da) diameter (.ANG.) virus 10.sup.6 133
immunoglobulin G (IgG) 10.sup.5 60 albumin 50 .times. 10.sup.4 50
.beta..sub.2-Microglobulin 10.sup.3 13 urea 60.sup. -- Na.sup.+
23.sup. --
[0389] Synthon and Macrocyclic Module Syntbesis Methods
[0390] All chemical structures illustrated and described in this
specification, both in the description above and the examples
below, as well as in the figures, are intended to encompass and
include all variations and isomers of the structure which are
foreseeable, including all stereoisomers and constitutional or
configurational isomers when the illustration, description, or
figure is not explicitly limited to any particular isomer.
[0391] Methods for Preparing Cyclic Synthons
[0392] To avoid the need to separate single configurational or
enantiomeric isomers from complex mixtures resulting from
non-specific reactions, stereospecific or at least stereoselective
coupling reactions may be employed in the preparation of the
synthons of this invention. The following are examples of synthetic
schemes for severa classes of synthons useful in the preparation of
macrocyclic modules of this invention. In general, the core
synthons are illustrated, and lipophilic moieties are not shown on
the structures, however, it is understood that all of the following
synthetic schemes might encompass additional lipophilic or
hydrophilic moieties used to prepare amphiphilic and other modified
macrocyclic modules. Species are numbered in relation to the scheme
in which they appear; for example, "S1-1" refers to the structure 1
in Scheme 1.
[0393] An approach to preparing synthons of
1,3-Diaminocyclohex-5-ene is shown in Scheme 1. Enzymatically
assisted partial hydrolysis of the 278
[0394] symmetrical diester S1-1 is used to give enantiomerically
pure S1-2. S1-2 is subjected to the Curtius reaction and then
quenched with benzyl alcohol to give protected amino acid S1-3.
lodolactonization of carboxylic acid S1-4 followed by
dehyrohalogenation gives unsaturated lactone S1-6. Opening of the
lactone ring with sodium methoxide gives alcohol S1-7, which is
converted with inversion of configuration to S1-8 in a one-pot
reaction involving mesylation, SN.sub.2 displacement with azide,
reduction and protection of the resulting amine with di-tert-butyl
dicarbonate. Epimerization of S1-8 to the more stable diequatorial
configuration followed by saponification gives carboxylic acid
S1-10. S1-10 is subjected to the Curtius reaction. A mixed
anhydride is prepared using ethyl chlorofornate followed by
reaction with aqueous NaN.sub.3 to give the acyl azide, which is
thermally rearranged to the isocyanate in refluxing benzene. The
isocyanate is quenched with 2-trimethylsilylethanol to give
differentially protected tricarbamate S1-11. Reaction with
trifluoroacetic acid (TFA) selectively deprotects the 1,3-diamino
groups to provide the desired synthon S1-12.
[0395] In another variation, an approach to preparing synthons of
1,3-Diaminocyclohexane is shown in Scheme 1a. 279
[0396] Some aspects of these preparations are given in Suami et
al., J. Org. Chem. 1975, 40, 456 and Kavadias et al. Can. J. Chem.
1978, 56, 404.
[0397] In another variation, an approach to preparing synthons of
1,3-substituted cyclohexane is shown in Scheme 1b. 280
[0398] This synthon will remain "Z-protected" until the macrocyclic
module has been cyclized. Subsequent deprotection to yield a
macrocyclic module with amine functional groups is done by a
hydrogenation protocol.
[0399] Norbomanes (bicycloheptanes) may be used to prepare synthons
of this invention, and stereochemically controlled
multifunctionalization of norbomanes can be achieved. For example,
Diels-Alder cycloaddition may be used to form norbornanes
incorporating various functional groups having specific,
predictable stereochemistry. Enantiomerically enhanced products may
also be obtained through the use of appropriate reagents, thus
limiting the need for chiral separations.
[0400] An approach to preparing synthons of 1,2-Diaminonorbomane is
shown in Scheme 2. 281
[0401] 5-(Benzyloxy-methyl)-1,3-cyclopentadiene (S2-13) is reacted
with diethylaluminum chloride Lewis acid complex of di-(l)-menthyl
fumarate (S2-14) at low temperature to give the diastereomerically
pure norbomene S2-15. Saponification with potassium hydroxide in
aqueous ethanol gives the diacid S2-16, which is subjected to a
tandem Curtius reaction with diphenylphosphoryl azide (DPPA), the
reaction product is quenched with 2-trimethylsilylethanol to give
the biscarbamate S2-17. Deprotection with TFA gives diamine
S2-18.
[0402] Another approach to this synthon class is outlined in Scheme
3. Opening of anhydride S3-19 with methanol in the presence of
quinidine gives the enantiomerically pure ester acid S3-20.
Epimerization of the ester group with sodium methoxide (NaOMe)
gives S3-21. A Curtius reaction with DPPA followed by quenching
with trimethylsilylethanol gives carbamate S3-22. Saponification
with NaOH gives the acid S3-23, which undergoes a Curtius reaction,
282
[0403] than quenched with benzyl alcohol to give differentially
protected biscarbamate S3-24. Compound S3-24 can be fully
deprotected to provide the diamine or either of the carbamates can
be selectively deprotected.
[0404] An approach to preparing synthons of
endo,endo-1,3-Diaminonorbomane is shown in Scheme 4.
5-Trimethylsilyl-1,3-cyclopentadiene (S4-25) is reacted with the
diethylaluminum chloride Lewis acid complex of di-(l)-menthyl
fumarate at low temperature to give nearly diastereomerically pure
norbomene S4-26. Crystallization of S4-26 from alcohol results in
recovery of greater than 99% of the single diastereomer.
Bromolactonization followed by silver mediated rearrangement gives
mixed diester S4-28 with an alcohol moiety at the 7-position.
Protection of the alcohol with benzyl bromide and selective
deprotection of the methyl ester gives the free carboxylic acid
S4-30. A Curtius reaction results in trimethylsilylethyl carbamate
norbomene S4-31. Biscarbonylation of the olefin in methanol,
followed by a single-step deprotection and dehydration gives the
mono-anhydride S4-33. Quinidine mediated opening of the anhydride
with methanol gives S4-34. Curtius transformation of S4-34 gives
the biscarbamate S4-35, which is deprotected with TFA or
tetrabutylammonium fluoride (TBAF) to give diamine S4-36. 283
[0405] Another approach to this class of synthons is outlined in
Scheme 5. Benzyl alcohol opening of S3-19 in the presence of
quinidine gives S5-37 in high enantiomeric excess.
lodolactonization followed by NaBH.sub.4 reduction gives lactone
S5-39. Treatment with NaOMe liberates the methyl ester and the free
alcohol to generate S5-40. Transformation of the alcohol S5-40 to
the inverted t-butyl carbamate protected amine S5-41 is
accomplished in a one-pot reaction by azide deplacement of the
mesylate S5-40 follwed by reduction to the amine, which is
protected with di-tert-butyl dicarbonate. Hydrogenolytic cleavage
of the benzyl ester and epimerization of the methyl ester to the
exo configuration is followed by protection of the free acid with
benzyl breomide to give S5-44. Saponification of the methyl ester
followed by a trimethylsilylethanol quenched Curtius reaction
284
[0406] gives biscarbamate S5-46, which is cleaved with TFA to give
the desired diamine S5-47.
[0407] An approach to preparing synthons of
exo,endo-1,3-Diaminonorbornane is shown in Scheme 6.
p-Methoxybenzyl alcohol opening of norbomene anhydride S3-19 in
presence of quinidine gives monoester S6-48 in high enantiomeric
excess. Curtius reaction of the free acid gives protected all endo
monoacid-monoamine S6-49. Biscarbonylation and anhydride formation
gives exo-monoanhydride S6-51. Selective methanolysis in the
presence of quinine gives S6-52. A trimethylsiylethanol quenched
Curtius reaction gives biscarbamate S6-53. Epimerization of the two
esters results in the more sterically stable S6-54. Cleavage of the
carbamate groups provides synthon S6-55. 285
[0408] Methods to Prepare Macrocyclic Modules
[0409] Synthons may be coupled to one another to form macrocyclic
modules. In one variation, the coupling of synthons may be
accomplished in a concerted scheme. Preparation of a macrocyclic
module by the concerted route may be performed using, for example,
at least two types of synthons, each type having at least two
functional groups for coupling to other synthons. The functional
groups may be selected so that a functional group of one type of
synthon can couple only to a functional group of the other type of
synthon. When two types of synthons are used, a macrocyclic module
may be formed having alternating synthons of different types.
Scheme 7 illustrates a concerted module synthesis.
[0410] Referring to Scheme 7,1,2-Diaminocyclohexane, S7-1, is a
synthon having two amino functional groups for coupling to other
synthons, and 2,6-diformyl-4-dodec-1-ynylphenol, S7-2, is a synthon
having two formyl groups for coupling to other synthons. An amino
group may couple with a formyl group to form an imine linkage. In
Scheme 7, a concerted product hexamer macrocyclic module is
shown.
[0411] In one variation, a mixture of tetramer, hexamer, and
octamer macrocyclic modules may be formed in the concerted scheme.
The yields of these macrocyclic modules can be varied by changing
the concentration of various synthons in the reagent mixture, and
among other factors, by changing the solvent, temperature, and
reaction time. 286
[0412] The imine groups of S7-3 can be reduced, e.g. with sodium
borohydride, to give amine linkages. If the reaction is carried out
using 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol instead of
2,6-diformyl-4-dodec-1-ynylphenol, the resulting module will
contain amide linkages. Similarly, if 1,2-dihydroxycyclohexane is
reacted with 2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol, the
resulting module will contain ester linkages.
[0413] In some variations, the coupling of synthons may be
accomplished in a stepwise scheme. In an example of the stepwise
preparation of macrocyclic modules, a first type of synthon is
substituted with one protected functional group and one unprotected
functional group. A second type of synthon is substituted with an
unprotected functional group that will couple with the unprotected
functional group on the first synthon. The product of contacting
the first type of synthon with the second type of synthon may be a
dimer, which is made of two coupled synthons. The second synthon
may also be substituted with another functional group which is
either protected, or which does not couple with the first synthon
when the dimer is formed. The dimer may be isolated and purified,
or the preparation may proceed as a one-pot method. The dimer may
be contacted with a third synthon having two functional groups,
only one of which may couple with the remaining functional group of
either the first or second synthons to form a trimer, which is made
of three coupled synthons. Such stepwise coupling of synthons may
be repeated to form macrocyclic modules of various ring sizes. To
cyclize or close the ring of the macrocyclic module, the n.sup.th
synthon which was coupled to the product may be substituted with a
second functional group which may couple with the second functional
group of a previously coupled synthon that has not been coupled,
which may be deprotected for that step. The stepwise method may be
carried out with synthons on solid phase support. Scheme 8
illustrates a stepwise preparation of module SC8-1.
[0414] Compound S8-2 is reacted with S8-3, in which the phenol is
protected as the benzyl ether and the nitrogen is shown as
protected with a group "P," which can be any of a large number of
protecting groups well-known in the art, in the presence of
methanesulfonyl chloride (Endo, K.; Takahashi, H. Heterocycles,
1999, 51, 337), to give S8-4. Removal of the N-protecting group
give the free amine S8-5, which can be coupled with synthon S8-6
using any standard peptide coupling reaction such as BOP/HOBt to
give S8-7. Deprotection/coupling is repeated, alternating synthons
S8-3 and S8-6 until a linear construct with eight residues is
obtained. The remaining acid and amine protecting groups on the
8-mer are removed and the oligomer is cyclized, see e.g., Caba, J.
M., et al., J. Org. Chem., 2001, 66:7568 (PyAOP cyclization) and
Tarver, J. E. et al., J. Org. Chem., 2001, 66:7575 (active ester
cyclization). The R group is H or an alkyl group linked via a
functional group to the benzene ring, and X is N, O, or S. Examples
of solid supports include Wang resin, hydrogels, silica gels,
sepharose, sephadex, agarose, and inorganic solids. Using a solid
support might simplify the procedure by obviating purification of
intermediates along the way. The final cyclization may be done in a
solid phase mode. A "safety-catch linker" approach (Bourne, G. T.,
et al., J. Org. Chem., 2001, 66:7706) may be used to obtain
cyclization and resin cleavage in a single operation. 287
[0415] In another variation, a concerted method involves contacting
two or more different synthons and a linker molecule as shown in
Scheme 9, where R may be an alkyl group or other lipophilic group.
288
[0416] In another variation, a stepwise linear method involves
various synthons and a soil phase support as shown in Scheme 10.
289290291292
[0417] In another variation, a stepwise convergent method involves
synthon trimers and a solid phase support as shown in Scheme 11.
This method can also be done without the solid phase support using
trimers in solution. 293
[0418] In another variation, a template method involves synthons
brought together by a template as shown in Scheme 12. Some aspects
of this approach (and an Mg2+ template) are given in Dutta et al.
Inorg. Chem. 1998, 37, 5029. 294
[0419] In another variation, a linker molecule method involves
cyclizing synthons in solution as shown in Scheme 13. 295
[0420] Reagents for the following examples were obtained from
Aldrich Chemical Company and VWR Scientific Products. All reactions
were carried out under nitrogen or argon atmosphere unless
otherwise noted. Solvent extracts of aqueous solutions were dried
over anhydrous Na.sub.2SO.sub.4. Solutions were concentrated under
reduced pressure using a rotary evaporator. Thin layer
chromatography (TLC) was done on Analtech Silica gel GF (0.25 mm)
plates or on Machery-Nagel Alugram Sil G/UV (0.20 mm) plates.
Chromatograms were visualized with either UV light, phosphomolybdic
acid, or KMnO.sub.4. All compounds reported were homogenous by TLC
unless otherwise noted. HPLC analyses were performed on a Hewlett
Packard 1100 system using a reverse phase C-18 silica column.
Enantiomeric excess was determined by HPLC using a reverse phase
(l)-leucine silica column from Regis Technologies. All .sup.1[H]
and .sup.13[C] NMR spectra were collected at 400 MHz on a Varian
Mercury system. Electrospray mass spectra were obtained by Synpep
Corp., or on a Thermo Finnigan LC-MS system.
Example 27
[0421] 2,6-Diformyl-4-bromophenol
[0422] Hexamethylenetetramine (73.84 g, 526 mmol) was added to TFA
(240 mL) with stirring. 4-Bromophenol (22.74 g, 131 mmol) was added
in one portion and the solution heated in an oil bath to
120.degree. C. and stirred under argon for 48 h. The reaction
mixture was then cooled to ambient temperature. Water (160 mL) and
50% aqueous H.sub.2SO.sub.4 (80 mL) were added and the solution
stirred for an additional 2 h. The reaction mixture was poured into
water (1600 mL) and the resulting precipitate collected on a
Buichner funnel. The precipitate was dissolved in ethyl acetate
(EtOAc) and the solution was dried over MgSO.sub.4. The solution
was filtered and the solvent removed on a rotary evaporator.
Purification by column chromatography on silica gel (400 g) using a
gradient of 15-40% ethyl acetate in hexanes resulted in a isolation
of the product as a yellow solid (18.0 g, 60%).
[0423] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.54 (s, 1 H,
OH), 10.19 (s, 2 H, CHO), 8.08 (s, 2 H, ArH).
Example 28
[0424] 2,6-Diformyl-4-(dodecyn-1-yl)phenol
[0425] 2,6-Diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecyne
(2.00 g, 12.0 mmol), CuI (65 mg, 0.33 mmol), and
bis(triphenylphosphine)palladium)- II) dichloride were suspended in
degassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL).
The yellow suspension was sparged with argon for 30 min and
degassed Et.sub.3N (1 mL) was added. The resulting brown suspension
was sealed in a pressure vial, warmed to 80.degree. C. and held
there for 12 h. The mixture was then partitioned between EtOAc and
KHSO.sub.4 solution. The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and concentrated under reduced pressure.
The dark yellow oil was purified by column chromatography on silica
gel (25% Et.sub.2O in hexanes) to give 1.56 g (46%) of the title
compound.
[0426] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.11.64 (s, 1 H, OH),
10.19 (s, 2 H, CHO), 7.97 (s, 2 H, ArH), 2.39 (t, 2 H, J=7.2 Hz,
propargylic), 1.59 (m, 3 H, aliphatic), 1.43, (m, 2 H, aliphatic),
1.28 (m, 11 H, aliphatic), 0.88 (t, 3 H, J=7.0 Hz, CH.sub.3).
[0427] .sup.13C NMR (400 MHz, CDCl.sub.3) .delta. 192.5, 162.4,
140.3, 122.8, 116.7, 91.4, 77.5 31.9 29.6, 29.5, 29.3, 29.1, 28.9,
28.5, 22.7, 19.2, 14.1.
[0428] MS (FAB): Calcd. for C.sub.20H.sub.27O.sub.3 315.1960; found
315.1958 [M+H].sup.+.
Example 29
[0429] 2,6-Diformyl-4-(dodecen-1-yl)phenol
[0430] 2,6-Diformyl-4-bromophenol (1.00 g, 4.37 mmol), 1-dodecene
(4.8 mL, 21.7 mmol), 1.40 g tetrabutylammonium bromide (4.34 mmol),
0.50 g NaHCO.sub.3 (5.95 mmol), 1.00 g LiCl (23.6 mmol) and 0.100 g
palladium diacetate (Pd(OAc).sub.2) (0.45 mmol) were combined in 30
mL degassed anhydrous dimethylformamide (DMF). The mixture was
sparged with argon for 10 min and then sealed in a pressure vial
which was warmed to 82.degree. C. and held for 40 h. The crude
reaction mixture was partitioned between CH.sub.2Cl.sub.2 and 0.1 M
HCl solution. The organic layer was washed with 0.1 M HCl
(2.times.), brine (2.times.), and saturated aqueous NaHCO.sub.3
(2.times.), dried over MgSO.sub.4 and concentrated under reduced
pressure. The dark yellow oil was purified by column chromatography
on silica gel (25% hexanes in Et.sub.2O) to give 0.700 g (51%) of
the title compound as primarily the Z isomer.
[0431] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.11.50 (s, 1 H, OH),
10.21 (s, 2 H, CHO), 7.95 (s, 2 H, ArH), 6.38 (d, 1 H, vinyl), 6.25
(m, 1 H, vinyl), 2.21 (m, 2 H, allylic), 1.30-1.61 (m, 16 H,
aliphatic), 0.95 (t, 3 H, J=7.0 Hz, CH.sub.3).
[0432] MS (FAB): Calcd. for C.sub.20H.sub.27O.sub.3 315.20; found
315.35 [M-H].sup.-.
Example 30
[0433] (1R,6S)-6-Methoxycarbonyl-3-cyclohexene-1-carboxylic Acid
(S1-2)
[0434] S1-1 (15.0 g, 75.7 mmol) was suspended in pH 7 phosphate
buffer (950 mL). Pig liver esterase (2909 units) was added, and the
mixture stirred at ambient temperature for 72 h with the pH
maintained at 7 by addition of 2M NaOH. The reaction mixture was
washed with ethyl acetate (200 mL), acidified to pH 2 with 2M HCl,
and extracted with ethyl acetate (3.times.200 mL). The extracts
were combined, dried, and evaporated to afford 13.8 g (99%) of
S1-2.
[0435] .sup.1H NMR: (CDCl.sub.3) .delta. 2.32 (dt, 2 H, 2.sub.ax-
and 5.sub.ax-H's), 2.55 (dt, 2 H, .sup.2.sub.eq- and 5.sub.eq-H's),
3.00 (m, 2 H, 1- and 6-H's), 3.62 (s, 3 H, CO.sub.2Me), 5.61 (m, 2
H, 3- and 4-H's).
Example 31
[0436] Methyl (1S,
6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylate (S1-3)
[0437] S1-2 (10.0 g, 54.3 mmol) was dissolved in benzene (100 mL)
under N.sub.2. Triethylamine (13.2 g, 18.2 mL, 130.3 mmol) was
added followed by DPPA (14.9 g, 11.7 mL, 54.3 mmol). The solution
was refluxed for 20 h. Benzyl alcohol (5.9 g, 5.6 mL, 54.3 mmol)
was added and reflux continued for 20 h. The solution was diluted
with EtOAc (200 mL), washed with saturated aqueous NaHCO.sub.3
(2.times.50 mL), water (20 mL), and saturated aqueous NaCl (20 mL),
dried and evaporated to give 13.7 g (87%) of S1-3.
[0438] .sup.1H NMR: (CDCl.sub.3) .delta. 2.19 (dt, 1 H,
5.sub.ax-H), 2.37 (tt, 2 H, 2.sub.ax- and 5.sub.eq-H's), 2.54 (dt,
1 H, 2.sub.eq-H), 2.82 (m, 1 H, 1-H), 3.65 (s, 3 H, CO.sub.2Me),
4.28 (m, 1 H, 6-H), 5.08 (dd, 2 H, CH.sub.2Ar), 5.42 (d, 1 H, NH),
5.62 (ddt, 2 H, 3- and 4-H's), 7.35 (mn, 5 H, Ar H's).
Example 32
[0439] (1S, 6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylic
acid (S1-4)
[0440] S1-3 (23.5 g, 81.3 mmol) was dissolved in MeOH (150 mL) and
the solution cooled to 0.degree. C. 2M NaOH (204 mL, 0.41 mol) was
added, the mixture allowed to come to ambient temperature and then
it was stirred for 48 h. The reaction mixture was diluted with
water (300 mL), acidified with 2M HCl, and extracted with
dichloromethane (250 mL), dried, and evaporated. The residue was
recrystallized from diethyl ether to give 21.7 (97%) of S1-4.
[0441] .sup.1H NMR: (CDCl.sub.3) .delta. 2.20 (d, 1 H, 5.sub.ax-H),
2.37 (d, 2 H, 2.sub.ax- and 5.sub.eq-H's), 2.54 (d, 1 H,
.sup.2.sub.eq-H), 2.90 (br s, 1 H, 1-H), 4.24 (br s, 1 H, 6-H),
5.08 (dd, 2 H, CH.sub.2Ar), 5.48 (d, 1 H, NH), 5.62 (dd, 2 H, 3-
and 4-H's), 7.35 (m, 5 H, Ar H's).
Example 33
[0442]
(1S,2R,4R,5R)-2-Benzyloxycarbonylamino-4-iodo-7-oxo-6-oxabicyclo[3.-
2.1]octane (S1-5)
[0443] S1-4 (13.9 g, 50.5 mmol) was dissolved in dichloromethane
(100 mL) under N.sub.2, 0.5 M NaHCO.sub.3 (300 mL), KI (50.3 g,
303.3 mmol), and iodine (25.6 g, 101 mmol) were added and the
mixture stirred at ambient temperature for 72 h. The mixture was
diluted with dichloromethane (50 mL) and the organic phase
separated. The organic phase was washed with saturated aqueous
Na.sub.2S.sub.2O.sub.3 (2.times.50 mL), water (30 mL), and
saturated aqueous NaCl (20 mL), dried and evaporated to afford 16.3
g (80%) of S1-5.
[0444] .sup.1H NMR: (CDCl.sub.3) .delta. 2.15 (m, 1 H, 8.sub.ax-H),
2.42 (m, 2 H, 3.sub.ax- and 8.sub.eq-H's), 2.75 (m, 2 H, 1- and
3.sub.eq-H's), 4.12 (br s, 1 H, 2-H), 4.41 (t, 1 H, 4-H), 4.76 (dd,
1 H, 5-H), 4.92 (d, 1 H, NH), 5.08 (dd, 2 H, CH.sub.2Ar), 7.35 (m,
5 H, Ar H's).
Example 34
[0445]
(1S,2R,5R)-2-Benzyloxycarbonylamino-7-oxo-6-oxabicyclo[3.2.1]oct-3--
ene (S1-6).
[0446] S1-5 (4.0 g, 10 mmol) was dissolved in benzene (50 mL) under
N.sub.2. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.8 g, 12 mmol)
was added and the solution refluxed for 16 h. The precipitate was
filtered and the filtrate was diluted with EtOAc (200 mL). The
filtrate was washed with 1M HCl (20 mL), saturated aqueous
Na.sub.2S.sub.2O.sub.3 (20 mL), water (20 mL), and saturated
aqueous NaCl (20 mL), dried and evaporated to give 2.2 g (81%)
S1-6.
[0447] .sup.1H NMR: (CDCl.sub.3) .delta. 2.18 (d, 1 H, 8.sub.ax-H),
2.39 (m, 1 H, 8.sub.eq-H), 3.04 (t, 1 H, 1-H), 4.70 (m, 1 H, 5-H),
4.82 (t, 1 H, 2-H), 5.15 (dd, 3 H, CH.sub.2Ar and NH), 5.76 (d, 1
H, 4-H), 5.92 (m, 1 H, 3-H), 7.36 (s, 5 H, Ar H's).
Example 35
[0448] (1S,2R,5R)-Methyl
2-Benzyloxycarbonylamino-5-hydroxycyclohex-3-enec- arboxylate
(S1-7)
[0449] S1-6 (9.0 g, 33 mmol) was suspended in MeOH (90 mL) and
cooled to 0.degree. C. NaOMe (2.8 g, 52.7 mmol) was added and the
mixture stirred for 3 h during which time a solution gradually
formed. The solution was neutralized with 2M HCl, diluted with
saturated aqueous NaCl (200 mL), and extracted with dichloromethane
(2.times.100 mL). The extracts were combined, washed with water (20
mL) and saturated aqueous NaCl (20 ml), dried, and evaporated. The
residue was flash chromatographed (silica gel (250 g), 50:50
hexane/EtOAc) to give 8.5 g (85%) of S1-7.
[0450] .sup.1H NMR: (CDCl.sub.3) .delta. 1.90 (m, 1 H, 6.sub.ax-H),
2.09 (m, 1 H, 6.sub.eq-H), 2.81 (m, 1 H, 1-H), 3.55 (s, 3 H,
CO.sub.2Me), 4.15 (m, 1 H, 5-H), 4.48 (t, 1 H, 2-H), 5.02 (dd, 2 H,
CH.sub.2Ar), 5.32 (d, 1 H, NH), 5.64 (dt, 1 H, 4-H), 5.82 (dt, 1 H,
3-H), 7.28 (s, 5 H, Ar H's).
Example 36
[0451] (1S,2R,5S)-Methyl
2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminoc-
yclohex-3-enecarboxylate (S1-8).
[0452] S1-7 (7.9 g, 25.9 mmol) was dissolved in dichloromethane
(150 mL) and cooled to 0.degree. C. under N.sub.2. Triethylamine
(6.3 g, 8.7 mL, 62.1 mmol) and methanesulfonyl chloride (7.1 g,
62.1 mmol) were added and the mixture stirred at 0.degree. C. for 2
h. (n-Bu).sub.4NN.sub.3 (14.7 g, 51.7 mmol) in dichloromethane (50
mL) was added and stirring continued at 0.degree. C. for 3 h
followed by 15 h at ambient temperature. The mixture was cooled to
0.degree. C. and P(n-Bu).sub.3 (15.7 g, 19.3 mL, 77.7 mmol) and
water (1 mL)were added and the mixture stirred at ambient
temperature for 24 h. Di-tert-butyl dicarbonate (17.0 g, 77.7 mmol)
was added and stirring continued for 24 h. The solvent was removed,
the residue dissolved in 2:1 hexane/EtOAc (100 mL), the solution
filtered, and evaporated. The residue was flash chromatographed
(silica gel (240 g), 67:33 hexane/EtOAc) to give 5.9 g (56%) of
S1-8.
[0453] .sup.1H NMR: (CDCl.sub.3) .delta. 1.40 (s, 9 H, Boc H's),
1.88 (m, 1 H, 6.sub.ax-H), 2.21 (m, 1 H, 6.sub.eq-H), 2.95 (m, 1 H,
1-H), 3.60 (s, 3 H, CO.sub.2Me), 4.15 (d, 1 H, Boc NH), 4.50 (m, 2
H, 2- and 5-H's), 5.02 (s, 2 H, CH.sub.2Ar), 5.38 (d, 1 H, Z NH),
5.65 (m, 2 H, 3- and 4-H's), 7.30 (s, 5 H, Ar H's).
Example 37
[0454] (1R,2R,5S)-Methyl
2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminoc-
yclohex-3-enecarboxylate (S1-9)
[0455] S1-8 (1.1 g, 2.7 mmol) was suspended in MeOH (50 mL). NaOMe
(0.73 g, 13.6 mmol) was added and the mixture refluxed for 18 h
after which 0.5 M NH.sub.4Cl (50 mL) was added and the resulting
precipitate collected. The filtrate was evaporated and the residue
triturated with water (25 mL). The insoluble portion was collected
and combined with the original precipitate to give 0.85 g (77%) of
S1-9.
[0456] .sup.1H NMR: (CDCl.sub.3) .delta. 1.38 (s, 9 H, Boc H's),
1.66 (m, 1 H, 6.sub.ax-H), 2.22 (d, 1 H, 6.sub.eq-H), 2.58 (t, 1 H,
1-H), 3.59 (3, 3 H, CO.sub.2Me), 4.22 (br s, 1 H, Boc NH), 4.50 (m,
2 H, 2- and 5-H's), 4.75 (d, 1 H, Z NH), 5.02 (s, 2 H, CH.sub.2Ar),
5.62 (s, 2 H, 3- and 4-H's), 7.30 (s, 5 H, Ar H's).
Example 38
[0457]
(1R,2R,5S)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-
-3-enecarboxylic acid (S1-10)
[0458] S1-9 (0.85 g, 2.1 mmol) was suspended in 50:50
MeOH/dichloromethane (5 mL) and cooled to 0.degree. C. under
N.sub.2 after which 2M NaOH (2.0 mL) was added and the mixture
stirred at ambient temperature for 16 h. The mixture was acidified
with 2M HCl upon which a white precipitate formed. The precipitate
was collected, washed with water and hexane, and dried to give 0.74
g (90%) of S1-10.
[0459] .sup.1H NMR: (CD.sub.3OD) .delta. 1.42 (s, 9 H, Boc H's),
1.66 (m, 1 H, 6.sub.ax-H), 2.22 (d, 1 H, 6.sub.eq-H), 2.65 (t, 1 H,
1-H), 4.18 (m, 1 H, 5-H), 4.45 (m, 1 H, 5-H), 5.04 (s, 2 H,
CH.sub.2Ar), 5.58 (m, 2 H, 3- and 4-H's), 7.35 (s, 5 H, Ar
H's).
Example 39
[0460]
(1R,2R,5S)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylamino-1-(2-tr-
imethylsilyl)ethoxycarbonylaminocyclohex-3-ene (S1-11)
[0461] S1-10 (3.1 g, 7.9 mmol) was dissolved in THF (30 mL) under
N.sub.2 and cooled to 0.degree. C. Triethylamine (1.6 g, 2.2 mL,
15.9 mmol) was added followed by ethyl chloroformate (1.3 g, 1.5
mL, 11.8 mmol). The mixture was stirred at 0.degree. C. for 1 h. A
solution of NaN.sub.3 (1.3 g, 19.7 mmol) in water (10 mL) was added
and stirring at 0.degree. C. was continued for 2 h. The reaction
mixture was partitioned between EtOAc (50 mL) and water (50 mL).
The organic phase was separated, dried, and evaporated. The residue
was dissolved in benzene (50 mL) and refluxed for 2 h.
2-Trimethylsilylethanol (1.0 g, 1.2 mL, 8.7 mmol) was added and
reflux continued for 3 h. The reaction mixture was diluted with
EtOAc (200 mL), washed with saturated aqueous NaHCO.sub.3 (50 mL),
water (20 mL), and saturated aqueous NaCl (20 mL), dried and
evaporated. The residue was flash chromatographed (silica gel (100
g), 67:33 hexane/EtOAc) to give 3.1 g (77%) of S1-11.
[0462] .sup.1H NMR: (CDCl.sub.3) .delta. -0.02 (s, 9 H, TMS), 0.90
(t, 3 H, CH.sub.2TMS), 1.40 (s, 9 H, Boc H's), 2.38 (m, 1 H,
.sup.6.sub.eq-H), 3.62 (m, 1 H, 1-H), 4.08 (m, 2 H,
OCH.sub.2CH.sub.2TMS), 4.18 (m, 1 H), 4.38 (m, 1 H), 4.62 (m, 1 H),
5.07 (dd, 2 H, CH.sub.2Ar), 5.18 (m, 1 H), 5.26 (m, 1 H), 5.58 (d,
1 H, olefinic H), 5.64 (d, 2 H, olefinic H), 7.30 (s, 5, Ar
H's).
Example 40
[0463]
(1R,2R,5S)-2-Benzyloxycarbonylamino-1,5-diaminocyclohex-3-ene
(S1-12)
[0464] S1-11 (2.5 g, 4.9 mmol) was added to TFA (10 mL) and the
solution stirred at ambient temperature for 16 h after which the
solution was evaporated. The residue was dissolved in water (20
mL), basified to pH 14 with KOH and extracted with dichloromethane
(3.times.50 mL). The extracts were combined, washed with water (20
mL), dried and evaporated to give 1.1 g (85%) of S1-12.
[0465] .sup.1H NMR: (CDCl.sub.3) .delta. 1.30 (m, 1 H, 6.sub.ax-H),
2.15 (br d, 1 H, 6.sub.eq-H), 2.68 (m, 1 H, 1-H), 3.42 (br s, 1 H,
5-H), 3.95 (m, 1 H, 2-H), 4.85 (d, 1 H, Z NH), 5.08 (t, 2 H,
CH.sub.2Ar), 5.45 (d, 1 H, 4-H), 5.62 (d, 1 H, 3-H), 7.32 (s, 5 H,
Ar H's). ESCI MS m/e 262 M+1.
Example 41
[0466] Isolation of S1b-2 was accomplished using the following
procedure: Using Schlenk technique 5.57 g (10.0 mmol) of methyl
ester compound, S1b-1, was dissolved in 250 mL of THF. In another
flask LiOH (1.21 g, 50.5 mmol) was dissolved in 50 mL water and
de-gassed by bubbling N.sub.2 through the solution using a needle
for 20 minutes. The reaction was started transferring the base
solution into the flask containing S1b-1 over one minute with rapid
stirring. The mixture was stirred at room temperature and work-up
initiated when the starting material S1b-1 was completely consumed
(Using a solvent system of 66% EtOAc/33% Hexane and developing with
phosphomolybdic acid reagent (Aldrich #31,927-9) the starting
material S1b-1 has an Rf of 0.88 and the product streaks with an Rf
of approx. 0.34 to 0.64.). The reaction usually takes 2 days.
Work-Up: The THF was removed by vacuum transfer until about the
same volume is left as water added to the reaction, in this case 50
mL. During this the reaction solution forms a white mass that
adheres to the stir bar surrounded by clear yellow solution. As the
THF is being removed a separatory funnel is set up including a
funnel to pour in the reaction solution and an Erlenmeyer flask is
placed underneath the separatory funnel. Into the Erlenmeyer flask
is added some anhydrous Na.sub.2SO.sub.4. This apparatus should be
set up before acidification is started. (It is important to set up
the separatory funnel and Erlenmeyer flask etc. before
acidification of the reaction solution to enable separation of
phases and extraction of the product away from the acid quickly
once the solution attains a pH close to 1. If the separation is not
preformed rapidly the Boc functional group will be hydrolyzed
significantly reducing the yield.) Once the volatiles are
sufficiently removed, CH.sub.2Cl.sub.2 (125 mL) and water (65 mL)
are added and the reaction flask cooled in an ice bath. The
solution is stirred rapidly and 5 mL aliquots of 1N HCl are added
by syringe and the reaction solution tested with pH paper. Acid is
added until the spot on the pH paper shows red (not orange) around
the edge indicating a pH is 1 to 2 has been achieved (The solution
being tested is a mixture of CH.sub.2Cl.sub.2 and water so the pH
paper will show the accurate measurement at the edge of the spot
and not the center.) and the phases are separated by quickly
pouring the solution into the separatory funnel. As the phases
separate the stopcock is turned to release the CH.sub.2Cl.sub.2
phase (bottom) into the Erlenmeyer flask and swirl the flask to
allow the drying agent to absorb water in the solution. (At this
scale of this procedure 80 mL of 1N HCl was used.) Soon after phase
separation the aqueous phase is extracted with CH.sub.2Cl.sub.2
(2.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4 and the
volatiles removed to produce 5.37 g/9.91 mmoles of a beautiful
white microcrystals reflecting a 99.1% yield. This product can not
be purified by chromatography since that process would also
hydrolyze the Boc functional group on the column.
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.33, 7.25 (5H, m,
Ph), 6.30 (1H, d, NH), 5.97 (1H, d, NH), 5.10 (2H, m, CH.sub.2Ph),
4.90 (1H, d, NH), 3.92, 3.58, 3.49 (1H, m, CHNH), 2.96, 2.48, 2.04,
1.95, 1.63 (1H, m, CH.sub.2CHNH), 1.34 (9H, s, CCH.sub.3).
[0468] IR (crystalline, cm.sup.-1) 3326 br w, 3066 w, 3033 w, 2975
w, 2940 w sh, 1695 vs, 1506 vs, 1454 m sh, 1391 w, 1367 m, 1300 m
sh, 1278 m sh, 1236 s, 1213 w sh, 1163 vs, 1100 w, 1053 m, 1020 m,
981 w sh, 910 w, 870 m, 846 w, 817 w, 775 w sh, 739 m, 696 m.
Example 42
[0469] Di-(l)-menthyl
bicyclo[2.2.1]hept-5-ene-7-anti-(trimethylsilyl)-2-e-
ndo-3-exo-dicarboxylate (S4-26)
[0470] To a solution of S4-25 (6.09 g, 0.0155 mol) in toluene (100
mL) was added diethylaluminum chloride (8.6 mL of a 1.8 M solution
in toluene) at -78.degree. C. under nitrogen and the mixture was
stirred for 1 hour. To the resulting orange solution was added
S2-14 (7.00 g, 0.0466 mol) dropwise as a -78.degree. C. solution in
toluene (10 mL). The solution was kept at -78.degree. C. for 2
hours, followed by slow warming to room temperature overnight. The
aluminum reagent was quenched with a saturated solution of ammonium
chloride (50 mL). The aqueous layer was separated and extracted
with methylene chloride (100 mL) which was subsequently dried over
magnesium sulfate. Evaporation of the solvent left a yellow solid
that was purified by column chromatography (10% ethyl
acetate/hexanes) to give S4-26 as a while solid (7.19 g, 0.0136
mol, 87% yield).
[0471] .sup.1H NMR: (CDCl.sub.3) .delta. -0.09 (s, 9 H,
SiMe.sub.3), 0.74-1.95 (multiplets, 36 H, menthol), 2.72 (d, 1 H,
.alpha.-menthyl carbonyl CH), 3.19 (bs, 1 H, bridgehead CH), 3.30
(bs, 1 H, bridgehead CH), 3.40 (t, 1 H, .alpha.-menthyl carbonyl
CH), 4.48 (d of t, 1 H, .alpha.-menthyl ester CH), 4.71 (d of t, 1
H, .alpha.-menthyl ester CH), 5.92 (d of d, 1 H, CH.dbd.CH), 6.19
(d of d, 1 H, CH.dbd.CH).
Example 43
[0472]
5-exo-Bromo-3-exo-(l)-menthylcarboxybicyclo[2.2.1]heptane-7-anti-(t-
rimethylsilyl)-2,6-carbolactone (S4-27)
[0473] A solution of bromine (3.61 g, 0.0226 mol) in methylene
chloride (20 mL) was added to a stirring solution of S4-26 (4.00 g,
0.00754 mol) in methylene chloride (80 mL). Stirring was continued
at room temperature overnight. The solution was treated with 5%
sodium thiosulfate (150 mL), and the organic layer separated and
dried over magnesium sulfate. The solvent was evaporated at reduced
pressure, and the crude product purified by column chromatography
(5% ethyl acetate/hexanes) to give S4-27 as a white solid (3.53 g,
0.00754 mol, 99% yield).
[0474] .sup.1H NMR: (CDCl.sub.3) .delta. -0.19 (s, 9 H,
SiMe.sub.3), 0.74-1.91 (multiplets, 18 H, menthol), 2.82 (d, 1 H,
.alpha.-lactone carbonyl CH), 3.14 (bs, 1 H, lactone bridgehead
CH), 3.19 (d of d, 1 H, bridgehead CH), 3.29 (t, 1 H,
.alpha.-menthyl carbonyl CH), 3.80 (d, 1 H, .alpha.-lactone ester),
4.74 (d of t, 1 H, .alpha.-menthyl ester CH), 4.94 (d, 1 H, bromo
CH).
Example 44
[0475]
Bicyclo[2.2.1]hept-5-ene-7-syn-(hydroxy)-2-exo-methyl-3-endo-(l)-me-
nthyl dicarboxylate (S4-28)
[0476] S4-27 (3.00 g, 0.00638 mol) was dissolved in anhydrous
methanol (150 mL), silver nitrate (5.40 g, 0.0318 mol) added and
the suspension refluxed for 3 days. The mixture was cooled,
filtered through Celite and the solvent evaporated to give an oily
residue. Purification by column chromatography gave S4-28 as a
light yellow oil (1.72 g, 0.00491 mol, 77% yield).
[0477] .sup.1H NMR: (CDCl.sub.3) .delta. 0.75-2.02 (multiplets, 18
H, menthol), 2.83 (d, 1 H, .alpha.-menthyl carbonyl CH), 3.03 (bs,
1 H, bridgehead CH), 3.14 (bs, 1 H, bridgehead CH), 3.53 (t, 1 H,
.alpha.-methyl carbonyl CH), 3.76 (s, 3 H, CH.sub.3), 4.62 (d of t,
1 H, .alpha.-menthyl ester CH), 5.87 (d of d, 1 H, CH.dbd.CH), 6.23
(d of d, 1 H, CH.dbd.CH).
Example 45
[0478]
2-exo-Methyl-3-endo-(l)-menthylbicyclo[2.2.1]hept-5-ene-7-syn-(benz-
yloxy) dicarboxylate (S4-29)
[0479] Benzyl bromide (1.20 g, 0.0070 mol) and silver oxide (1.62
g, 0.0070 mol) were added to a stirring solution of S4-28 (0.490 g,
0.00140 mol) in DMF (25 mL). The suspension was stirred overnight
and then diluted with ethyl acetate (100 mL). The solution was
washed repeatedly with water followed by 1 N lithium chloride. The
organic layer was separated and dried with magnesium sulfate. The
solvent was evaporated under reduced pressure and the crude product
was purified by column chromatography on silica gel to give S4-29
as an oil (0.220 g, 0.000500 mol, 36% yield).
[0480] .sup.1H NMR: (CDCl.sub.3) .delta. 0.74-2.08 (multiplets, 18
H, menthol), 2.83 (d, 1 H, .alpha.-menthyl carbonyl CH), 3.18 (bs,
1 H, bridgehead CH), 3.44 (bs, 1 H, bridgehead CH), 3.52 (t, 1 H,
bridge CH), 3.57 (s, 3 H, CH.sub.3), 3.68 (t, 1 H, .alpha.-methyl
carbonyl CH), 4.42 (d of d, 2 H, benzyl --CH.sub.2--), 4.61 (d of
t, 1 H, .alpha.-menthyl ester CH), 5.89 (d of d, 1 H, CH.dbd.CH),
6.22 (d of d, 1 H, CH.dbd.CH), 7.25-7.38 (m, 5 H,
C.sub.6H.sub.5).
Example 46
[0481]
Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exocarboxy-3-endo-(l)--
menthyl carboxylate (S4-30)
[0482] S4-29 (0.220 g, 0.00050 mol) was added to a mixture of
tetrahydrofuran (1.5 mL), water (0.5 mL), and methanol (0.5 mL).
Potassium hydroxide (0.036 g, 0.00065 mol) was added and the
solution stirred at room temperature overnight. The solvent was
evaporated under reduced pressure and the residue purified by
column chromatography (10% ethyl acetate/hexanes) to give S4-30
(0.050 g, 0.00012 mol, 23% yield).
[0483] .sup.1H NMR: (CDCl.sub.3) .delta. 0.73-2.01 (multiplets, 18
H, menthol), 2.85 (d, 1 H, .alpha.-menthyl carbonyl CH), 3.18 (bs,
1 H, bridgehead CH), 3.98 (bs, 1 H, bridgehead CH), 3.53 (bs, 1 H,
bridge CH), 3.66 (t, 1 H, .alpha.-methyl carbonyl CH), 4.44 (d of
d, 2 H, benzyl --CH.sub.2--), 4.63 (d of t, 1 H, .alpha.-menthyl
ester CH), 5.90 (d of d, 1 H, CH.dbd.CH), 6.23 (d of d, 1 H,
CH.dbd.CH), 7.25-7.38 (m, 5 H, C.sub.6H.sub.5).
[0484] Mass Spec: calculated for C.sub.26H.sub.34O.sub.5 426.24;
found 425.4 (M-1) and 851.3 (2M-1).
Example 47
[0485]
Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exo-(trimethylsilyleth-
oxycarbonyl)-amino-3-endo-(l)-menthyl carboxylate (S4-31)
[0486] To a solution of S4-30 in benzene is added triethylamine and
diphenylphosphoryl azide. The solution is refluxed for 24 hours
then cooled to room temperature. Trimethylsilylethanol is added,
and the solution refluxed for an additional 48 hours. The benzene
solution is partitioned between ethyl acetate and 1 M sodium
bicarbonate. The organic layers are combined, washed with 1 M
sodium bicarbonate and dried over sodium sulfate. The solvent is
evaporated under reduced pressure to give the crude Curtius
reaction product.
Example 48
[0487]
Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxy-
carbonyl)-amino-3-endo-(l)-menthyl-5-exo-methyl-6-exo-methyl
tricarboxylate (S4-32)
[0488] S4-31, dry copper(II) chloride, 10% Pd/C, and dry methanol
are added to a flask with vigorous stirring. After degassing, the
flask is charged with carbon monoxide to a pressure just above 1
atm., which is maintained for 72 hours. The solids are filtered and
the residue worked up in the usual way to afford the
biscarbonylation product.
Example 49
[0489]
Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxy-
carbonyl)-amino-3-endo-(l)-menthylcarbox-5-exo-6-exo-dicarboxylic
anhydride (S4-33)
[0490] A mixture of S4-32, formic acid, and a catalytic amount of
p-toluenesulfonic acid is stirred at 90.degree. C. overnight.
Acetic anhydride is added and the reaction mixture refluxed for 6
hours. Removal of the solvents and washing with ether gives the
desired anhydride.
Example 50
[0491]
Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxy-
carbonyl)-amino-3-endo-(l)-menthyl-6-exo-carboxy-5-exo-methyl
dicarboxylate (S4-33)
[0492] To a solution of S4-32 in equal amounts of toluene and
carbon tetrachloride is added quinidine. The suspension is cooled
to 65.degree. C. and stirred for 1 hour. Three equivalents of
methanol are slowly added over 30 minutes. The suspension is
stirred at -65.degree. C. for 4 days followed by removal of the
solvents under reduced pressure. The resulting white solid is
partitioned between ethyl acetate and 2M HCl. The quinine is
recovered from the acid layer and S4-33 obtained from the organic
layer.
Example 51
[0493]
Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxy-
carbonyl)-amino-3-endo-(l)-menthyl-6-exo-(trimethylsilylethoxycarbonyl)ami-
no-5-exo-methyl dicarboxylate (S4-35)
[0494] To a solution of S4-34 in benzene is added triethylamine and
diphenylphosphoryl azide. The solution is refluxed for 24 hours.
After cooling to room temperature, 2-trimethylsilylethanol is added
and the solution refluxed for 48 hours. The benzene solution is
partitioned between ethyl acetate and 1M sodium bicarbonate. The
organic layers are combined, washed with 1M sodium bicarbonate, and
dried over sodium sulfate. The solvent is evaporated under reduced
pressure to give the crude Curtius reaction product.
Example 52
[0495]
endo-Bicyclo[2.2.1]hept-5-ene-2-benzylcarboxylate-3-carboxylic acid
(S5-37)
[0496] Compound S3-19 (4.00 g, 0.0244 mol) and quinidine (8.63 g,
0.0266 mol) were suspended in equal amounts of toluene (50 mL) and
carbon tetrachloride (50 mL). The suspension was cooled to
-55.degree. C. after which benzyl alcohol (7.90 g, 0.0732 mol) was
added over 15 minutes. The reaction mixture became homogenous after
3 hours and was stirred at -55.degree. C. for an additional 96
hours. After removal of the solvents, the residue was partitioned
between ethyl acetate (300 mL) and 2M hydrochloric acid (100 mL).
The organic layer was washed with water (2.times.50 mL) and
saturated aqueous sodium chloride (1.times.50 mL). Drying over
magnesium sulfate and evaporation of the solvent gave S5-37 (4.17
g, 0.0153 mol, 63% yield).
[0497] .sup.1H NMR: (CDCl.sub.3) .delta. 1.33 (d, 1 H, bridge
CH.sub.2), 1.48 (d of t, 1 H, bridge CH.sub.2), 3.18 (bs, 1 H,
bridgehead CH), 3.21 (bs, 1 H, bridgehead CH), 3.33 (t, 2 H,
.alpha.-acid CH), 4.98 (d of d, 2 H, CH.sub.2Ph), 6.22 (d of d, 1
H, CH.dbd.CH), 6.29 (d of d, 1 H, CH.dbd.CH), 7.30 (m, 5 H,
C.sub.6H.sub.5).
Example 53
[0498]
2-endo-Benzylcarboxy-6-exo-iodobicyclo[2.2.1]heptane-3,5-carbolacto-
ne (S5-38)
[0499] S5-37 (4.10 g, 0.0151 mol) was dissolved in 0.5 M sodium
bicarbonate solution (120 mL) and cooled to 0.degree. C. Potassium
iodide (15.0 g, 0.090 mol) and iodine (7.66 g, 0.030 mol) were
added followed by methylene chloride (40 mL). The solution was
stirred at room temperature overnight. After dilution with
methylene chloride (100 mL), sodium thiosulfate was added to quench
the excess iodine. The organic layer was separated and washed with
water (100 mL) and sodium chloride solution (100 mL). Drying over
magnesium sulfate and evaporation of the solvent gave S5-38 (5.44
g, 0.0137 mol, 91% yield).
[0500] .sup.1H NMR: (CDCl.sub.3) .delta. 1.86 (d of q, 1 H, bridge
--CH.sub.2--), 2.47 (d of t, 1 H, bridge --CH.sub.2--), 2.83 (d of
d, 1 H, .alpha.-lactone carbonyl CH), 2.93 (bs, 1 H, lactone
bridgehead CH), 3.12 (d of d, 1 H, .alpha.-benzyl ester CH), 3.29
(m, 1 H, bridgehead CH), 4.63 (d, 1 H, .alpha.-lactone ester CH),
5.14 (d of d, 2 H, CH.sub.2Ph), 5.19 (d, 1 H, iodo CH), 7.38 (m, 5
H, C.sub.6H.sub.5).
Example 54
[0501] 2-endo-Benzylcarboxy-bicyclo[2.2.1]heptane-3,5-carbolactone
(S5-39)
[0502] S5-38 (0.30 g, 0.75 mmol) was placed in DMSO under N.sub.2,
NaBH.sub.4 (85 mg, 2.25 mmol) added and the solution stirred at
85.degree. C. for 2 h. The mixture was cooled, diluted with water
(50 mL) and extracted with dichloromethane (3.times.20 mL). The
extracts were combined, washed with water (4.times.15 mL) and
saturated aqueous NaCl (10 mL), dried, and evaporated to give 0.14
g (68%) of S5-39.
Example 55
[0503]
5-endo-hydroxybicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methyl
dicarboxylate (S5-40)
[0504] Compound S5-39 is dissolved in methanol and sodium methoxide
added with stirring. Removal of the solvent gives S5-40.
Example 56
[0505]
Bicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methyl-5-exo-(t-butoxyca-
rbonyl)-amino dicarboxylate (S5-41)
[0506] In a one-pot reaction S5-40 is converted to the
corresponding mesylate with methanesulfonyl chloride, sodium azide
added to displace the mesylate to give exo-azide, which is followed
by reduction with tributyl phosphine to give the free amine, which
is protected as the t-Boc derivative to give S5-41.
Example 57
[0507]
Bicyclo[2.2.1]heptane-2-enadocarboxy-3-exo-methyl-5-exo-(t-butoxyca-
rbonyl)-amino carboxylate (S5-42)
[0508] The benzyl ether protecting group is removed by catalytic
hydrogenolysis of S5-41 with 10% Pd/C in methanol at room
temperature for 6 hours. Filtration of the catalyst and removal of
the solvent yields crude S5-42.
Example 58
[0509]
Bicyclo[2.2.1]heptane-2-endo-carboxy-3-exo-methyl-5-exo-(t-butoxyca-
rbonyl)-amino carboxylate (S5-43)
[0510] Sodium is dissolved in methanol to generate sodium
methoxide. S5-42 is added and the mixture stirred at 62.degree. C.
for 16 hr. The mixture is cooled and acetic acid added with cooling
to neutralize the excess sodium methoxide. The mixture is diluted
with water and extracted with ethyl acetate. The extract is dried
and evaporated to give S5-43.
Example 59
[0511]
Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-methyl-5-exo-(t-butoxycar-
bonyl)-amino dicarboxylate (S5-44)
[0512] Compound S5-43 is reacted with benzyl bromide and cesium
carbonate in tetrahydrofuran at room temperature to give benzyl
ester S5-44, which is isolated by acid work-up of the crude
reaction mixture.
Example 60
[0513]
Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-carboxy-5-exo-(t-butoxyca-
rbonyl)-amino carboxylate (S5-45)
[0514] Compound S5-44 is dissolved in methanol and cooled to
0.degree. C. under N.sub.2. 2M NaOH (2 equivalents) is added
dropwise, the mixture allowed to come to ambient temperature and is
stirred for 5 h. The solution is diluted with water, acidified with
2M HCl and extracted with ethyl acetate. The extract is washed with
water, saturated aqueous NaCl, dried and evaporated to give
S5-45.
Example 61
[0515]
Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-(trimethylsilylethoxycarb-
onyl)-amino-5-exo-(t-butoxycarbonyl)amino carboxylate (S5-46)
[0516] To a solution of S5-45 in benzene is added triethylamine and
diphenylphosphoryl azide. The solution is refluxed for 24 hours and
then cooled to room temperature. Trimethylsilylethanol is added and
the solution refluxed for 48 hours. The solution is partitioned
between ethyl acetate and 1M sodium bicarbonate. The organic layer
is washed with 1M sodium bicarbonate and dried over sodium sulfate.
The solvent is evaporated under reduced pressure to give crude
Curtius product S5-46.
Example 62
[0517]
endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzylcarboxylate-3-carb-
oxylic acid (S6-48)
[0518] Compound S3-19 and quinidine are suspended in equal amounts
of toluene and carbon tetrachloride and cooled to -55.degree. C.
p-Methoxybenzyl alcohol is added over 15 minutes and the solution
stirred at -55.degree. C. for 96 hours. After removal of the
solvents, the residue is partitioned between ethyl acetate and 2 M
hydrochloric acid. The organic layer is washed with water and
saturated aqueous sodium chloride. Drying over magnesium sulfate
and removal of the solvent gives S6-48.
Example 63
[0519]
endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzyl-3-(trimethylsilyl-
ethoxycarbonyl)amino carboxylate (S6-49)
[0520] To a solution of S6-48 in benzene is added triethylamine and
diphenylphosphoryl azide. The solution is refluxed for 24 hours,
cooled to room temperature, trimethylsilylethanol is added, and the
solution is refluxed for an additional 48 hours. The benzene
solution is partitioned between ethyl acetate and 1 M sodium
bicarbonate. The organic layers are combined, washed with 1 M
sodium bicarbonate, and dried with sodium sulfate. The solvent is
evaporated under reduced pressure to give crude Curtius product
S6-49.
Example 64
[0521]
Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsil-
ylethoxycarbonyl)amino-5-exo-methyl-6-exo-methyl tricarboxylate
(S6-50).
[0522] S6-49, copper(II) chloride, 10% Pd/C, and dry methanol are
added to a flask with vigorous stirring. After degassing the
suspension, the flask is charged with carbon monoxide to a pressure
just above 1 atm. The pressure of carbon monoxide is maintained
over 72 hours. The solids are filtered off, and the crude reaction
mixture worked up in the usual way to afford S6-50.
Example 65
[0523]
Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsil-
ylethoxycarbonyl)amino-5-exo-6-exo-dicarboxylic anhydride
(S6-51).
[0524] S6-50, formic acid, and a catalytic amount of
p-toluenesulfonic acid is heated at 90.degree. C. overnight. Acetic
anhydride is added to the reaction mixture, and it is refluxed for
an additional 6 hours. Removal of the solvents and washing with
ether affords S6-51.
Example 66
[0525]
Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsil-
ylethoxycarbonyl)amino-5-exo-carboxy-6-exo-methyl dicarboxylate
(S6-52).
[0526] To a solution of S6-51 in equal amounts of toluene and
carbon tetrachloride is added quinine. The suspension is cooled to
-65.degree. C. and stirred for 1 hour. Three equivalents of
methanol are added slowly over 30 minutes. The suspension is
stirred at -65.degree. C. for 4 days followed by removal of the
solvents. The resulting white solid is partitioned between ethyl
acetate and 2 M HCl, with S6-52 worked up from the organic
layer.
Example 67
[0527]
Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsil-
ylethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-exo-met-
hyl dicarboxylate (S6-53).
[0528] To a solution of S6-52 in benzene is added triethylamine and
diphenylphosphoryl azide. The solution is refluxed for 24 hours
then cooled to room temperature. 2-Trimethylsilylethanol is added,
and the solution is refluxed for an additional 48 hours. The
benzene solution is partitioned between ethyl acetate and 1 M
sodium bicarbonate. The organic layers are combined, washed with 1
M sodium bicarbonate, and dried with sodium sulfate. The solvent is
evaporated under reduced pressure to give S6-53.
Example 68
[0529]
Bicyclo[2.2.1]heptane-2-exo-(4-methoxy)benzyl-3-endo-(trimethylsily-
lethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-endo-met-
hyl dicarboxylate (S6-54).
[0530] To a solution of S6-53 in tetrahydrofuran is carefully added
potassium tert-butoxide. The basic solution is refluxed for 24
hours followed by addition of acetic acid. Standard extraction
methods give the double epimerized product S6-54.
Example 69
[0531] Preparation of hexamer: 296
[0532] To 0.300 g (1R, 2R)-(-)-trans-1,2-diaminocyclohexane (2.63
mmol) in 5 mL CH.sub.2Cl.sub.2 at 0.degree. C. was added 0.600 g of
2,6-diformyl-4-bromophenol (2.62 mmol) in 5 mL of CH.sub.2Cl.sub.2.
The yellow solution was allowed to warm to room temperature and
stirred for 48 hours. The reaction solution was decanted, and added
to 150 mL of methanol. After standing for 30 minutes, the yellow
precipitate was collected, washed with methanol, and air-dried
(0.580 g; 72% yield).
[0533] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 14.31 (s, 3 H,
OH), 8.58 (s, 3 H, CH.dbd.N), 8.19 (s, 3 H, CH.dbd.N), 7.88 (d, 3
H, J=2.0 Hz, ArH), 7.27 (d, 3 H, J=2.0 Hz, ArH), 3.30-3.42 (m, 6 H,
CH.sub.2--CH--N), 1.41-1.90 (m, 24 H, aliphatic).
[0534] MS (FAB): Calcd for C.sub.42H.sub.46N.sub.6O.sub.3Br.sub.3
923.115; found 923.3 [M+H].sup.+.
Example 70
[0535] Preparation of hexamer: 297
[0536] To 0.300 g (1R, 2R)-(-)-trans-1,2-diaminocyclohexane (2.63
mmol) in 6 mL CH.sub.2Cl.sub.2 at 0.degree. C. was added 0.826 g of
2,6-diformyl-4-(1-dodec-1-yne)phenol (2.63 mmol) in 6 mL of
CH.sub.2Cl.sub.2. The orange solution was stirred at 0.degree. C.
for 1 hour and then allowed to warm to room temperature after which
stirring was continued for 16 hours. The reaction solution was
decanted and added to 150 mL of methanol. A sticky yellow solid was
obtained after decanting the methanol solution. Chromatographic
cleanup of the residue gave a yellow powder.
[0537] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 14.32 (s, 3 H,
OH), 8.62 (s, 3 H, CH.dbd.N), 8.18 (s, 3 H, CH.dbd.N), 7.84 (d, 3
H, J=2.0 Hz, ArH), 7.20 (d, 3 H, J=2.0 Hz, ArH), 3.30-3.42 (m, 6 H,
CH.sub.2--CH--N), 2.25 (t, 6 H, J=7.2 Hz, propargylic),
1.20-1.83(m, 72 H, aliphatic), 0.85 (t, 9 H, J=7.0 Hz,
CH.sub.3).
[0538] .sup.13C NMR (400 MHz, CDCl.sub.3) .delta. 163.4, 161.8,
155.7, 136.9, 132.7, 123.9, 119.0, 113.9, 88.7, 79.7, 75.5, 73.2,
33.6, 33.3, 32.2, 29.8, 29.7, 29.6, 29.4, 29.2, 29.1, 24.6, 24.5,
22.9,19.6, 14.4.
[0539] MS (FAB): Calcd for C.sub.78H.sub.109N.sub.6O.sub.3
1177.856; found: 1177.8 [M+H].sup.+.
Example 71
[0540] Preparation of hexamer: 298
[0541] To 0.240 g of 2,6-diformyl-4-(1-dodecene)phenol (0.76 mmol)
in 10 mL of benzene was added a 10 mL benzene solution of (1R,
2R)-(-)-trans-1,2-diaminocyclohexane (0.087 g, 0.76 mmol). The
solution was stirred at room temperature for 48 hours shielded from
the light. The orange solution was taken to dryness and
chromatographed (silica, 50/50 acetone/Et.sub.2O) to give a yellow
sticky solid (33% yield).
[0542] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 14.12 (s, 3 H,
OH), 8.62 (s, 3 H, CH.dbd.N), 8.40 (s, 3 H, CH.dbd.N), 7.82 (d, 3
H, J=2.0 Hz, ArH), 7.28 (d, 3 H, J=2.0 Hz, ArH), 6.22 (d, 3 H,
vinyl), 6.05 (d, 3 H, vinyl), 3.30-3.42 (m, 6 H, CH.sub.2--CH--N),
1.04-1.98(m, 87 H, aliphatic).
[0543] MS (FAB): Calcd for C.sub.78H.sub.115N.sub.6O.sub.3 1183.90;
found: 1184.6 [M+H].sup.+.
Example 72
[0544] Preparation of tetramer: 299
[0545] Preparation of hexamer: 300
[0546] Triethylamine (0.50 mL, 3.59 mmol) and (1R,
2R)-(-)-trans-1,2-diami- nocyclohexane (0.190 g, 1.66 mmol) were
combined in 150 mL EtOAc and purged with N.sub.2 for 5 minutes. To
this solution was added 0.331 g isophthalolyl chloride (1.66 mmol)
dissolved in 100 mL EtOAc dropwise over six hours. The solution was
filtered and the filtrate taken to dryness. TLC (5%
methanol/CH.sub.2Cl.sub.2) shows the product mixture to be
primarily composed of two macrocyclic compositions. Chromatographic
separation (silica, 5% methanol/CH.sub.2Cl.sub.2) gave the above
tetramer (0.020 g, 5% yield) and hexamer (about 10%).
[0547] Tetramer:
[0548] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.82 (s, 1 H),
7.60 (br s, 2 H), 7.45 (br s, 2 H), 7.18 (br s, 1 H), 3.90 (br s, 2
H), 2.22 (d, 2H), 1.85 (m, 4 H), 1.41 (m, 4 H).
[0549] MS (ESI): Calcd for C.sub.28H.sub.33N.sub.4O.sub.4 489.25;
found 489.4 [M+H].sup.+.
[0550] Hexamer:
[0551] MS (ESI): Calcd for C.sub.42H.sub.49N.sub.6O.sub.6 733.37;
found 733.5 [M+H].sup.+.
Example 73
[0552] Preparation of macrocyclic modules from benzene and
cyclohexane cyclic synthons: 301
[0553] To a 5 mL dichloromethane solution of 4-dodecyl-2,6-diformyl
anisole (24 mg; 0.072 mmol) was added a 5 mL dichloromethane
solution of (1R, 2R)-(-)-trans-1,2-diaminocyclohexane (8.5 mg;
0.074 mmol). This solution was stirred at room temperature for 16
hours and then added to the top of a short silica column. Elution
with diethyl ether and then removal of solvent led to the isolation
of 22 mg of an off-white solid. Positive ion electrospray mass
spectrometry demonstrated the presence of the tetramer (m/z 822,
MH+), hexamer (m/z 1232, MH.sup.+), and the octamer (m/z 1643,
MH.sup.+) in the off-white solid. Calculated molecular weights were
as follows: tetramer+H (C.sub.54H.sub.85N.sub.4O.sub.2, 821.67);
hexamer+H (C.sub.81H.sub.127N.sub.6O.sub.3, 1232.00); octamer+H
(C.sub.108H.sub.169N.sub.8O.sub.4, 1643.33).
Example 74
[0554] 302
[0555] Templated Imine Octamer. To a 3 neck 100 mL round bottomed
flask with stirbar, fitted with condenser and addition funnel under
argon, amphiphilic dialdehyde phenol 1 (500 mg, 1.16 mmol) was
added. Next, Mg(NO.sub.3).sub.2. 6 H.sub.2O (148 mg, 0.58 mmol) 2
and Mg(OAc).sub.2. 4 H.sub.2O (124 mg, 0.58 mmol) were successively
added. The flask was put under vacuo and backfilled with argon
3.times.. Anhydrous methanol was transferred to the flask via
syringe under argon and the resulting suspension stirred. The
mixture was then refluxed for 10 min affording a homogeneous
solution. The reaction was allowed to cool to room temperature
under positive argon pressure. (1R, 2R)-(-)-trans-1,2-diamino-
cyclohexane 4 was added to the addition funnel followed by cannula
transfer of anhydrous MeOH (11.6 mL) under argon. The diamine/MeOH
solution was added to the stirred homogeneous metal
template/dialdehyde solution drop wise over a period of 1 h
affording an orange oil. The addition funnel was replaced with a
glass stopper and the mixture was refluxed for 3 days. The solvent
was removed in vacuo affording a yellow crystalline solid that was
used without further purification.
[0556] Amine Octamer. To a 50 mL schlenk flask with stirbar under
argon Imine Octamer (314 mg, 0.14 mmol) was added. Next anhydrous
THF (15 mL) and MeOH (6.4 mL) were added via syringe under argon
and the suspension stirred at room temperature. To the homogeneous
solution, NaBH.sub.4 (136 mg, 3.6 mmol) was added in portions and
the mixture stirred at room temperature for 12 h. The solution was
filtered, followed by addition of 19.9 mL H.sub.2O. The pH was
adjusted to ca. 2 by addition of 4 M HCl, then 6.8 mL of an
ethylenediamine tetraaceticacid disodium salt dihydrate (0.13 M in
H.sub.2O) was added and the mixture stirred for 5 min. To the
solution, 2.0% ammonium hydroxide was added and stirring continued
for an additional 5 min. The solution was extracted with ethyl
acetate (3.times.100 mL) the organic layer separated, dried over
Na.sub.2SO.sub.4 and the solvent removed via rotoevaporation
affording a pale yellow solid. Recrystallization from chloroform
and hexanes afforded the Amine Octamer. Molecular weight was
confirmed by ESIMS M+H=experimental=2058.7 m/z, calcd=2058.7
m/z.
Example 75
[0557] 303
[0558] Hexamer 1j. The two substrates,
(-)-R,R-1,2-trans-diaminocyclohexan- e (0.462 mmol, 0.053 g) and
2,6-diformyl-4-hexadecyl benzylphenol carboxylate (0.462 mmol,
0.200 g) were added to a 10 mL vial containing a magnetic stirbar
followed by the addition of 2 mL of CH.sub.2Cl.sub.2. The yellow
solution was stirred at room temperature. After 24 h the reaction
solution was plugged through silica gel with diethyl ether, and the
solvent removed via roto-evaporation. (232 mg; 98% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 14.11 (s, 3 H, OH), 8.67 (s, 3
H, CH.dbd.N), 8.23 (s, 3 H, CH.dbd.N), 7.70 (s, 3 H, ArH), 7.11 (s,
3 H, ArH), 4.05-3.90 (t, 6 H, 3J=6.6 Hz,
CH.sub.2C(O)OCH.sub.2(CH.sub.2).sub.1- 4CH.sub.3), 3.44 (s, 6 H,
CH.sub.2C(O)OCH.sub.2(CH.sub.2).sub.14CH.sub.3), 3.30-3.42 (m, 6 H,
CH.sub.2--CH--N), 1.21-1.90 (m, 108 H, aliphatic) 0.92-0.86 (t, 9
H, 3J=6.6 Hz. ESIMS (+) Calcd for C.sub.96H.sub.151N.sub.-
6O.sub.9: 1533; Found: 1534 [M+H].sup.+.
[0559] Hexamer 1jh. To a 100 mL pear-shaped flask with magnetic
stirbar under argon, Hexamer 1j (0.387 mmol, 0.594 g) was added and
dissolved in THF:MeOH (7:3, 28:12 mL, respectively). Next,
NaBH.sub.4 (2.32 mmol, 0.088 g) was added slowly in portions at
room temperature for 6.5 h. The solvent was removed by
roto-evaporation, the residue dissolved in 125 mL ethyl acetate and
washed 3.times.50 mL of H.sub.2O. The organic layer was separated,
dried over Na.sub.2SO.sub.4 and the solvent removed by
roto-evaporation. The resulting residue was recrystallized from
CH.sub.2Cl.sub.2 and MeOH affording a white solid (0.440 g; 74%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 6.86 (s, 6 H,
ArH), 4.10-4.00 (t, 6 H, 3J=6.6 Hz, CH.sub.2C(O)OCH.sub.2
(CH.sub.2).sub.14CH.sub.3), 3.87-3.69 (dd, 6 H, 3J=13.7 Hz, 3J
(CNH)=42.4 Hz CH.sub.2--CH--N), 3.43 (s, 6 H, CH.sub.2C(O)OCH.sub.2
(CH.sub.2).sub.14CH.sub.3), 2.40-2.28 (m, 6 H, aliphatic),
2.15-1.95 (m, 6 H, aliphatic), 1.75-1.60 (m, 6 H, aliphatic),
1.60-1.55 (m, 6 H, aliphatic) 1.37-1.05 (m, 84 H, aliphatic)
0.92-0.86 (t, 9 H, 3J=6.8 Hz. ESIMS (+) Calcd for
C.sub.96H.sub.163N.sub.- 6O.sub.9: 1544; Found: 1545
[M+H].sup.+.
Example 76
[0560] 304
[0561] Hexamer 1A-Me. A solution of
2-hydroxy-5-methyl-1,3-benzenedicarbox- aldehye (53 mg, 0.32 mmol)
in dichloromethane (0.6 mL) was added to a solution of
(1,2R)-(-)-1,2-diaminocyclohexane (37 mg, 0.32 mmol) in
dichloromethane (0.5 mL). The mixture was stirred at ambient
temperature for 16 h, added dropwise to methanol (75 mL) and
chilled (4.degree. C.) for 4 h. The precipitate was collected to
afford 71 mg (92%) of hexamer 1A-Me. .sup.1H NMR (CDCl.sub.3):
.delta. 13.88 (s, 3H, OH), 8.66 (s, 3H, ArCH.dbd.N), 8.19 (s, 3H,
ArCH.dbd.N), 7.52 (d, 3H, J=2 Hz, Ar H), 6.86 (d, 3H, J=2 Hz, Ar
H), 3.35 (m, 6H, cyclohexane 1,2-H's), 2.03 (3, 9H, Me), 1.6-1.9
(m, 18H, cyclohexane 3,6-H.sub.2 and 4eq,5eq-H's), 1.45 (m, 6H,
cyclohexane 4ax,5ax-H's); 13C NMR .delta. 63.67, 159.55, 156.38,
134.42, 129.75, 127.13, 119.00, 75.68, 73.62, 33.68, 33.41, 24.65,
24.57, 20.22; ESI(+) MS m/e (%) 727 M+H (100); IR 1634
cm.sup.-.
Example 77
[0562] 305
[0563] 32.7 mg Hexamer 1jh (recrystallized times) was added to 30
mL dry THF. 100 .mu.L triethylamine and 100 .mu.L acryloyl chloride
(freshly distilled) were added subsequently to the THF mixture
using Schlenk technique. Solution was stirred for 18 hrs in an
acetone/dry ice bath. After removal of solvent a white precipitate
remained. The precipitate was redissolved in CH.sub.2Cl.sub.2 and
filtered through a fritted funnel. CH.sub.2Cl.sub.2 solution was
added to the separatory funnel and washed one time with water
followed by two brine (NaCl) washes. The CH.sub.2Cl.sub.2 solution
was dried over MgSO.sub.4 and then filtered to remove MgSO.sub.4. A
yellow precipitate remained after solvent removal. .sup.1H NMR
(CDCl.sub.3): .delta. -0.867-0.990 (3 H), 1.259 (21.8 H), 1.39
(1.86 H), 1.64 (12.7 H), 2.8 (1.25 H), 3.46-3.62 (2.47 H), 3.71
(0.89 H), 3.99 (2.46 H), 5.06 (0.71 H), 5.31 (3.80 H), 5.71 (1.43
H), 5.90 (0.78 H), 6.2-6.4 (2.49 H), 6.59 (0.80 H), 6.78 (0.47 H),
6.98 (0.28 H). FTIR-ATR: 3340, 2926 (--CH.sub.2--), 2854
(--CH.sub.2--), 1738 (Ester Carbonyl), 1649 and 1613 (Acrylate),
983 (.dbd.CH), 959 sh (.dbd.CH.sub.2). ESI-MS: 1978.5
(Hex1JhAC+8-AC), 1948.8 (Hex1JhAC+7-AC+Na+), 1923.3 (Hex1JhAC+7AC),
1867.6 (Hex1JhAC+6-AC), 1842.6, 1759.7 (Hex1JhAC+4-AC).
Example 78
[0564] The Langmuir isotherm and isobaric creep for hexamer 1a-Me
are shown in FIGS. 20A and 20B, respectively. 306
[0565] The relative stability of the Langmuir film of Hexamer 1a-Me
is illustrated by the isobaric creep data shown in FIG. 20B. The
area of the film decreased by about 30% after about 30 min at 5
mN/m surface pressure. The Langmuir isotherm and isobaric creep for
Hexamer 1a-C15 are shown in FIGS. 21A and 21B, respectively. The
relative stability of the Langmuir film of Hexamer 1a-C15 is
illustrated by the isobaric creep data shown in FIG. 21B. The area
of the film decreased by about 1-2% after about 30 min at 10 mN/m
surface pressure, and by about 2% after about 60 min. The collapse
pressure was about 18 mN/m for Hexamer 1a-C15.
* * * * *