U.S. patent application number 11/352445 was filed with the patent office on 2006-09-07 for methods for producing gallium and other oxo/hydroxo-bridged metal aquo clusters.
This patent application is currently assigned to State of Oregon acting by & through the State Board of Higher Edu on behalf of the Univ of Oreg.. Invention is credited to Jason T. Gatlin, Elisabeth Rather Healey, Darren W. Johnson.
Application Number | 20060199972 11/352445 |
Document ID | / |
Family ID | 36793807 |
Filed Date | 2006-09-07 |
United States Patent
Application |
20060199972 |
Kind Code |
A1 |
Johnson; Darren W. ; et
al. |
September 7, 2006 |
Methods for producing gallium and other oxo/hydroxo-bridged metal
aquo clusters
Abstract
Metallic clusters can be produced by contacting a metal salt
such as a metal nitrate with an organic reducing agent. Metals can
be selected from a group consisting of metals exhibiting octahedral
coordination, and nitrates of the selected metal or metals are
contacted with, for example nitrosobenzene. Binary, tertiary, or
other clusters can be produced.
Inventors: |
Johnson; Darren W.; (Eugene,
OR) ; Healey; Elisabeth Rather; (Tampa, FL) ;
Gatlin; Jason T.; (Eugene, OR) |
Correspondence
Address: |
KLARQUIST SPARKMAN, LLP
121 SW SALMON STREET
SUITE 1600
PORTLAND
OR
97204
US
|
Assignee: |
State of Oregon acting by &
through the State Board of Higher Edu on behalf of the Univ of
Oreg.
|
Family ID: |
36793807 |
Appl. No.: |
11/352445 |
Filed: |
February 9, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60651582 |
Feb 9, 2005 |
|
|
|
Current U.S.
Class: |
556/1 |
Current CPC
Class: |
C01P 2002/77 20130101;
C01G 15/00 20130101; C01G 1/00 20130101; C01P 2002/72 20130101;
C01F 7/66 20130101; C01P 2002/30 20130101 |
Class at
Publication: |
556/001 |
International
Class: |
C07F 5/00 20060101
C07F005/00 |
Claims
1. A method of producing a material, comprising: providing a metal
nitrate, wherein the metal is selected from a group consisting of
metals exhibiting octahedral coordination geometry; and contacting
the metal reagent with an effective amount of an organic reducing
agent to produce the material.
2. The method of claim 1, wherein the organic reducing agent has a
formula R--NO, wherein R is aliphatic, aromatic, or
heteroaromatic.
3. The method of claim 1, wherein the metal is selected from a
group consisting of Al, Mn, Fe, Ga, In, Ni, Fe, Ge, Eu, Th, or
Sm.
4. The method of claim 1, further comprising contacting the metal
reagent and the organic reducing agent in a solvent, wherein the
metal reagent and the organic reducing agent are soluble in the
solvent, and the organic reducing agent is nitrosobenzene.
5. The method of claim 4, wherein the solvent is an alcohol.
6. The method of claim 5, wherein the solvent consists essentially
of methanol.
7. The method of claim 4, further comprising evaporating the
solvent to obtain crystals of the material.
8. The method of claim 1, further comprising providing a nitrate of
a first metal and a nitrate of a second metal different from the
first metal, wherein the first metal and the second metal are
selected from the group of metals exhibiting octahedral
coordination, and contacting the first metal nitrate and the second
metal nitrate with the organic reducing agent.
9. The method of claim 8, wherein the material has a formula
[M.sub.AN.sub.B7(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](N-
O.sub.3).sub.15, M and N represent the first metal and the second
metal, respectively, and A and B are integers greater than or equal
to zero such that A+B=13, and .mu..sub.3 denotes a number of OH
groups bridging three atoms of M or N, and .mu. denotes a number of
OH groups bridging two atoms of M or N.
10. The method of claim 9, wherein the material has a formula
[Ga.sub.7In.sub.6(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](-
NO.sub.3).sub.15.
11. The method of claim 1, wherein the material is a cluster having
a formula
[M.sub.13(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](-
NO.sub.3).sub.15, wherein M is the metal selected from a group
consisting of metals exhibiting octahedral coordination geometry,
.mu..sub.3 denotes a number of OH groups bridging three atoms of M,
and .mu. denotes a number of OH groups bridging two atoms of M.
12. The method of claim 11, wherein M is selected from the group
consisting of Al, Mn, Fe, Ga, In, Ni, Fe, Ge, Eu, Th, and Sm.
13. The method of claim 12, wherein M is Ga or Al.
14. The method of claim 1, wherein the organic reducing agent is
selected from a group consisting of phosphines and sulfoxides.
15. A composition, having a formula
[Ga.sub.13(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](NO.sub.-
3).sub.15, wherein .mu..sub.3 denotes a number of OH groups
bridging three atoms of Ga, and .mu. denotes a number of OH groups
bridging two atoms of Ga.
16. A composition, having a formula
[Ga.sub.7In.sub.6(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](-
NO.sub.3).sub.15, wherein .mu..sub.3 denotes a number of OH groups
bridging three atoms of Ga or In, and .mu. denotes a number of OH
groups bridging two atoms of Ga or In.
17. A method of producing a material, comprising: providing a first
metallic reagent having a formula
[M.sub.13(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](NO.sub.3-
).sub.15, wherein M is a metal is selected from a group consisting
of metals exhibiting octahedral coordination geometry, .mu..sub.3
denotes a number of OH groups bridging three atoms of Ga, and .mu.
denotes a number of OH groups bridging two atoms of Ga; and
contacting the first metallic reagent with an effective amount of
an organic reducing agent to produce the material.
18. The method of claim 17, wherein the organic reducing agent has
a formula R--NO, wherein R is aliphatic, aromatic, or
heteroaromatic to produce the material.
19. The method of claim 17, where the metal M is selected from the
group consisting of Ga, Al, and In.
20. The method of claim 17, further comprising contacting the first
metallic reagent with the organic reducing agent in a basis
solution.
21. The method of claim 17, wherein the organic reducing agent has
a formula R--NO, wherein R is aliphatic, aromatic, or
heteroaromatic to produce the material.
22. The method of claim 21, wherein the organic reducing agent is
nitrosobenzene.
23. A method of making a bridged metal cluster, comprising:
providing a reagent having a formula A.sub.xB.sub.y, wherein A is a
metal selected from a group of metals exhibiting octahedral
coordination geometry, B is an oxyanion, and x and y are integers
between 0 and 10; and contacting the reagent with an organic
reducing agent.
24. The method of claim 24, wherein the metal is selected from the
group consisting Al, Mn, Fe, Ga, In, Ni, Fe, Ge, Eu, Th, or Sm, and
B is an oxyanion selected from a group consisting of nitrate,
sulfate, carbonate, and phosphate.
25. The method of claim 25, wherein the organic reducing agent is
selected from a group consisting of nitroso compounds and
nitroamines.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 60/651,582, filed Feb. 9, 2005, which
is incorporated herein by reference.
TECHNICAL FIELD
[0002] The disclosure pertains to methods of producing
oxo/hydroxo-bridged metal aquo nanoclusters.
BACKGROUND
[0003] Several types of Keggin structures are known. Representative
Keggin structures having a central tetrahedral Al(O)4 core are
illustrated in FIGS. 6A-6C. These structures correspond to
so-called .epsilon.-Keggin (Al.sub.13), .delta.-Keggin (Al.sub.13),
and an Al.sub.30 cluster. These and other Keggin structures are
described in Casey et al., Reviews in Mineralogy & Geochemistry
44:167-190 (2001).
[0004] While these Keggin structures have potential practical
applications, the synthesis of these structures limits their use.
Synthesis of Keggin-like clusters typically involves lengthy
reaction times and harsh reaction conditions. For example,
synthesis of the Keggin-like Al cluster
[Al.sub.13(.mu..sub.3-OH).sub.6(.mu..sub.2-OH).sub.18(H.sub.2O)24]Cl.sub.-
15 requires a 4-5 month synthesis/crystallization procedure as
reported by Seichter et al., Eur. J. Inorg. Chem. (1998). Synthesis
of the Keggin-like Al cluster
[Al.sub.8(.mu.3-OH).sub.2(.mu.2-OH).sub.12(H.sub.2O).sub.18](SO.sub.4).su-
b.5 requires a 7 year synthesis/crystallization procedure as
reported by Casey et al., Inorg. Chem. (2005). Synthesis of the
Keggin-like Al cluster
[Al.sub.15(.mu.3-O).sub.4(.mu.3-OH).sub.6(.mu..sub.2-OH).sub.14(h-
pdta)].sub.3 requires an 8 day ligand-shell stabilized synthesis as
reported in Schmitt et al., Angew. Chem. (2001). For convenience,
diagrams of these Al(O).sub.6 core materials are shown in FIGS.
7A-7C.
[0005] Because of the limitations of conventional synthesis,
improved synthesis methods are needed, and new synthetic products
made available by such improved synthesis methods.
SUMMARY
[0006] Nanoscale inorganic clusters can be formed synergistically
with a mild organic oxidation reaction. A tridecameric cluster
[Ga.sub.13(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](NO.sub.-
3).sub.15 (referred to herein as Ga.sub.13) forms when a mild
organic reducing agent (such as nitrosobenzene) facilitates the
conversion. This is an example of an organic reaction mediating an
inorganic transformation, and provides a link between organic and
inorganic synthesis that allows both processes to occur under
aerobic, ambient conditions with good yields. Previous syntheses of
inorganic clusters suffer from extremely long reaction times
(months to years), harsh conditions, and/or poor yields. The mild
organic oxidation reaction can be tolerant to many functional
groups, and other mild organic oxidation reactions can be similarly
implemented.
[0007] The representative clusters described herein have
applications in areas ranging from environmental chemistry (mimics
for mineral surfaces) to the cracking of gas oil (pillaring agents
for montmorillonite clay catalysts). Other nanocluster applications
include: models for the active sites of minerals for catalysis,
single molecule magnets (with magnetic or paramagnetic metal ions),
magnetic memory devices, conductive/semiconductive metal oxide
layers for circuits and integrated circuits, high-density
metal-based contrast agents (e.g., .sup.67Ga positron emission
tomography (PET) contrast agents), osmotic-type molecular transport
phenomena using the high charge of the clusters, environmental
remediation of toxic metal ions, and the use of the clusters as
synthons for materials via aquo ligand exchange reactions.
[0008] Conventional syntheses of these clusters typically involve
traditional inorganic methods: ligand exchange, oxidation of
metal(0) starting materials, salt metathesis, acid/base hydrolysis,
etc. Disclosed herein are novel synthetic strategies in which a
simple organic reaction is used to facilitate the formation of
tridecameric clusters such as gallium clusters. For example, by
using Ga(NO.sub.3).sub.3.(H.sub.2O).sub.6 as a reagent for the
extremely mild conversion of nitrosobenzene to nitrobenzene, robust
crystals of the nitrate-deficient gallium cluster
[Ga.sub.13(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](NO.sub.-
3).sub.15 have been formed as described in detail below. The novel
synthesis described herein can generate, for example, gallium,
aluminum, or other clusters with high yields in times ranging from
about a few hours, a few days, or a few weeks under ambient,
aerobic conditions.
[0009] Solid state and solution investigations of group 13 clusters
reveal that the majority of the compounds are polyoxocations based
upon the modified-Keggin structure, which possesses octahedral
peripheral metal cations bridged to a central tetrahedral M(III)
ion. While the presence of chelating organic ligands stabilizes a
range of "Keggin-like" polynuclear clusters (where the central
metal ion is octahedral rather than tetrahedral) and allows for
their crystallization, isolation of the purely inorganic Ga(III)
clusters analogous to the Keggin-like Al.sub.13 clusters has not
been previously accomplished. As described herein, a
straightforward method has been developed to prepare clusters such
as Ga.sub.13 using a simple organic reaction to drive the formation
of the crystalline inorganic cluster.
[0010] The present disclosure is directed to synthesis methods that
can form previously synthesized inorganic clusters or previously
unavailable inorganic clusters. The synthesis methods are typically
based on functional group tolerant organic oxidations that occur
under "mild" conditions, i.e., typically do not require
temperature, pressure, or pH extremes, or lengthy reaction times.
Inorganic clusters based on gallium, aluminum, and combinations of
indium and gallium are described in detail. For convenience, these
clusters are referred to as M.sub.13 or N.sub.AM.sub.B, wherein M,
N refer to metallic species, and for the binary cluster
N.sub.AM.sub.B, A+B=13. Representative clusters include Ga.sub.13,
A.sub.13, Ga.sub.7In.sub.6, and GaAl.sub.12.
[0011] One aspect of the present disclosure includes novel
compounds, compositions and methods for using such compounds and
compositions for use in scintigraphy or PET or other diagnostic
imaging applications.
[0012] The foregoing and other features and advantages of the
disclosed technology will become more apparent from the following
detailed description, which proceeds with reference to the
accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIGS. 1A-1B are space-filling representations of a single
crystal X-ray structure of a Ga.sub.13 nanocluster.
[0014] FIGS. 2A-2B are wireframe representations of a single
crystal X-ray structure of a Ga.sub.13 nanocluster.
[0015] FIG. 3A is an X-ray powder diffraction pattern obtained from
Ga.sub.13 produced as described herein.
[0016] FIG. 3B is an X-ray power diffraction pattern obtained by
calculation.
[0017] FIGS. 4A-4B are space-filling representations of Al.sub.13
derived from the measured single crystal X-ray structure of
Al.sub.13.
[0018] FIGS. 5A-5B are space-filling representations of
In.sub.6Ga.sub.7 derived from the measured single crystal X-ray
structure of In.sub.6Ga.sub.7.
[0019] FIGS. 6A-6C are space-filling representations of
.epsilon.-Keggin, Al.sub.13, .delta.-Keggin (Al.sub.13), and an
Al.sub.30 cluster, respectively.
[0020] FIGS. 7A-7C illustrate
[Al.sub.13(.mu..sub.3-OH).sub.6(.mu..sub.2-OH).sub.18(H.sub.2O).sub.24]Cl-
.sub.15,
[Al.sub.8(.mu..sub.3-OH).sub.2(.mu..sub.2-OH).sub.12(H.sub.2O).su-
b.18](SO.sub.4).sub.5, and
[Al.sub.15(.mu..sub.3-O).sub.4(.mu..sub.3-OH).sub.6(.mu..sub.2-OH).sub.14-
(hpdta)].sub.3, respectively.
DETAILED DESCRIPTION
[0021] The following explanations of terms and methods are provided
to better describe the present compounds, compositions, and
methods, and to guide those of ordinary skill in the art in the
practice of the present disclosure. It is also to be understood
that the terminology used in the disclosure is for the purpose of
describing particular embodiments and examples only and is not
intended to be limiting.
[0022] Ranges can be expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another embodiment includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another embodiment. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint.
[0023] In this specification and in the claims which follow,
reference will be made to a number of terms which shall be
understood to have the following meanings. "Optional" or
"optionally" means that the subsequently described event or
circumstance can but need not occur, and that the description
includes instances where said event or circumstance occurs and
instances where it does not. "Nanoscale" cluster compounds or
"nanocluster" generally refers to clusters having dimensions of
from about 0.1 nm to 200 nm, preferably between about 0.2 nm and
100 nm, more preferably between about 0.5 nm and 50 nm, and still
more preferably between about 1 nm and 5 nm. In one representative
example, a gallium nanocluster is disk shaped and has a diameter of
about 2 nm and a thickness of about 1 nm. Materials are referred to
as soluble or appreciably soluble if millimolar concentrations can
be achieved under typical reaction conditions such as ambient
temperatures.
Cluster Synthesis
[0024] Disclosed herein are methods based on organic reactions that
result in metallic clusters such as a tridecameric gallium cluster
or other clusters. A representation of a generic synthesis is
illustrated in Formula 1. ##STR1##
[0025] Metal salts generally are selected from a group consisting
of salts of aluminum, germanium, indium, gallium, iron, manganese,
nickel, lanthanides such as, for example, samarium, europium, and
terbium, or other metals having octahedral coordination geometry.
Metal nitrates are convenient, although metal sulfates, metal
carbonates, metal phosphates and other metal salts of oxyanions can
be used. The solvent is generally selected so that both the organic
reducing agent and the metal salt are soluble in the solvent.
Methanol, ethanol, or other alcohols can be suitable depending on
solubility of the organic reducing agent and the metal salt.
Although not shown in Formula 1, solvent pH and temperature can be
selected to enhance production of the metal cluster. Metal species
associated with more acidic Lewis acids may react more favorably if
the solvent pH is adjusted to become slightly basic, but a range of
pH values from about 2 to about 13 may typically be used.
[0026] The organic reducing agent (ORA) is typically selected to
reduce the metal salt by, for example, reducing a constituent of
the ligand to which a metallic species in the metal salt is bound.
For example, some suitable metal salts are metal nitrates, and the
ORA is selected to reduce a nitrate group to a nitrite group.
Representative ORAs include nitrosobenzene, nitroalkanes and
bromonitoalkanes (from oximes), sulfoxides, and phosphines.
[0027] Some suitable ORAs include nitroso compounds that can be
represented by the formula R--N.dbd.O, wherein R is an aliphatic or
aromatic moiety. Nitrosamines having a chemical formula
R.sub.2--N--N.dbd.O. In one embodiment, R includes at least one
site of unsaturation, which may be conjugated to the nitrosamine
moiety. For example, certain nitrosamines are directly attached to
an alkenyl moiety. Other examples of conjugated nitrosamines
include aryl nitrosamines, such as optionally substituted phenyl
nitrosamines.
[0028] The term "aliphatic group" includes alkyl, alkenyl, alkynyl,
halogenated alkyl and cycloalkyl groups. A "lower aliphatic" group
is a branched or unbranched aliphatic group having from 1 to 10
carbon atoms.
[0029] The term "aryl group" refers to any carbon-based aromatic
group including, but not limited to, benzene, naphthalene, etc. The
term "aromatic" also includes "heteroaryl group," which is defined
as an aromatic group that has at least one heteroatom incorporated
within the ring of the aromatic group. Examples of heteroatoms
include, but are not limited to, nitrogen, oxygen, sulfur, and
phosphorous. The aryl group can be substituted with one or more
groups including, but not limited to, alkyl, alkynyl, alkenyl,
aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy,
carboxylic acid, or alkoxy, or the aryl group can be
unsubstituted.
[0030] The oxidation associated with such ORAs, such as the
oxidation of nitrosoaromatics to nitroaromatics, are generally a
mild oxidations that exhibit wide functional group tolerance.
Functional group tolerance can be evaluated and functional groups
selected based on the scheme illustrated in Formula 2. As shown in
Formula 2, diverse substrates including electron-withdrawing to
electron-donating substituents can be evaluated and selected.
##STR2##
[0031] There are numerous mild organic oxidation reactions that can
be used to drive cluster synthesis such as, for example, the
oxidation of phosphines to phosphine oxides and sulfoxides to
sulfones. Examples are illustrated in Formula 3 and Formula 4
below. With such reactions, synthesis of an inorganic nanocluster
drives the organic reaction. ##STR3##
[0032] Synthesis based on oximes and nitrosoalkanes is illustrated
in Formula 5. Since oximes and nitrosoalkanes are tautomers, and
equilibrium lies far to the oxime, a mild oxidation of a
nitrosoalkane to a nitroalkane can be accomplished using metal
nitrates, provided sufficient nitrosoalkane is present in solution.
A wide array of oximes is readily available and can be based on
aliphatic or aromatic moieties such as those described with
reference to nitrosamines. ##STR4##
[0033] In another example, bromination of an oxime to a
bromonitroso compound, followed by mild oxidation to a
bromonitroalkane can be used to produce a nitroalkane upon
reduction with sodium borohydride. This procedure is illustrated in
Formula 6. In Formula 6, NBS represents n-bromosuccinimide, and R
represents any of the moieties described previously. ##STR5##
[0034] Combinations of metal salts of metals M and N can be used to
produce an N.sub.aM.sub.b cluster. For example, while a cluster of
13 gallium atoms has been produced, in other syntheses, a cluster
based on 7 gallium atoms and 6 indium atoms was produced. Other
binary, tertiary, or higher order clusters can also be produced.
For binary tridecameric clusters, a sum of numbers of M-type ions
and N-type ions (N.sub.a and N.sub.b, respectively) is thirteen, so
that various numbers of atoms of each of the binary constituent can
be used, subject to the constraint N.sub.a+N.sub.b=13. Similar
considerations apply to tertiary clusters, wherein a sum
N.sub.a+N.sub.b+N.sub.c=13, wherein N.sub.c refers to a number of
ions of a third metallic constituent.
EXAMPLE
Gallium Clusters
[0035] In an example shown in Formula 7,
Ga(NO.sub.3).sub.3.(H.sub.2O) is used as a reagent for the mild
conversion of nitrosobenzene to nitrobenzene, forming crystals of a
nitrate deficient gallium cluster. In additional examples, other
inorganic clusters can be made, and functional groups other than
the nitroso group can be used for the organic portion of the
reaction. ##STR6## In Formula 7, the symbols .mu. and .mu..sub.3
refer to the numbers of gallium atoms bridged by the OH groups,
with .mu. referring to the 18 OH groups that bridge two gallium
atoms and .mu..sub.3 referring to the six OH groups that bridge
three gallium atoms. In some examples, .mu..sub.2 is used to denote
groups bridging two gallium atoms instead of .mu.. The same
notation can be used in describing other cluster compounds as
well.
[0036] In the representative synthesis of a gallium cluster
illustrated in Formula 7, robust crystals of
[Ga.sub.13(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](NO.sub.-
3).sub.15.6H.sub.2O (referred to herein as Ga.sub.13) were obtained
in 65% yield from slow evaporation at room temperature of a
methanolic solution of hydrated Ga(NO.sub.3).sub.3 in the presence
of stoichiometric amounts of nitrosobenzene. In this process the
nitrosobenzene acts as a scavenger of nitrate ions and facilitates
the synthesis of Ga.sub.13 via a redox reaction in which the
nitrosobenzene is oxidized to nitrobenzene with concomitant
reduction of some of the nitrate counterions LC-MS and .sup.1H NMR
data verified that nitrobenzene was formed during the reaction.
Furthermore, it is known that nitric acid can oxidize nitroso
derivatives into the corresponding nitro compounds. This procedure
represents a milder form of this reaction, in which a nitrate
oxidizes nitrosobenzene at a slightly acidic pH. As a result of
consumption of some of the nitrate counterions of
Ga(NO.sub.3).sub.3, the remaining gallium-containing species form a
higher nuclearity cluster where the ratio of nitrate to
gallium(III) is less than 3:1--in this case, the stoichiometric
ratio is 15:13.
[0037] The solid state structure of Ga.sub.13 is shown in FIGS.
1A-2B. The gallium cluster compound crystallizes as the Keggin-like
cluster similar to other tridecameric gallium clusters stabilized
by supporting ligands, wherein the central gallium is octahedral
and surrounded by two concentric rings of six gallium ions each,
with bridging hydroxo ligands between them. The cluster is capped
on its periphery by 24 aquo ligands generating a nanoscale
disk-like compound with a diameter of about 1.81 nm and a thickness
of about 1.03 nm. Ga.sub.13 is expected to persist in solution.
Ga.sub.13 is water-soluble, and upon recrystallization from aqueous
solution, Ga.sub.13 is regenerated, rather than decomposing to a
mixture of Ga.sub.2O.sub.3, Ga(O)OH, Ga(OH).sub.3 and/or
Ga(NO.sub.3).sub.3.
Gallium Clusters: Experimental
[0038] Slow evaporation of a 5 mL methanolic solution of
Ga(NO.sub.3).sub.3.6H.sub.2O (0.47 g, 0.13 mmol) in the presence of
nitrosobenzene (0.025 g, 0.24 mmol) yielded 0.018 g (0.0065 mmol,
65%) of Ga.sub.13. Crystals of the product were shown to be
representative of the bulk by comparison of the X-ray powder
pattern collected on a fresh sample with the corresponding pattern
calculated from the crystal structure. X-ray powder spectra based
on the reaction product and calculated based on the crystal
structure are shown in FIGS. 3-4, respectively. Various Ga.sub.13
cluster parameters based on single crystal X-ray diffraction
measurements are listed in the table below. [0039] Ga.sub.13
Summary [0040] Avg. Ga--O: 1.97 .ANG. [0041] Trigonal, R-3 [0042]
.alpha.=20.214(3) .ANG., c=18.353(4) .ANG. [0043]
.alpha.=.beta.=90.00.degree., .gamma.=120.degree. [0044] V=6494(2)
.ANG. 3, Z=3 [0045] R1=0.0349 [0046] wR2(all)=0.0988 [0047]
GOF=1.035
[0048] In the synthesis, the original light blue solution of
nitrosobenzene and Ga(NO.sub.3).sub.3.6H.sub.2O turns pale green
after one day indicating oxidation of nitrosobenzene to
nitrobenzene. The pH of a solution of Ga.sub.13 dissolved in water
(1.6 nM) was measured as 2.28. Dissolution of Ga.sub.13 in water
followed by recrystallization via evaporation resulted in the sole
formation of Ga.sub.13 as determined by single crystal unit cell
determination and X-ray powder diffraction. The entire synthesis
can be completed in less than a week. Attempts to produce Ga.sub.13
in the presence of water alone, pyridine, 2,6-lutidine, and
nitrobenzene were unsuccessful and resulted in the formation of
Ga(NO.sub.3).sub.3 or GaL.sub.2(NO.sub.3).sub.3, wherein L is
2,6-lutidine.
Other Clusters
[0049] The Keggin-like Al.sub.13 cluster has been conventionally
synthesized as both the Cl-salt and with supporting
aminocarboxylate ligands. However, conventional synthesis methods
are difficult and require months to complete. The procedure
describe herein for the formation of Ga.sub.13 clusters by the
organic oxidation of nitrosobenzene and crystallization of the
Ga.sub.13 cluster can be viewed as a generic reaction applicable to
the synthesis of isostructural analogous Al.sub.13 clusters or
other isotructural clusters. Using the disclosed organic mediated
reaction, the Al.sub.13 cluster can be isolated in less than 2
weeks.
[0050] The general strategy for making a cluster is to dissolve
both the metal salt (13 equivalents) and the nitrosobenzene (24
equivalents) in methanol, mix them together and, for aluminum
clusters, add 0.1 equivalent of methanolic KOH to adjust pH. The
mixture is allowed to slowly evaporate over 4-8 days, yielding
large single crystals (about 65% yield) for single crystal X-ray
diffraction and elemental analysis. For aluminum nitrate, Al.sub.13
clusters are produced having a formula
[Al.sub.13(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](NO.sub.-
3).sub.15, wherein .mu..sub.3 and .mu. refer to OH groups that
bridge 3 or 2 aluminum ions, respectively. The aluminum cluster
reaction proceeds with about a 65% yield with respect to metal
salt. Selection of the numbers of equivalents of the reactants can
be associated with reaction rate, but typically the same product is
obtained with a range of equivalents of the reactants.
[0051] This procedure can be applied to other metals and metal
mixtures to synthesize clusters containing gallium and/or indium.
Mixing thirteen equivalents of gallium nitrate with nitrosobenzene
in methanol with no added base produced the Ga.sub.13 cluster. A
mixed metal cluster of gallium and indium was synthesized using 7
equivalents of gallium nitrate and 6 of indium nitrate to produce
Ga.sub.7In.sub.6 clusters with a chemical formula of
[Ga.sub.7In.sub.6(.mu..sub.3-OH).sub.6(.mu.-OH).sub.18(H.sub.2O).sub.24](-
NO.sub.3).sub.15. These clusters have both been produced and
structurally characterized by single crystal X-ray diffraction. The
presence of nitrobenzene as a product was verified by .sup.1H NMR
spectroscopy and LC mass spectrometry. The production of these
clusters is described with additional detail below, and the general
procedure is outlined in Formula 8. ##STR7##
Aluminum Clusters
[0052] Formula 9 illustrates a synthesis of Al.sub.13 using a
method similar to that described above for Ga.sub.13. The
polymerization equilibria of aluminum species is dependent on pH,
concentration of base and aluminum (they form readily with
[Al.sup.3+]>10.sup.-5 M), stirring rate, temperature, aging time
and rate of base addition. Because aluminum is more acidic than
gallium, the concentration of Al(NO.sub.3).sub.3 and pH may be
adjusted (from pH 2-13). ##STR8## Some of the measured single
crystal x-ray structural properties of these aluminum clusters are
listed in the table below. [0053] Al.sub.13 Summary [0054]
Triclinic, P-1 [0055] .alpha.=12.86 .ANG., b=13.17 .ANG., c=13.43
.ANG. [0056] .alpha.=78.27.degree., .beta.=74.15.degree.,
.gamma.=87.96.degree. [0057] V=2143 .ANG. 3, Z=1
[0058] Other M.sub.13 nanoclusters can be formed by the treatment
of a hydrated M(NO.sub.3).sub.3 with nitrosobenzene. For example,
In.sub.13 clusters and binary clusters such as Ga.sub.7In.sub.6 can
be produced as illustrated in Formula 10. Ga.sub.7In.sub.6 has been
produced such that the seven Ga ions are situated at the innermost
sites in the cluster. A summary of Ga.sub.7In.sub.6 properties
based on single crystal X-ray diffraction measurements is included
in the table below. Other clusters include GeAl.sub.12, Fe.sub.13,
and Mn.sub.13 clusters, and can be produced using, for example,
either a hydrated metal nitrate or in the presence of water.
##STR9## [0059] Ga.sub.7In.sub.6 Summary [0060] Trigonal, R-3
[0061] .alpha.=20.41 .ANG., b=20.41 .ANG., c=18.36 .ANG. [0062]
.alpha.=.beta.=90.degree., .gamma.=120.degree. [0063] V=6621 .ANG.
3,Z=3
Higher Order Clusters
[0064] In addition to the clusters described above, higher
nuclearity versions of these cluster types can be formed. Typically
these larger clusters are formed by stabilizing the core with
peripheral ligands or by exposure of smaller nuclearity clusters to
base over time. Stable M.sub.13 or other clusters can be exposed to
an ORA such as nitrosobenzene and base in a methanolic or aqueous
solution. Slow evaporation and/or heating can yield higher
nuclearity clusters devoid of stabilizing non-aquo ligands as
illustrated in Formula 11. ##STR10## While clusters based on 13 or
30 metal ions have been described, other cluster configurations can
be selected. For example, clusters having 8, 13, 30, or 32 metal
ions can be produced.
Pharmaceutical Applications
[0065] While there are numerous applications of the disclosed
compounds, one of particular significance is use in pharmaceutical
compositions. Such compositions are prepared for administration to
a subject and include a diagnostically effective amount of one or
more of the currently disclosed compounds. The diagnostically
effective amount of a disclosed compound will depend on the route
of administration, the type of mammal that is the subject and the
physical characteristics of the subject being investigated.
Specific factors that can be taken into account include disease
severity and stage, weight, diet and concurrent medications. The
relationship of these factors to determining a diagnostically
effective amount of the disclosed compounds is understood by those
of ordinary skill in the art. Therapeutically effective amounts are
subject to similar considerations.
[0066] Any of the nanocluster compositions described herein can be
combined with a pharmaceutically acceptable carrier to form a
pharmaceutical composition. Pharmaceutical carriers are known to
those skilled in the art. These most typically would be standard
carriers for administration of compositions to humans, including
solutions such as sterile water, saline, and buffered solutions at
physiological pH. The compositions could also be administered
intramuscularly, subcutaneously, or in an aerosol form. Other
compounds will be administered according to standard procedures
used by those skilled in the art.
[0067] Nanoclusters intended for pharmaceutical delivery can be
formulated in a pharmaceutical composition. Pharmaceutical
compositions can include carriers, thickeners, diluents, buffers,
preservatives, surface active agents and the like in addition to
the molecule of choice. Pharmaceutical compositions can also
include one or more additional active ingredients such as
antimicrobial agents, anti-inflammatory agents, anesthetics, and
the like. Pharmaceutical formulations can include additional
components, such as carriers. The pharmaceutically acceptable
carriers useful for these formulations are conventional.
Remington's Pharmaceutical Sciences, by E. W. Martin, Mack
Publishing Co., Easton, Pa., 15th Edition (1975), describes
compositions and formulations suitable for pharmaceutical delivery
of the compounds herein disclosed.
[0068] In general, the nature of the carrier will depend on the
particular mode of administration being employed. For instance,
parenteral formulations usually contain injectable fluids that
include pharmaceutically and physiologically acceptable fluids such
as water, physiological saline, balanced salt solutions, aqueous
dextrose, glycerol or the like as a vehicle. For solid compositions
(for example, powder, pill, tablet, or capsule forms), conventional
non-toxic solid carriers can include, for example, pharmaceutical
grades of mannitol, lactose, starch, or magnesium stearate. In
addition to biologically-neutral carriers, pharmaceutical
compositions to be administered can contain minor amounts of
non-toxic auxiliary substances, such as wetting or emulsifying
agents, preservatives, and pH buffering agents and the like, for
example sodium acetate or sorbitan monolaurate.
[0069] Diagnostic tests based on gallium nanoclusters permit
investigation of how a subject's body processes the composition
containing the nanoclusters, and typically include images based on
radioactivity associated with the nanoclusters. For example, the
nanoclusters can be chemically bound to a substance that has a
particular processing characteristic within the body (i.e., the
substance acts as a tracer). Presence of disease or abnormality is
then associated with abnormal or unusual processing of the
substance by the body. In some examples, accumulation of a
substance is enhanced due to disease while in other examples, the
substance is excluded from a region in which it would normally
accumulate. Accumulation of a substance is associated with a "hot
spot" in an image while exclusion of a substance is associated with
a "cold spot."
[0070] For example, nanoclusters can be attached to a substance
that is preferentially accumulated in a particular body region or
tissue (such as for example, bone, kidneys, lungs, etc.). The
accumulation (or lack thereof) can be used in imaging. Increased
physiological function such as associated with, for example, bone
fracture, can result in abnormally high accumulation of the
substance and produces a hot spot in an image. In other examples,
the substance is excluded due to disease or injury.
[0071] Nanoclusters and nanocluster compositions can be used in
in-vivo and in-vitro analysis. In-vivo analysis is based on subject
evaluations using, for example, gamma camera imaging or non-imaging
measurement of radioactivity in the subject. In-vitro analysis is
typically based on samples extracted from a subject such as, for
examples, blood or urine samples.
[0072] Radioisotopes can be produced using, for example, a nuclear
reactor or a cyclotron. Gallium 67 can be produced by bombardment
of zinc with energetic protons using a cyclotron. In some cases, a
zinc target is exposed so as to be substantially free of stable
gallium isotopes. Other isotopes of gallium or radioactive indium
can also be used in imaging applications.
[0073] Compositions can be applied for patient imaging in various
ways. For example, a liquid containing a nanocluster composition
can be injected intravenously. Subcutaneous injection can also be
used, wherein the composition is injected under the skin. In other
examples, intrasynovial injection is used, wherein the composition
is injected into a joint space. In other examples, a composition is
inhaled for use in lung investigations or ingested for evaluation
and study of digestive tract function. In further examples, a
composition can be applied topically. For a particular application,
a composition can be configured as, for example, an aerosol
dispersion, an ingestible substance (included with a food), or in a
sterile, injectable carrier.
[0074] The gallium compounds described herein may be formed using
one or more gallium isotopes such as the radioactive isotopes
gallium 66, gallium 67, and/or gallium 68. Such radioactive gallium
compounds may be used in imaging applications in, for example,
nuclear medicine. Gallium 67 emits gamma radiation, and the gamma
emission from such compounds may be applied to gamma scintigraphy
in which a gamma camera or a SPECT (single photon emission computed
tomography) camera is used for imaging. Alternatively, such
compounds may be used in positron emission tomography (PET) in
which photons produced in positron decay are detected. In medical
applications, such compounds may be injected into patients, and a
distribution of compound in the patient detected. Such compounds
can be referred to as contrast agents in these and other imaging
techniques. Similar methods may be used to form radioactive indium
compounds.
[0075] Radiation emitted from the radionuclide inside the body is
usually detected using a gamma camera. Traditionally, gamma-cameras
have consisted of a gamma-ray detector, such as a single large
sodium iodide NaI(Tl) scintillation crystal, coupled with an
imaging sub-system such as an array of photomultiplier tubes and
associated electronics.
[0076] The technology has been described with reference to example
embodiments. It will be apparent to those of ordinary skill in the
art that changes and modifications may be made without departing
from the teachings of this disclosure, and we claim all that is
encompassed by the appended claims.
* * * * *