U.S. patent application number 13/469299 was filed with the patent office on 2012-09-20 for lithium-porous metal oxide compositions and lithium reagent-porous metal compositions.
This patent application is currently assigned to SIGNA CHEMISTRY, INC.. Invention is credited to James L. DYE, James JACKSON, Michael LEFENFELD, Partha NANDI.
Application Number | 20120235084 13/469299 |
Document ID | / |
Family ID | 39158135 |
Filed Date | 2012-09-20 |
United States Patent
Application |
20120235084 |
Kind Code |
A1 |
LEFENFELD; Michael ; et
al. |
September 20, 2012 |
LITHIUM-POROUS METAL OXIDE COMPOSITIONS AND LITHIUM REAGENT-POROUS
METAL COMPOSITIONS
Abstract
The invention relates to lithium metal/porous metal oxide
compositions. These lithium metal compositions are prepared by
mixing liquid lithium metal with a porous metal oxide in an inert
atmosphere under exothermic conditions sufficient to absorb the
liquid lithium metal into the porous metal oxide pores. The lithium
metal/porous metal oxide compositions of the invention are
preferably loaded with lithium metal up to about 40% by weight,
with about 20% to 40% by weight being the most preferred loading.
The invention also relates to lithium reagent-porous metal oxide
compositions having RLi absorbed into a porous oxide. In formula
RLi, R is an alkyl group, an alkenyl group, an alkynyl group, an
aryl group, an alkaryl group, or an NR.sup.1R.sup.2 group; R.sup.1
is an alkyl group, an alkenyl group, an alkynyl group, an aryl
group, an alkaryl group; and R.sup.2 is hydrogen, an alkyl group,
an alkenyl group, an alkynyl group, an aryl group, and an alkaryl
group. The preparation and use of these compositions are also
described.
Inventors: |
LEFENFELD; Michael; (New
York, NY) ; DYE; James L.; (East Lansing, MI)
; NANDI; Partha; (East Lansing, MI) ; JACKSON;
James; (Haslett, MI) |
Assignee: |
SIGNA CHEMISTRY, INC.
New York
NY
|
Family ID: |
39158135 |
Appl. No.: |
13/469299 |
Filed: |
May 11, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11852820 |
Sep 10, 2007 |
8197707 |
|
|
13469299 |
|
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Current U.S.
Class: |
252/182.3 ;
252/182.32; 252/182.35 |
Current CPC
Class: |
C07F 1/02 20130101; C01P
2002/87 20130101; Y02P 20/52 20151101; C01C 1/026 20130101; C01D
15/00 20130101; C01P 2002/86 20130101; C01P 2002/89 20130101; C01P
2006/16 20130101 |
Class at
Publication: |
252/182.3 ;
252/182.32; 252/182.35 |
International
Class: |
C09K 3/00 20060101
C09K003/00 |
Claims
1. A lithium metal/porous metal oxide composition prepared by a
process comprising: mixing liquid lithium metal with a porous metal
oxide in an inert atmosphere under exothermic conditions sufficient
to absorb the liquid lithium metal into the porous metal oxide
pores.
2. The lithium metal/porous metal oxide composition of claim 1,
wherein the lithium metal is loaded up to about 40% by weight, the
pores of the porous metal oxide have an average pore size of 30
.ANG. to 500 .ANG., and the porous metal oxide is selected from
porous alumina, porous titanium oxide, porous calcium oxide, porous
zirconia, porous iron oxide, porous Co.sub.3O.sub.4, porous metal
phosphate, porous hybrid phosphosilicate, porous aluminates, porous
vanadates, and molybdates.
3. The lithium metal/porous metal oxide composition of claim 2,
wherein the lithium metal is loaded to about 20% to 40% by
weight.
4. The lithium metal/porous metal oxide composition of claim 2,
wherein the porous metal oxide is alumina.
5. The lithium metal/porous metal oxide composition of claim 2,
wherein the pores of the porous metal oxide have an average pore
size of 60 .ANG. to 190 .ANG..
6. A method for preparing a lithium reagent-porous metal oxide
composition comprising the steps of: mixing liquid lithium metal
with a porous metal oxide in an inert atmosphere under exothermic
conditions sufficient to absorb the liquid lithium metal into the
porous metal oxide, and reacting the resulting lithium metal/porous
metal oxide composition with a compound RX at a temperature of
about -80.degree. C. to 0.degree. C., wherein R is an alkyl group,
an alkenyl group, an alkynyl group, an aryl group, an alkaryl
group, or an NR.sup.1R.sup.2 group; R.sup.1 is an alkyl group, an
alkenyl group, an alkynyl group, an aryl group, an alkaryl group or
an Si(R.sup.3).sub.3 group; R.sup.2 is hydrogen, an alkyl group, an
alkenyl group, an alkynyl group, an aryl group, an alkaryl group,
or an Si(R.sup.3).sub.3 group; R.sup.3 is an alkyl group, an
alkenyl group, an alkynyl group, an aryl group, or an alkaryl
group; and X is a halogen.
7. The method for preparing a lithium reagent-porous metal oxide
composition of claim 6, wherein the lithium metal is loaded up to
about 40% by weight, the pores of the porous metal oxide have an
average pore size of 30 .ANG. to 500 .ANG., and the porous metal
oxide is selected from porous alumina, porous titanium oxide,
porous calcium oxide, porous zirconia, porous iron oxide, porous
Co.sub.3O.sub.4, porous metal phosphate, porous hybrid
phosphosilicate, porous aluminates, porous vanadates, and
molybdates.
8. The method for preparing a lithium reagent-porous metal oxide
composition of claim 6, wherein the lithium metal is loaded to
about 20% to 40% by weight.
9. The method for preparing a lithium reagent-porous metal oxide
composition of claim 6, wherein the porous metal oxide is
alumina.
10. The method for preparing a lithium reagent-porous metal oxide
composition of claim 6, wherein the pores of the porous metal oxide
have an average pore size of 60 .ANG. to 190 .ANG..
11. A method for preparing an organolithium-porous metal oxide
composition comprising the step of: mixing lithium metal, a porous
metal oxide, and an alkyl halide solution in the presence of a
solvent under conditions sufficient to absorb the lithium into the
pores of the porous metal oxide, and evaporating any excess
solvent.
12. The method for preparing an organolithium-porous metal oxide
composition of claim 11, wherein the lithium metal is loaded up to
about 40% by weight, the pores of the porous metal oxide have an
average pore size of 30 .ANG. to 500 .ANG., and the porous metal
oxide is selected from porous alumina, porous titanium oxide,
porous calcium oxide, porous zirconia, porous iron oxide, porous
Co.sub.3O.sub.4, porous metal phosphate, porous hybrid phospho
silicate, porous aluminates, porous vanadates, and molybdates.
13. The method for preparing an organolithium-porous metal oxide
composition of claim 11, wherein the lithium metal is loaded to
about 20% to 40% by weight.
14. The method for preparing an organolithium-porous metal oxide
composition of claim 11, wherein the porous metal oxide is
alumina.
15. The method for preparing an organolithium-porous metal oxide
composition of claim 11, wherein the pores of the porous metal
oxide have an average pore size of 60 .ANG. to 190 .ANG..
16. A method of absorbing an organolithium species into the pores
of a porous material, comprising: contacting the organolithium
species with the porous material under cold conditions, wherein the
porous material is selected from the group consisting of porous
silica gel and a porous metal oxide, distilling any excess solvent,
and drying the resulting organolithium material.
Description
RELATED CASE INFORMATION
[0001] This application claims priority to U.S. Provisional Patent
Application No. 60/824,964, filed Sep. 8, 2006, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to lithium metal-porous oxide
compositions made by the interaction of metallic lithium with
porous metal oxide powders, such as alumina gel, and their use to
prepare organolithium and lithium amide reagents, both in situ and
as solid free flowing easily handled and stored materials. These
compositions do not require flammable solvents and/or cold
conditions for storage, shipment and use, yet the absorbed lithium
and lithium reagents retain their reactivity and synthetic
utility.
BACKGROUND OF INVENTION
[0003] Organolithium and lithium amide compounds are important
reagents used routinely in synthetic chemistry transformations.
Traditionally, organolithium reagents are made by combining finely
divided lithium metal at low temperature with solutions of
haloorganics or by metal-halogen exchange reactions. Lithium amides
are most commonly prepared by the deprotonation of amines using an
organolithium reagent. However, stability, storage, and handling of
organolithium compounds remain problems that often make their use
difficult for organic synthesis, including their use to make
lithium amides.
[0004] Organolithium as used herein, and as commonly used in the
art, refers to lithium compounds of carbon-centered anions.
Organolithium reagents are synthetically useful because they are
strong bases, effective nucleophiles, and effective catalysts for
radical and anionic polymerizations. Such reagents are, however,
very reactive, often spontaneously catching fire in the presence of
air. To control these hazards, they are only commercially available
as solutions in hydrocarbon or ether solvents. These solvents can
moderate the pyrophoric nature of the organolithiums, but are
themselves volatile and flammable, adding further hazards
associated with the use of organolithium reagents.
[0005] Lithium amide, as used herein, refers to lithium salts of
primary and secondary amines. Lithium amide reagents are
synthetically useful because they are strong bases, freely soluble
in common organic solvents, and highly versatile. These reagents
are, however, very reactive and difficult to handle. With some
exceptions, they are not available commercially and must be
synthesized immediately prior to their use by adding a primary or
secondary amine to an organolithium reagent, such as
butyllithium.
[0006] Lithium metal is commonly used to generate an organolithium
reagent, which is an organometallic compound with a direct bond
between a carbon and a lithium atom. Since the electropositive
nature of lithium places most of the charge density of the bond on
the carbon atom, a carbanion species is created. This enables
organolithium reagents to act as extremely powerful bases and
nucleophiles. Typically, organolithium reagents are synthesized
commercially by the reaction of a haloorganic with lithium metal,
according to R--X+2Li.fwdarw.R--Li+LiX (See U.S. Pat. No. 5,523,447
by Weiss et al. and U.S. Patent Application Publication No.
20060049379 by Emmel et al). A side reaction that occurs during
this synthesis, especially with alkyl iodides, is the Wurtz
reaction, where the R group couples with itself. This side reaction
can be nearly eliminated by using cold temperatures or chlorine or
bromine as the halogen. Other methods of creating organolithium
reagents include, for example: (i) reacting a organic halide with a
radical anion lithium salt, (ii) performing a metal-halogen
exchange between an organic halogen compound and an organolithium
species (e.g., Gilman, H. et. al., J. Am. Chem. Soc. 1932; 54,
1957), (iii) an exchange between an organolithium species and
another organometallic compound, (iv) the deprotonation of an
organic compound with an organolithium reagent, (v) reductive
cleavage of the carbon-heteroatom (such as sulfur, oxygen,
phosphorus, or silicon) bonds (e.g., Gilman, H., et. al., Org.
Chem. 1958; 23, 2044,), or (vi) lithium-hydrogen exchange from LiOH
and toluene to make benzyl lithium in DMSO (U.S. Patent Application
Publication No. 20060170118 by Everett et. al.).
[0007] Organolithium reagents, specifically butyllithium (BuLi),
methyllithium (MeLi), phenyllithium (PhLi), and others, are widely
used as chemical building blocks and as strong bases in both the
pharmaceutical and the industrial manufacturing industry. Lithium
amides find related applications; for example, lithium
diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS)
are both strong bases that are also capable of performing
enantioselective alkylation by virtue of the strong coordinating
ability of lithium (Hilpert, H. Tetrahedron, 2001, 57, 7675).
Carbon-centered organolithiums, such as nBuLi, are considered to be
both powerful nucleophiles and strong bases at the same time.
(Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R, A.; Volante,
R. P.; Shinkai, I. J. Org. Chem. 1992, 57, 2771). These
characteristics enable their use as initiators for anionic
polymerizations (Hungenberg, Klaus-Dieter; Loth, Wolfgang; Knoll,
Konrad; Janko, Lutz; Bandermann, Friedhelm. Method for producing
statistical styrene-butadiene copolymers. PCT Int. Appl. WO 9936451
A1.
[0008] Little can be done to modify the reactivity or selectivity
of ordinary organolithium and lithium amide reagents, yet
modification is a growing need in many chemical industries,
especially for pharmaceutical and polymerization processes.
Traditional stir-batch modes of synthesis with either of these
types of compounds generate significant quantities of solvent
waste, which is undesirable for any chemical process. A cleaner
process, which would involve either a solvent-free organolithium or
lithium amide material or a packed-bed flow reactor setup, would be
ideal for large scale industrial synthesis, as it would decrease
solvent disposal issues and might eliminate tedious purification or
work-up steps. One solution would be the creation of a solid source
of organolithium reagents which could be used in flow chemistry and
would control the efficiency and effectiveness of the reagent in a
process. This notion has spawned efforts to develop crystalline
Grignard reagents (Marcus, V., et. al. Angew Chem. Int. Ed. 2000,
39, 3435) and other solid carbanion sources (Davies, S. G. et. al.
J. Am. Chem. Soc. 1977, 4, 135 and Eaborn, C., et. al. J. Am. Chem.
Soc. 1994, 116, 12071) in recent years. However, the methods of
preparation of these crystalline reagents are typically tedious and
specialized for specific carbanion systems, limiting their utility
in large-scale applications and their applicability as general
carbanion sources. Grignard reagents, the broadest class of
carbanion donors, furthermore undergo the Schlenk equilibrium
between two equivalents of an alkyl or aryl magnesium halide (2
RMgX) and one equivalent each of the dialkyl- or diarylmagnesium
compound (RMgR) and the magnesium halide salt (MgX.sub.2). This
disproportionation reaction multiplies the reactive species
present, and is a sometimes problematic complication in their
applications as carbanion sources.
[0009] Only a few of the known organolithium compounds, such as
butyllithium, methyllithium, and phenyllithium, are commercially
available. Many organolithiums that are not commercially available
must be prepared from metal-halogen exchange reactions (for a
general reference, see Wakefield, B. Organolithium Methods;
Academic Press: London, 1988) that use one organolithium reagent
and an organic halide in an exchange reaction. Alternatively, pure
lithium metal and an organic halide can be reacted to form an
organolithium. These transformations represent equilibrium
reactions between organic halides, lithium metal, lithium halides
and organolithium compounds. Synthesizing a clean organolithium
product is difficult since there is often contamination with
unreacted organic halides, which adds hardship to any large scale
process development. Lithiation can also be performed by
deprotonation reactions or by reductive cleavage of ethers and
thioethers (Schlosser, M. Organometallics in Syntheses; Wiley and
Sons: Chichester, 1994, 47), the Shapiro method (Shapiro, R. H.
Org. React. 1976, 23, 405), or arene-catalyzed lithiation (Yus, M.;
Ramon, D. J.; J. Chem. Soc., Chem. Commun. 1991, 398). These
methods begin by utilizing organolithium itself, functioning as a
base, and therefore they are not atom-economic from a synthetic
standpoint. The approach of directly reacting lithium metal with
the halogenated form of the target organic group is strongly
avoided in most industries because of the high reactivity and
pyrophoric nature of finely divided Li metal. Dispersed lithium
prepared in a refluxing hydrocarbon also causes hardship in large
scale ups (Joshi, D. K.; Sutton, J. W.; Carver, S.; Blanchard, J.
P. Org. Process Res. Dev.; 2005; 9(6); 997-1002.). Alternatively,
mercury-lithium (Schollkopf, U.; Gerhart, F. Angew. Chem. Int. Ed.
Engl. 1981, 20, 795), tellurium lithium (Shiner, C. S.; Berks, A.
H.; Fisher, A. M. J. Am. Chem. Soc. 1988, 110, 957, Hiiro, T.;
Mogami, T.; Kambe, N.; Fujiwara, S-I.; Sonoda, N. Synth. Commun.
1990, 20, 703) and tin-lithium (Hoffmann, R. W.; Breitfelder, S.;
Schlapbach, A. Helv. Chim. Acta 1996, 79, 346) mediated
transmetallations are also possible, but mercury, tellurium and tin
compounds are generally toxic, making these reagents unsuitable for
large scale industrial processes.
[0010] In a different strategy from the present invention,
alkyllithiums (MeLi, EtLi) are stabilized by adsorbing the
alkyllithium onto the surface of a nonporous inorganic support,
such as SiO.sub.2, CaO, or Al.sub.2O.sub.3, and then coated with a
paraffin wax (Deberitz et al. U.S. Pat. No. 5,149,889). However, in
this case, one has to use pre-made alkyllithium reagents. Then, to
activate the reactivity, the user must remove the oil, wax, or
hydrocarbon, which can add another undesirable separation step. An
additional major difference from the current invention is the fact
that the alkyllithium is adsorbed onto the surface of the inorganic
support, not absorbed into the support. This strategy highlights
the chemical industry's need and desire for stabilized and easily
useable alkyllithium reagents.
[0011] Like organolithium compounds, lithium amides have a limited
commercial availability. While they can be prepared with difficulty
from lithium and a primary or secondary amine, they are most
conveniently prepared by treatment of a primary or secondary amine
with an organolithium reagent. Thus, lithium amide use suffers from
many of the same limitations as the organolithium reagents from
which they are typically derived. The three most common
organolithium reagents used for generating lithium amides are
methyllithium, butyllithium, and phenyllithium, which produce
methane, butane, and benzene respectively during the reaction. All
of these byproducts pose drawbacks in a manufacturing environment
since they are all volatile, flammable materials. Methane and
butane are flammable gases at room temperature and their generation
as stoichiometric byproducts in large scale manufacturing is
problematic and costly. Benzene is toxic and a known
carcinogen.
[0012] A need exists, therefore, to have organolithium and lithium
amide reagents available in a dry form that may be easily handled,
stored, and used without a significant loss of their reactivity.
This invention answers that need.
SUMMARY OF INVENTION
[0013] In one embodiment, this invention relates to lithium
metal/porous metal oxide compositions. These lithium metal
compositions are prepared by mixing liquid lithium metal with a
porous metal oxide in an inert atmosphere under exothermic
conditions sufficient to absorb the liquid lithium metal into the
porous metal oxide pores. The lithium metal/porous metal oxide
compositions of the invention are preferably loaded with lithium
metal up to about 40% by weight, with about 20% to 40% by weight
being the most preferred loading.
[0014] In another embodiment, this invention also relates to
lithium reagent-porous metal oxide compositions having RLi absorbed
into a porous oxide. In formula RLi, R is an alkyl group, an
alkenyl group, an alkynyl group, an aryl group, an alkaryl group,
or an NR.sup.1R.sup.2. group; R.sup.1 is an alkyl group, an alkenyl
group, an alkynyl group, an aryl group, an alkaryl group; and
R.sup.2 is hydrogen, an alkyl group, an alkenyl group, an alkynyl
group, an aryl group, an alkaryl group.
[0015] Accordingly this invention also relates to methods for
creating new compositions of lithium, organolithium, and lithium
amide species formed and stored inside porous metal oxides, like
alumina (Al.sub.2O.sub.3, alumina gel). Lithium absorbed into
porous Al.sub.2O.sub.3 can be used to prepare and form
organolithium and lithium amide compounds inside the pores, as well
as for in situ generation of carbanions for nucleophilic addition
and polymerizations. Pre-made organolithium compounds can also be
absorbed into the pores of solid inorganic supports, such as silica
or alumina gel, enabling their solvent-free storage and delivery
for use in synthetic transformations. These new compositions are
solid-state free-flowing powders that are suitable for use in both
batch and flow reactors.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIGS. 1A-1C shows spectra representative of the results of
Example 3.
[0017] FIG. 2 shows a .sup.1H NMR spectrum representative of the
results of Example 4.
[0018] FIGS. 3A-3C show .sup.1H NMR, .sup.13C NMR, and ESI-MS
spectra representative of the results of Example 7.
[0019] FIG. 4 shows an .sup.1H NMR spectra representative of the
results of Example 8.
[0020] FIGS. 5A-5C show .sup.1H NMR, GC-MS, and .sup.13C NMR
spectra representative of the results of Example 9.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The ability to utilize alkali metals, their equivalents, and
their derivatives in a convenient form continues to be a need in
academia, the chemical industry, and for the hydrogen production
community. Answering that need, the invention relates to absorbing
lithium metal into a porous metal oxide. The porous metal oxides
utilized in the composition invention are non-reducible porous
metal oxides, porous alumina being a particularly preferred porous
metal oxide. The invention also relates to lithium reagent-porous
metal oxide compositions, organolithium reagents and lithium amides
absorbed into a porous metal oxide. These lithium reagent-porous
metal oxide compositions provide a greater variety of accessible
nucleophiles and possess significant advantages in handling and
storage over currently known lithium reagents.
[0022] Lithium Metal-Porous Metal Oxide Compositions
[0023] Lithium, the chemical element with the symbol Li, is in
Group 1 of the periodic table, among the alkali metals. It is the
lightest of all metals and has a density of only half that of
water. Lithium is a soft, silvery metal that has a single valence
electron, which it readily loses to become a positive ion. Because
of this, lithium is flammable and reactive when exposed to oxygen
or nitrogen, and especially water. Accordingly, the metal should be
stored in a non-reactive atmosphere or in a non-reactive liquid,
such as a hydrocarbon or naphtha. Though in Group 1, lithium also
exhibits some properties of the alkaline-earth metals in Group
2.
[0024] In preparing the lithium-porous metal oxide compositions,
lithium metal is preferably mixed with a porous metal oxide (e.g.
porous alumina gel) and then heated until the lithium metal melts
and is absorbed into the metal oxide pores. One method to
accomplish this is heating the lithium metal in an inert
atmosphere, such as argon or helium, prior to mixing it with a
porous metal oxide. Alternatively, the lithium metal may be mixed
as a solid with the porous alumina and the mixture heated to melt
the lithium metal. The heat treatment to absorb the lithium metal
can range from 160-325.degree. C., preferably between
160-225.degree. C. Another possible way to introduce the lithium
metal into the porous alumina is from the vapor phase as done with
zeolites (See A. S. Ichimura, J. L. Dye, M. A. Camblor and L. A.
Villaescusa, J. Am. Chem. Soc., 124, 1170-1171 (2002) and D. P.
Wernette, A. S. Ichimura, S. A. Urbin and J. L. Dye, Chem. Mater.
15, 1441-1443, (2003)). In another possible method, the lithium
metal could be deposited into the porous alumina from a
metal-ammonia solution (See M. Makesya and K. Grala, Syn. Lett.
1997, pp. 267-268).
[0025] A lithium porous metal oxide composition, such as the
preferred lithium-alumina gel (Li-AG), may be prepared directly
heating a mixture of bulk, or shaved, lithium metal with the
calcined porous metal oxide, e.g. alumina, to form loose black
powders that retain much of the reducing ability of the parent
metals. This reaction preferably occurs in an inert atmosphere,
such as in argon or helium. It is believed the lithium-porous metal
oxide compositions have small clusters of neutral lithium metal
absorbed in the porous metal oxide pores as well as possibly
ionized lithium metal (Li.sup.+) located at the walls of the pores
with the electron delocalized from the atom. The materials are
pyrophoric, but less reactive in air than finely divided neat
lithium metal. The heating of the lithium metal with the porous
alumina gel occurs between about 160.degree. C. and about
325.degree. C., preferably between about 160.degree. C. and about
225.degree. C. The heating may be done over a period of time until
all of the lithium metal is absorbed, and even overnight.
[0026] The lithium metal is believed to be so finely dispersed
inside the alumina gel or other porous metal oxides. The
lithium-alumina gel is capable of reacting almost completely with
nitrogen (N.sub.2) gas. The product of the reaction of
lithium-alumina gel with nitrogen gas produces finely dispersed
lithium nitride (Li.sub.3N) inside the pores of the alumina. The
reaction of this Li.sub.3N with water calmly produces clean ammonia
gas on demand by the following reaction (where AG signifies alumina
gel):
Li.sub.3N-AG.sub.(s)+3H.sub.2O.sub.(l).fwdarw.3LiOH.sub.(aq)+NH.sub.3(g)
This material, therefore, produces ammonia by a method that avoids
the hazards of its transportation, transfer, and storage. This pure
ammonia can be used for many applications including, but not
limited to, the treatment of stack gases containing oxides of
nitrogen (NO.sub.x) from fossil fuel combustion processes. The
lithium-porous metal oxide compositions of the invention may,
accordingly, be used to scrub nitrogen gas from inert
environments.
[0027] The lithium metal-porous metal oxide composition of the
invention is preferably loaded with lithium metal up to about 40%
by weight, with about 10% to 20% by weight being the most preferred
loading.
[0028] The porous metal oxides which may be used may be any metal
oxide that is not reduced by the lithium metal. The porous metal
oxide powder used in this invention that is most preferable is
porous alumina (also referred to as alumina gel, particularly
.gamma.-alumina gel). Other porous metal oxide powders that may be
used for this invention are any transition metal oxide that is not
reduced by the lithium metal, such as porous titanium oxide (i.e.
TiO, TiO.sub.2, Ti.sub.2O.sub.3, Ti.sub.3O.sub.5), porous calcium
oxide (CaO), porous zirconia (i.e. ZrO.sub.2), porous iron oxide
(i.e. Fe.sub.2O.sub.3 or Fe.sub.3O.sub.4), porous Co.sub.3O.sub.4,
porous metal phosphate (MPO), porous hybrid phosphosilicate, porous
aluminates, porous alumino silicates, porous vanadates, molybdates,
etc. Silica gel can only be used to absorb pre-made solvated
organolithium reagents due to the high reactivity between silica
and neat lithium metal. Given their porous nature, these porous
metal oxides can take up large amounts of absorbed material. The
composition of this invention has the lithium metal absorbed inside
the pores of the oxide along with the created carbanion or amide
species. Porous alumina can be purchased from many companies, such
as W.R. Grace & Co. or Almatis AC.
[0029] The porous metal oxides used in the porous metal oxide
compositions of the invention preferably have average pore sizes
ranging from 30 .ANG. to 500 .ANG.. More preferably, the average
pore size may range from 60 .ANG. to 190 .ANG..
[0030] Although porous metal oxides, when purchased, are
free-flowing powders, they typically contain gaseous material, such
as water and air. These are preferably removed prior to mixing the
porous oxide powders with lithium metal to form compositions of the
invention. The porous metal oxide may be de-gassed using methods
known in the art. For example, to remove the gaseous material the
porous metal oxide may be heated under vacuum in an evacuable
flask, first with a hot air dryer and then with a torch. Such
heating achieves temperatures of approximately 300.degree. C. It is
also possible, and is actually preferred, to remove the gases more
easily and to passivate active sites by heating the porous metal
oxide to 600.degree. C. or hotter (.about.900.degree. C.) in air
(calcination). The porous metal oxide is typically cooled to room
temperature in a dry (and preferably inert) atmosphere before
preparing a composition of the invention.
[0031] Lithium Reagent-Porous Metal Oxide Compositions
[0032] This invention also relates to lithium reagent-porous metal
oxide compositions having RLi absorbed into a porous metal or
non-metal oxide. In formula RLi, R is an alkyl group, an alkenyl
group, an alkynyl group, an aryl group, an alkaryl group, or an
NR.sup.1R.sup.2 group; R.sup.1 is an alkyl group, an alkenyl group,
an alkynyl group, an aryl group, an alkaryl group, an XR.sub.n
group (where X can be a heteroatom such as, for example, Si, S, Sn,
Ge, P, and n is an integer), or a Si(R.sup.3).sub.3 group; R.sup.2
is hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an
aryl group, an alkaryl group, or an Si(R.sup.3).sub.3 group; and
R.sup.3 is an alkyl group, an alkenyl group, an alkynyl group, an
aryl group, an alkaryl group. The lithium reagent-porous metal
oxide compositions may be prepared by reacting a lithium
metal-porous metal oxide composition with an organo halide, RX; by
the in situ combination of lithium metal, a porous metal oxide, and
an organo halide, RX; by absorption of a lithium reagent, RLi, into
a porous metal oxide; or by reacting a lithium metal-porous oxide
composition with a primary or secondary amine. HNR.sup.1R.sup.2.
The groups R, R.sup.1, R.sup.2 and R.sup.3 may be further
substituted with functional groups or contain heteroatoms such as
N, O, S, etc. which do not react with the lithium in such a way as
to prevent the formation of a lithium reagent-porous metal oxide
composition of the invention. Preferred and exemplary embodiments
for R, R.sup.1, R.sup.2 and R.sup.3 are described below.
[0033] To prepare a lithium reagent-porous metal oxide composition
of the invention, the Li-porous metal oxide composition, prepared
as described above, may be cooled in a reaction vessel between
about 0.degree. C. and about -78.degree. C. Then a haloorganic
compound, or when R.dbd.R.sup.1R.sup.2N, a primary or secondary
amine, (both within RX), is slowly added to the Li-porous metal
oxide, either neat or in a solvent. The haloorganic or amine moves
into the pores, and reacts with the lithium metal to create the
organolithium compound inside the pores of the metal oxide. After
the reaction is heated to room temperature, any excess haloorganic,
amine, and/or solvent is distilled off to complete the formation of
a dry, free-flowing powder of a Li reagent-porous metal oxide
composition. As shown in Example 8 below organolithium-porous metal
oxide compositions may also be prepared by the reductive cleavage
of carbon-heteroatom bond such as vinyllithium from ethyl vinyl
ether.
[0034] When the lithium reagent is an organo-lithium compound, the
haloorganic compounds, RX, that may be used include, but are not
limited to, alkyl halides, alkenyl halides aryl halides, and
alkaryl halides. Preferred halogens are chloride, bromide, and
iodide. The alkyl, alkenyl, and alkynyl groups may be straight or
branched chains as well as cyclic and heterocyclic alkyl, alkenyl
or alkynyl groups. The aryl and alkaryl groups can be heteroaryl
and alk-heteroaryl groups. The alkyl groups may preferably a
C.sub.1-C.sub.12 alkyl or a C.sub.5 to C.sub.12 cycloalkyl group.
The alkenyl groups may preferably a C.sub.2-C.sub.12 alkenyl or a
C.sub.3 to C.sub.12 cycloalkenyl group. The alkynyl groups may
preferably a C.sub.2-C.sub.12 alkynyl or a C.sub.3 to C.sub.12
cycloalkynyl group. The aryl and alkaryl groups can be heteroaryl
and alk-heteroaryl groups. The "alk" portion of the alkaryl group
may be an alkyl, an alkenyl, or an alkynyl group as described
here.
[0035] Preferred alkyl groups are methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclopropyl,
cyclobutyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl,
homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl,
n-octyl, and the like. Preferred alkenyl groups include ethenyl,
allyl, and isomers of butenyl, pentenyl, hexenyl, heptenyl,
octenyl, nonenyl, decenyl cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohepentenyl,
cycloheptadienyl, cyclooctenyl, cyclooctadienyl, and the like.
Preferred alkenyl groups include acetylenyl and isomers of butynyl,
pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl. Preferred
aryl and alkaryl groups are phenyl, benzyl, and isomers of tolyl,
anisyl, analinyl, naphthyl, indenyl, anthryl, pyrrolyl, pyridyl,
pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl,
furyl, thienyl, imidazoyl, pyrazoyl, thiophene, N-alkylated pyrole,
.alpha.-alkylated pyridine, indolyl, quinolinyl, iso-quinolinyl and
the like.
[0036] When RLi is R.sub.1R.sub.2NLi, the primary or secondary
amines used to form the Li amide-alumina gel composition include,
but are not limited to, alkylamines, dialkylamines, alkylarylamine,
and diarylamines, as well as cyclic secondary amines. The organic
groups bound to nitrogen in these amines or for R.sup.3 in the
silyl group Si(R.sup.3).sub.3 can include those described above for
R. Preferred alkyl groups are preferably methyl, ethyl, n-propyl,
isopropyl, n-butyl, trimethylsilyl, triethylsilyl, t-butyl,
isobutyl, sec-butyl, homologs, and isomers of, for example,
n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Preferred aryl
and alkaryl groups are phenyl, benzyl, and isomers of tolyl,
anisyl, analinyl, naphthyl, indenyl, anthryl. Preferred cyclic
secondary amines are pyrrolidine, piperidine, and
2,2,5,5-tetramethylpiperidine.
[0037] Any inert solvent which does not react with the lithium may
be used in the preparation of the lithium reagent compositions of
the invention. For example, non-reactive hydrocarbons such as
hexanes or heptane or a non-reactive ether such as THF may be used.
THF is generally preferred. Highly polar solvents may unfavorably
compete with the reagent RX when forming the lithium
reagents-porous metal oxide compositions.
[0038] Another method to generate organolithium-porous metal oxide
compositions of the invention is via a carbon-hydrogen activation,
meaning that the organolithium-alumina gel performs a deprotonation
of a carbon atom of an added reagent to generate a new carbanion
species. This organolithium exchange is typically performed at cold
temperatures (e.g. about 23.degree. C. to about -80.degree. C.).
Once the new organolithium reagent is formed, it can then be used
as a nucleophile or base in a subsequent reaction with available
substrates. This reaction can be performed either in a batch or
flow reactor setup.
[0039] Yet another method to generate organolithium-porous metal
oxide compositions of the invention is to perform an in situ
metal-halogen (metal-element) exchange to transform one
organolithium-porous metal oxide to a second organolithium-porous
metal oxide. A single reaction vessel, either batch or flow, is
charged with a haloorganic compound, RX, or any activated species
with a C--Z bond (where Z can be any halide or an acidic hydrogen,
etc.), can first be dissolved in THF at cold temperatures and then
have organolithium-porous metal oxide added to the vessel. After
the cold (i.e. between about 23.degree. C. and about -80.degree.
C.) slurry has been well mixed for a time, the organolithium is
available to react in the conventional manner with subsequently
added reagents.
[0040] The organolithium-alumina gel may also be prepared by an in
situ reaction using cut pieces of lithium, porous alumina gel, and
alkyl halide solution (preferably, for example, hydrocarbon or
ether), and evaporating off the solvent.
[0041] The organolithium reagent-porous metal oxide compositions of
the invention may also be prepared by the absorption of a pre-made
organolithium species in a solvent into the pores of silica gel or
alumina gel under cold conditions. The excess solvent is then
distilled away and the powder is vacuum dried. The product is
non-pyrophoric and is preferably referred to as
organolithium-silica gel or organolithium-alumina gel. The method
absorbs an organolithium species into the pores of a porous metal
oxide material by contacting the organolithium species with the
porous material under cold conditions (e.g. about 23.degree. C. to
about -80.degree. C.), distilling any excess solvent, and drying
the resulting organolithium material.
[0042] The resulting free-flowing powders, organolithium-porous
metal oxide compositions having RLi absorbed into a porous metal
oxide performs all the reaction types of conventional organolithium
compounds, such as nucleophilic additions to electrophiles,
initiation of polymerizations, and base-catalyzed reactions, among
many others. When there is no residual lithium metal in the
material, the powder is also stable under nitrogen. With or without
residual lithium, this material has an extended shelf life at room
temperature compared to commercially available and conventional
solutions of organolithium compounds that tend to aggregate, react,
and decompose in the solvents they are stored inside.
[0043] Another method to generate lithium amide-porous metal oxode
with the invention is to use an organolithium-porous metal oxide to
deprotonate a primary or secondary amine. In a single reaction
vessel, either batch or flow, a primary or secondary amine,
preferably dissolved in a solvent, is charged to a stirring batch
of organolithium-porous metal oxide. After the slurry is well mixed
and allowed to react, any excess amine and/or solvent are decanted,
removed under vacuum, or distilled at low temperature to complete
the formation of a dry, free-flowing powder of lithium amide-porous
metal oxide.
[0044] The lithium amide-porous metal oxide compositions
(R.dbd.R.sup.1R.sup.2N) (free-flowing powders) perform the
reactions known for conventional lithium amide compounds. These
reactions include, but are not limited to, deprotonation of most
common carbon acids including alcohols and carbonyl compounds
(aldehydes and ketones). When there is no residual lithium metal in
the material, the powder is also stable under nitrogen. With or
without residual lithium, the material has an extended shelf life
at room temperature compared to commercially available or
conventional lithium amide compounds that tend to aggregate and
decompose slowly. Usual methods for making these lithium amides
involves the reaction of alkyl lithium species with the
corresponding amine (e.g., international Patent Application
Publication No. WO 03033505 by Detlef et. al.), heating a mixture
of lithium with an amine above the melting point of the metal (Chiu
et al., U.S. Pat. No. 5,420,322) or with small amount of isoprene
as an electron carrier (Corella et al., U.S. Pat. No.
6,169,203).
[0045] As discussed above, a lithium-porous metal oxide
composition, such as a lithium-alumina gel composition, may be used
as a starting component for the generation of the corresponding
lithium reagent composition of the invention, e.g. the
corresponding organolithium-alumina gel or lithium amide-alumina
gel composition. As a more specific example of the preparation of
such a corresponding composition, the lithium-alumina gel is cooled
to temperatures ranging from about -80.degree. C. to about
0.degree. C. and stirred for several minutes. To the stirring
lithium-alumina gel, a haloorganic, either in its neat form or in
solution of a non-reactive hydrocarbon or ether solvent such as
tetrahydrofuran (THF), is slowly added. The reaction mixture is
stirred for several hours at cold temperatures. Any excess
unreacted haloorganic, or solvent, may be distilled off under
vacuum while the system temperature is raised to room temperature.
The strength (reaction equivalents per gram) of the final
organolithium-alumina gel composition is measured by performing the
nucleophilic addition to an electrophile in a separate reaction
setup. In the case of butyl bromide, the reaction appears to
be:
2Li+BuBr.fwdarw.BuLi+LiBr
Using the pure compound densities of LiBr (3.464 g/cm.sup.3) and
BuLi (0.67 g/cm.sup.3), the volume per mole of products is 25.1
cm.sup.3 for LiBr and 95.5 cm.sup.3 for BuLi for a total of 120.6
cm.sup.3/mole. The void volume in alumina gel (from mercury
porosimetry) is 1.56 cm.sup.3/g. Assuming that the products fit in
the pores without increasing the volume, then for a sample of
alumina gel of mass 8.0 g, there is a maximum of 12.5 cm.sup.3 of
void space. That means that 8.0 g of AG could accommodate
12.5/120.6=0.110 moles of reaction, which would require 1.53 grams
of Li. This would correspond to a Li loading of
(1.53/9.53).times.100=16.0 wt %. The loading of BuLi would then be
0.110/9.53=0.0115 moles/g lithium-alumina gel or 11.5 mmol/g
lithium-alumina gel.
[0046] The maximum loading of the organolithium-alumina gel for two
example systems, butyllithium-alumina gel and methyllithium-alumina
gel, are shown in Table 1 below on the basis of 10 g total weight
of lithium-alumina gel used:
TABLE-US-00001 TABLE 1 Maximum Loadings For BuLi: 2Li + BuBr -->
BuLi + LiBr Loading of Lithium Alumina Gel 15.0% Total Available
Volume 13.26 cc Volume per Mole of BuLi Produced 95.52 cc/mol
Volume per Mole of LiBr Produced 25.12 cc/mol Reaction Potential in
Alumina (mol) 0.11 moles Amount of Li to Complete Reaction (g) 1.54
g Volume of BuLi Produced 10.50 cc Volume of LiBr Produced 2.76 cc
Amount of BuLi in Alumina 10.99 mmol/g of Li-AG For MeLi: 2Li + Mel
--> MeLi + Lil Loading of Lithium Alumina Gel 17.2% Total
Available Volume 12.92 cc Volume per Mole of MeLi Produced 66.67
cc/mol Volume per Mole of Lil Produced 38.35 cc/mol Reaction
Potential in Alumina (mol) 0.12 moles Amount of Li to Complete
Reaction (g) 1.72 g Volume of MeLi Produced 8.20 cc Volume of Lil
Produced 4.72 cc Amount of MeLi in Alumina 12.30 mmol/g of
Li-AG
[0047] The amount of lithium metal loading is dependent upon the
pore size and pore density of the actual porous metal oxide used.
Typically, the lithium metal may be present in the compositions of
the invention up to about 40% by weight. Preferably, the amount of
metal ranges from 20% to 40% by weight, if the material is being
used for typical reductions and in situ lithiation applications.
The preferred loading to generate organolithium-porous metal oxide
and lithium amide-alumina gel compositions ranges from 10% to 20%
lithium by weight. In the lithium-porous metal oxide compositions
of the invention, loadings above about 40% by weight can result in
some free metal remaining on the surface of the porous metal
oxide.
[0048] Various additives known to stabilize organo lithium reagents
may also be used with the lithium reagent-porous metal oxides.
These include but are limited to stabilizers, such as tetramethyl
ethylenediamine (TMEDA), diazabicycloundecane (DBU), sparteine (see
Tsumaki et al., U.S. Pat. No. 6,024,897), may also be added to
further increase the stability of the carbanions in these solids.
For example, stabilized versions of organolithium species can be
made by using tetramethylethylenediamine (TMEDA) as an additive to
the synthesis. Typically, for every two (2) moles of lithium, one
(1) mole of haloorganic and one (1) mole of TMEDA is used to make
organolithium-TMEDA-porous metal oxide. The molecular structure of
TMEDA corresponds to one molecule of 1,2-diaminoethane alkylated
with two methyl groups on each of the two amine nitrogen atoms.
TMEDA, or other tertiary amine stabilizers, can be used as
additives to help stabilize these reagents by virtue of the
tertiary nitrogen coordination with the lithium cation.
Potentially, this ion complexation expands the effective radius and
reduces the electrophilicity of the lithium cation, isolating it
from the carbanion portion and thus limiting its capacity for
beta-hydride abstraction from the alkyl carbanion. This mode of
stabilization is also thought to enhance the carbanion's
availability for reaction with externally added reagents.
[0049] Use of Lithium- and Lithium Reagent-Porous Metal Oxide
Compositions
[0050] The lithium-porous metal oxide compositions and the lithium
reagent-porous metal oxide compositions of the invention may be
used for the same reactions as is lithium metal, organolithium
reagents and lithium amide reagents. These include, but are not
limited to nucleophilic addition reactions, polymerization
reactions, and base-catalyzed reactions. Table 2 provides an
exemplary list of such reactions. The compositions of the
invention, however, have the advantage of being free flowing
powders and more storage stable.
TABLE-US-00002 TABLE 2 Reagent Use Reaction example Reference
RLi-AG (1) Nucleophilic additions RLi +
R.sub.2CO.fwdarw.R.sub.3COLi Wu, G. Huang, M. to carbon centered
RLi + CO.sub.2.fwdarw. RCO.sub.2Li Chem. Rev.2006, electrophile
106, 2596. (2) Preparation of 2RLi + Walborsky, H. M.;
organocuprate or Gilman's CuX.fwdarw.R.sub.2CuLi + LiX Ronman, P.
J. Org. reagent Chem., 1978, 43, 731 (3) Preparation of RLi +
PX.sub.3.fwdarw.PR.sub.3 + 3LiX organophosphorous, RLi +
RSCN.fwdarw.RSR + LiCN organosulfur, organoboron, organotin
compounds from appropriate electrophiles (4) Preparation of lithium
RLi + House et al., J. Org. amides such as LDA and
R.sub.2NH.fwdarw.R.sub.2NLi + RH Chem., 1978, 43, LiHMDS 700. (5)
Directed ortho-lithiation and subsequent quenching with
electrophiles. (6) Preparation of enolates nBuLi + toluene.fwdarw.
Eisch, J. J. and other deprotonations BnLi + nBuH Organomet. Synth.
(e.g., preparation of other 1981, 2, 95. organolithium by Li--H
exchange) (7) Initiator for anionic polymerizations (8) Generation
of Ylides in R.sub.3PCH.sub.3Br.fwdarw.R.sub.3P.dbd.CH.sub.2
Maercker, A. Org. Wittig reaction React. 1965, 14, 270. (9)
Generation of carbene R.sub.2CX.sub.2.fwdarw.R.sub.2C: Xu, L.; Tao,
F.; Yu, T. Tetrahedron Lett. 1985, 26, 4231. (10) Isotopic
labelling (e.g., RLi + D.sub.2O.fwdarw.RD + LiOD D, T) (11) Shapiro
reaction R.sub.2NLi-AG (1)As non-nucleophilic base Elimination
(e.g., .beta.-H), Lochmann et al., J. such as LDA sigmatropic
carbanion Organometallic rearrangements, Chem, 1979, 123.
generation of carbanions, reductive cleavage of ethers,
ortholithiations, aldol reactions, anionic polymerizations Li-AG
(1) Preparing organolithium RX + 2Li.fwdarw.LiX + RLi Main Group
Metals compounds by halogen- RSR + Li.fwdarw.RLi + RSLi in Organic
metal exchange or reductive Synthesis by cleavage of C--O, C--S or
C--P Tomooka, K.; Ito, M. bonds. 2005, Wiley- (2) Reductions of
cabonyls, R.sub.2CO .fwdarw. R.sub.2CHOH Verlag, Gmb.quadrature.H
aromatics (Birch reduction) (3) Generation of reactive NpH +
Li.fwdarw.Np(-)Li(+) intermediates such as arenides,
[0051] Additionally, as solid state reagents, the lithium-porous
metal oxide compositions and the lithium reagent-porous metal oxide
compositions of the invention may be used for reaction purposes in
several ways. The simplest mode is a conventional batch reaction in
which the solid reagent is stirred in a slurry with a solution of
substrate(s). Here, the principle advantages over commercially
available solid lithium preparations or solutions of organolithium
or lithium amide reagents are in (a) ease of solids handling and
(b) minimization of organic solvent usage in reaction, quenching,
and workup procedures. In favorable cases, when solid acids are
included in the slurry, direct isolation of the organic solution
containing only neutralized product is facilitated by the affinity
of the solid oxide gel (e.g. alumina or silica) for ionic
byproducts which therefore do not have to be removed via separate
organic/aqueous partition and washing steps.
[0052] A second mode of use is in a process flow reactor, (e.g. a
column flow reactor), in which solutions of reaction substrate
percolate through a packed bed of the solid lithium alumina gel,
organolithium-solid oxide, or lithium amide-solid oxide reagent.
With flow process reactors, or continuous flow reactors, fresh
reactant solution is continuously added to the reactor solid-state
reagent. Reaction products are continuously removed while the waste
is either left bound to the supported reagent or co-eluted with
desired products. The advantages of using a flow process reactor
are numerous. For example, the reactor insures efficient use of all
the reagent material, only having to be shut down when its reaction
capacity is fully exhausted. The result is a process both more
productive and more efficient in gel material and in solvent than a
conventional batch reaction. An example of a flow process reactor
is a fixed-bed flow reactor in which a liquid solution of reaction
substrate is percolated through a column of solid reagent, such as
for example an organolithium-alumina gel, with direct collection of
the product solution at the column's exit. While virtually any type
of reaction process and reactor may be used for the reactions
described herein, a flow process reactor, such as a fixed-bed flow
column reactor, is the preferred reactor type for the reactions of
the invention.
[0053] Depending on choice of solvent and the nature of the organic
portions, organolithium or lithium amide species formed via
reaction of haloorganic or organic amines with lithium-alumina gel
may be soluble enough to be eluted, providing flexible access to
freshly prepared solutions of pure organolithium or lithium amide
reagents. Alternatively, when a targeted organolithium species is
expected to be particularly unstable or short-lived, its
electrophilic partner (e.g. proton source, ketone, etc.) may be
directly included in solid form in the bed of the packed column,
again providing quenched neutral product in pure form at the column
exit.
[0054] Alternatively, a sequential reaction scheme is possible, in
which a solid oxide-bound organolithium or lithium amide formed in
situ from the lithium-alumina gel is then allowed to react with a
solution of substrate, fed in the same or different solvent, and
forming product that is subsequently eluted from the column. This
method is thus advantageous in terms of (a) efficient usage of the
lithium's reactivity, (b) safety, since the eluted product is free
of lithium metal, (c) in applications that call for the
intermediacy of unstable organolithium species, and (d) in allowing
sequential formation and reaction of supported reactants, followed
by their elution from polar/ionic byproducts and unreacted lithium
metal.
EXAMPLES
Example 1
Preparation of Li-AG (10% w/w)
[0055] In a He glove box 3.16 g of lithium ribbon (1.425 g/ft) was
weighed out and cut into small pieces and coated thoroughly with
28.4 g Alumina gel (AG) before putting into the steel reactor. The
steel reactor was heated to 100.degree. C. for 6 hours, 165.degree.
C. for overnight, 182.degree. C. for 8 hours and 190.degree. C. for
overnight. The steel reactor was cooled and transferred into the
glovebox. A small representative sample of 76.7 mg was tested for
H.sub.2 evolution with water. The amount of H.sub.2 collected came
out to be equivalent to 9.2% of Li. Variations in the amount of
lithium loadings have been prepared ranging from 5 wt % to 40 wt %
by varying the stoichiometric ratio of lithium metal to porous
alumina gel.
Example 2
Preparation of Organolithium Species Stabilized Inside
Lithium-Alumina Gel
[0056] RX+2Li in .gamma.-Al.sub.2O.sub.3.fwdarw.RLi+LiX
where RX can be halides (chloride, bromide or iodides) of aliphatic
(methyl, butyl etc), aromatic (Phenyl), benzylic, allylic,
homoallylic, propargyllic, sec-alkyl, tert alkyl or neopentyl
groups.
[0057] 1 g 10% (14 mmole Li) Li in .gamma.-Al.sub.2O.sub.3 was
taken in a round bottom flask and chilled in a dry ice-acetone bath
at -78.degree. C. followed by dropwise addition of methyl iodide (2
mL) (neat) into the stirring slurry. The reaction was stirred cold
for 2 hours. The excess methyl iodide was distilled off after the
addition was complete and the mixture reached room temperature. A
small amount of ethane and I.sub.2 was produced during this
preparation, but this Wurtz coupled product could be minimized by
maintaining the cold temperature for a longer duration. The
strength of MeLi in alumina was determined through the nucleophilic
addition reaction with excess benzophenone. Between various runs,
the loading of MeLi in alumina (prepared from 10-25% Li in
.gamma.-Al.sub.2O.sub.3) was determined to be between 3-7 mmol/g.
For stoichiometric reactions of organolithium and benzophenone the
nucleophilic addition product yield varied between 75%-90% along
with traces of ortholithiation product.
[0058] PhCH.sub.2Li, n-BuLi, allyllithium and homoallyllithium were
prepared using the same procedure and tested for reactivity with
enzophenone.
##STR00001##
Example 3
Preparation of Organolithium-Alumina Gel with TMEDA Stabilizer
[0059] In a flask containing 2 g of Li-AG (25% Li by weight) a
mixture of 2 g TMEDA, 3 g n-butyl bromide in 20 mL of pentane was
distilled in and stirred at -80 C for 3 hours, followed by a
replacement by a dry ice bath at -40.degree. C. and stirring the
reaction overnight till it reached room temperature. The solvents
were removed under vacuum to afford a grey free flowing powder. 200
mg of this material was reacted with 1.1 mmole (200 mg) of PhCOPh
to afford butyl diphenyl alcohol in 60% yield. FIG. 1A shows the
.sup.1H NMR of the butyldiphenyl alcohol product.
[0060] The presence of the butyl anion was also confirmed by
running a gas evolution reaction of this material with water and
analyzing the gas by GC-MS that indicated formation of butane
(MW=58) according to the following reaction. See FIGS. 1A-1B.
C.sub.4H.sub.9Li+H.sub.2O.fwdarw.C.sub.4H.sub.10+LiOH
Example 4
Generation of Organo Lithium-Porous Metal Oxide Composition and One
Pot Nucleophilic Addition to Ketone
##STR00002##
[0062] 1.5 mmole of homoallylbromide (195 mg) was dissolved in 5 mL
dry and distilled THF and this solution was cooled to -78.degree.
C. To this cooled solution 0.5 g of Li in .gamma.-Al.sub.2O.sub.3,
(8-12% w/w, 7-10 mmole of Li), was added through a solid addition
tube for a period of 15 minute. The slurry was stirred for 30
minutes under the same cold condition. To the cold stirring slurry,
1 mmole of benzophenone (182 mg) dissolved in 3 mL THF was added
over a period of 15 minutes. The reaction was warmed to room
temperature slowly (6 h), followed by quenching with cold water and
extraction with EtOAc. The organic layer was evaporated under
nitrogen yielding 200 mg (85%) of oily residue.
[0063] FIG. 2 shows the .sup.1H NMR (.delta. in ppm) of the product
1H homoallyldiphenyl methyl ketone with peaks as follows: 7.2-7.8
(m, 10H), 5.8-6.0 (m, 1H), 5.0-5.2 (m, 2H), 2.4-2.6 (m, 2H),
2.05-2.15 (m, 2H).
Example 5
Generation of Organolithium (Lithium Amide) from the Reaction of a
Secondary Amine with Lithium in Alumina Gel
[0064] 1 g of lithium-alumina gel (loaded with 25 wt. % Li) was
reacted with dimethyl amine (.about.4 mL) to afford a deep blue
solution at -60.degree. C. Upon gradual warming to room
temperature, the solution mixture began to bubble presumably due to
formation of hydrogen gas. On standing at room temperature for
another 1 h, the blue color of the solution completely disappeared.
Excess unreacted dimethyl amine was evaporated under vacuum and the
resulting solid was weighed. 1.35 g Me.sub.2NLi-alumina gel was
obtained (.about.40% yield with respect to amount of Li used).
2Me.sub.2NH+2Li-AG.fwdarw.2Me.sub.2NLi-AG+H.sub.2
Comparative Example 1
Attempt to Generate Lithium Dimethylamide from the Reaction of a
Secondary Amine with Lithium Metal
[0065] 30 mg of fresh and finely divided lithium metal was taken in
a round bottom flask equipped with a vacuum stopper, to which
Me.sub.2NH was condensed. The reaction vessel was initially kept at
-60.degree. C. for several minutes and then was gradually warmed up
to room temperature and maintained at that temperature overnight
with a pressure gauge. No coloration of the Me.sub.2NH or H.sub.2
gas evolution was observed.
Comparative Example 2
Attempt to Generate Lithium Dimethylamide from the Reaction of a
Secondary Amine with Lithium Metal in the Presence of Alumina
Gel
[0066] 30 mg of porous alumina gel was combined with 20 mg of
finely divided lithium metal in a flask equipped with a vacuum
stopper, and to this mixture Me.sub.2NH was condensed. The reaction
vessel was initially kept cool and was then gradually brought to
room temperature and was maintained there for 2 h. No coloration of
the Me.sub.2NH or H.sub.2 gas evolution was observed.
[0067] Comparative Examples 1 and 2 demonstrate that lithium metal,
alone or in the presence of alumina, does not form the lithium
amide starting from dimethyl amine.
Example 6
Continuous Flow Reaction of Organolithium in a Column
##STR00003##
[0069] 1 mmole (182 mg) of benzophenone dissolved in 5 mL of THF
was passed through a cold jacketed column (-40.degree. C.) packed
with MeLi in alumina (5 mM, 2 g) for a period of 1 h. The column
was washed with excess THF and the collected product was subjected
to quenching in cold water, followed by extraction in EtOAc and
evaporation of the organic layer to afford an oily liquid (185 mg)
in 92% crude yield (containing traces of ortholithiation product).
The pure alcohol was isolated by reversed phase (C.sub.18) column
chromatography by eluting with MeOH (73%).
Example 7
Reduction of a Ketone Using Lithium-Alumina Gel
##STR00004##
[0071] 1 mmole (182 mg) of benzophenone dissolved in 5 mL THF was
stirred with 0.5 g of 12% Li-AG and solid state proton sources such
as NH.sub.4Cl, (NH.sub.4).sub.2HPO.sub.4, or dropwise addition of
glacial AcOH at room temperature after a deep blue colored solution
is produced. The color of the reaction vessel gradually fades and
becomes grey at the end indicating complete consumption of lithium.
The reaction mixture was filtered, the solids washed with hexane,
and the solvent was removed from the combined organic solutions
under vacuum to obtain a white solid corresponding to diphenyl
methanol as confirmed by .sup.1H, .sup.13C NMR and ESI-MS. See
FIGS. 3A-3C.
Example 8
Preparation of RLi-AG from a Three Component Reaction of RX,
Lithium Metal, and Alumina Gel
[0072] In a flask containing 2 g of calcined alumina gel and 202 mg
of lithium ribbon cut into 5 small pieces were massed out and
equipped with a glass coated magnetic stir bar and a rubber septum.
This flask was chilled to -10.degree. C. for 10 minutes in a
cryobath. To this flask, 40 mL of dry hexane was added followed by
an additional 200 .mu.L of n-BuBr. The reaction was stirred for 30
minutes causing the lithium pieces to turn shiny. An additional 500
.mu.L of n-BuBr was added for the next 1 hr followed by an
additional 800 .mu.L of n-BuBr for the next 20 minutes. The
reaction mixture was stirred in cold for another 3 hr until all of
the lithium and organic derivative was incorporated into the
alumina gel. At this point, the reaction was stopped and maintained
cold and the hexane layer was analyzed for n-BuLi.
[0073] 212.5 mg of diphenyl acetic acid solution in THF was placed
in a round bottom flask to which the n-BuLi in hexane layer from
the reaction mixture was added. 15.5 mL of hexane solution was
needed to produce a color change of the diphenylacetic acid, which
corresponds to 2 mmol of n-BuLi. Based on this finding, the total
hexane layer should have 5.16 mmol of n-BuLi making the n-BuLi
absorbed in the solid alumina gel should equal 8.84 mmol.
[0074] 609 mg of BuLiAG when reacted with 1 mmol of PhCOPh (182 mg)
afforded nearly 90% conversion of the desired nucleophilic adduct
by .sup.1H NMR. .delta. (ppm): 7.2-7.5 (m, 10H), 2.3 (t, 2H), 1.4
(m, 4H), 0.95 (t, 3H). (See FIG. 4).
##STR00005##
Example 9
Preparation of Vinyllithium from Reductive Cleavage of
Ethylvinylether
##STR00006##
[0076] 500 mg Li-AG (12% w/w) was weighed out in a round bottom
flask equipped with a magnetic stirbar and rubber septum. To this
flask, 2 mL ethyl vinyl ether was added via a syringe at
-40.degree. C. After stirring the mixture at -40.degree. C. for 20
minutes a solution of 1 mmol benzophenone in 3 mL ethylvinylether
was added to the reaction mixture dropwise. The rate of addition
was maintained in such a way that it was not allowed for the blue
color of benzoketyl radical anion to persist (waited till the blue
color disappeared after each drop). The total addition took about
an hour after this time the color of the reaction started to turn
red. The reaction was stirred for additional 1 hour in cold and
then brought to room temperature before quenching with water. The
organic layer was extracted with ether (multiple times), dried and
the crude yield was recorded to be 200 mg (57%).
[0077] The .sup.1H NMR (FIG. 5A) of the crude mixture also
indicates conversion of 54%, and shows .sup.1H NMR (.delta. in ppm)
peaks as follows: 2.27 (br, 1H), 5.32 (d, 1H), 5.33 (d, 1H), 6.51
(dd, 1H), 7.2-7.5 (m, 10H).
[0078] The GC-MS (FIG. 5B) indicates formation of nucleophilic
adduct corresponding to its m/z peak at 210.
[0079] .sup.13C NMR in CDCl.sub.3 (.delta. in ppm) (FIG. 5C) shows
peaks at 145.7, 143.5, 128.6, 127.9, 126.9, 114, 79.4
* * * * *