Safer solvents for reactive organometallic reagents

Article abstract of DOI:10.1016/j.tetlet.2018.09.041

This paper describes the use of poly(α -olefin)s (PAOs) as safer alternatives to cyclohexane, hexanes, and heptane as solvents for alkyllithium reagents. While PAOs like any alkane are flammable, PAOs do not readily catch on fire because they contain 20 or more carbon atoms, a low volatility, and have a high flash point vis-à-vis alkanes like hexane. Also unlike conventional alkanes, PAOs can be quantitatively separated from polar organic solvents and polar organic products either by a simple gravity separation or by an extraction after a reaction. Any leaching of the PAO solvent into a polar phase during such a separation can be minimized by addition of small amounts of water to the polar phase. However, while these PAO solvents have some physical differences from conventional low molecular weight volatile alkanes, they otherwise behave like alkanes and alkyllithium reagents in these PAO solvents can used in their conventional reactions in these PAO solvents.

Full text of DOI:10.1016/j.tetlet.2018.09.041

Accepted Manuscript
Safer Solvents for Reactive Organometallic Reagents
Thomas J. Malinski, David E. Bergbreiter
PII:
S0040-4039(18)31131-6
https://doi.org/10.1016/j.tetlet.2018.09.041
TETL 50280
DOI:
Reference:
Tetrahedron Letters
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Accepted Date:
14 August 2018
16 September 2018
Please cite this article as: Malinski, T.J., Bergbreiter, D.E., Safer Solvents for Reactive Organometallic Reagents,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.041
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Thomas J. Malinski, David E. Bergbreiter

1
Tetrahedron Letters
Safer Solvents for Reactive Organometallic Reagents
Thomas J. Malinski and David E. Bergbreiter
Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77842-3012, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This paper describes the use of poly(-olefin)s (PAOs) as safer alternatives to cyclohexane,
hexanes, and heptane as solvents for alkyllithium reagents. While PAOs like any alkane are
flammable, PAOs do not readily catch on fire because they contain 20 or more carbon atoms, a
low volatility, and have a high flash point vis-à-vis alkanes like hexane. Also unlike conventional
alkanes, PAOs can be quantitatively separated from polar organic solvents and polar organic
products either by a simple gravity separation or by an extraction after a reaction. Any leaching
of the PAO solvent into a polar phase during such a separation can be minimized by addition of
small amounts of water to the polar phase. However, while these PAO solvents have some
physical differences from conventional low molecular weight volatile alkanes, they otherwise
behave like alkanes and alkyllithium reagents in these PAO solvents can used in their conventional
reactions in these PAO solvents.
Available online
Keywords:
Alkyllithium reagents
Safety
Alternative Solvents
Green Chemistry
Reactive organometallics
2009 Elsevier Ltd. All rights reserved.
Introduction
solvents for n-butyl-, sec-butyl-, and tert-butyllithium. In that role,
they behave like conventional alkane solvents. The only
Reactive organometallic reagents have important uses in
organic chemistry. Alkyllithium reagents for example were the
initial examples of initators for living polymerizations and are still
used in that application.1 Alkyllithiums are also used as reagents
for metalation of aryl halides,2 as nucleophiles for 1,2-addition to
electrophilic functional groups like aldehydes, ketones and esters,3
as strong bases for generation of regioselective hindered bases like
lithium diisopropylamide (LDA),4 or as reagents for C-H
activation in arenes with that form stabilized anions or have
suitable directing groups.5 However, while alkyllithium reagents
like n-butyl-, sec-butyl-, or tert-butyllithium that serve in these
roles are commercially available and sold in bulk,6 these reagents
are extremely hazardous. At high concentration, the commercially
available solutions in alkanes like pentane or hexane can ignite on
contact with air. Even in more modest concentrations, their
exothermic reaction with water generates sufficient heat to ignite
the volatile alkane solvents used to in these commercial reagents,
making their use a serious laboratory hazard.7,8
difference between PAOs and a low molecular weight alkane is
that the conventional alkane solvent is most commonly removed
by distillation at reduced pressure. PAOs have to be separated
from polar organic products by extraction or chromatography.
While either of these separation strategies can work, the simpler
process of using a physical gravity-based separation works well
for PAOs since PAOs are refined so that they have a specific
molecular weight and low solubility in polar solvents.
While the use of PAOs as solvents for reactions like those
discussed in this paper is not known, the general idea that a higher
molecular weight alkane medium can serve as a safer and more
convenient vehicle for a reactive organometallic species has
precedent. For example, Taber described using paraffin to prepare
dispersions of potassium hydride or Grubbs’ catalyst.12, 13 We later
described using polyethylene oligomers as sometimes solid
solvents and noted that as waxy solids that they protected
transition metal catalysts from reaction with polar reagents.14,15
Subsequently, the Buchwald group noted that solid paraffin can be
used as a protective vehicle for many other catalysts.16-18
Alternative solvents for reactions involving alkyllithium reagents
too have been explored.19 However, work like that of the Hevia
group using deep eutectic solvents as a reaction media does not
address the solvents for the alkyllithium reagents themselves.
Similar issues exist for other reactive organometallics like KH,
alkali metal dispersions, alkylmagnesium, alkylboron, and
alkylaluminum reagents. While there are safe ways to handle these
reagents, none of these reagents can ever be considered
nonhazardous. However, these reagents’ hazards can be mitigated
(but not eliminated) by dispersing these reactive metal dispersions
as suspensions in inert solvents9 or by diluting highly pyrophoric
reagents like alkylaluminum reagents in an inert alkane
solvent.10,11 As part of our work developing poly(-olefin)s
(PAOs) as sustainable and greener alternatives to conventional
alkane solvents, we have observed that PAOs’ flammability is
demonstrably different than conventional alkanes. Here we
describe those studies and show that PAOs can serve as inert
While solid paraffins can be used as vehicles for catalysts, they
are unlikely to be useful for alkyllithium reagents since they have
to be in the melt form to be used to prepare an alkyllithium
dispersion. In the case of paraffins or polyethylene oligomers, this
typically involves heating to > 70 ℃,15,17 a problem for thermally
unstable organometallics like alkyllithium reagents.
An
alternative that has seen use for dispersions of reactive metals and

2
Tetrahedron
related species is mineral oil.10 Mineral oil is generally
PAO283 and/or PAO432. The hexane or cyclohexane was then
considered a relatively safe material with a history of use as an
over-the-counter laxative, as a skin moisturizer, and as cleaning
product. However, mineral oil contains a mixture of hydrocarbons
ranging from with 12-40 carbons and can also include some
aromatic species. The later species could react with some
removed from these solutions at reduced pressure until the solution
volume approximated that of the PAO283 or PAO432 solvent. This
generally led to a clear solution of the alkyllithium reagent whose
titer was measured by a standard titration for alkyllithium and total
base. The solutions of n-butyllithium in PAO were typically ca.
2.7 M. The solutions of sec-butyllithium in PAO were typically
ca. 1.5 M. The solutions of tert-butyllithium in PAO were
typically ca. 1.0 M. While this work still used commercially
alkyllithium reagents in low molecular weight alkane solvents,
commercially available alkyllithium reagents cold be directly
synthesized in a PAO solvent, circumventing the need for any low
molecular weight alkane solvent.
alkyllithium reagents.
The smaller molecular weight
hydrocarbons also can contaminate an organic product
necessitating a column chroma-tography purification. In contrast,
PAOs are fully hydrogenated oligomers derived from alkenes like
decene (or dodecene) that are fractionated into fractions containing
ca. 20 (24), 30 (36), or more carbons.20-22 The work here uses
dimers and trimers of decene containing ca. 20 or 30 carbons that
have Mn values of ca. 283 and 432 Da and modest viscosities.
Higher molecular weight PAOs have increased viscosity and likely
less usefulness as solvents. However, all PAOs and especially
those with 30 or more carbons have the property that they
minimally contaminate polar organic phases in a biphasic
liquid/liquid separation.20 This latter property differentiates them
from other materials like mineral oil. While any hydrocarbon
contaminants are easily removed by an extraction with hexanes or
by column chromatography, PAO432 contamination of a polar
organic solvent like acetonitrile is in the 10-100 ppm range, a level
of contamination that minimizes the need for an extra purification
step and that can be further reduced by adding small amounts of
water to the polar phase.
To demonstrate the lower flammability of the PAO solvents
compared to hexane, ca. 20 mL of hexane, 20 mL of PAO432 or 20
mL of 1.60 M tert-butyllithium in PAO432 was transferred to a petri
dish in open air. Notably, the tert-butyllithium solution did not
ignite, behavior that was also seen when a similar experiment with
1.21 M n-butyllithium was similarly transferred by forced siphon
to a petrri dish in open air. These PAO solutions of alkyllithium
reagents were sampled after they were transferred to the petri dish
and analyzed for active alkyllithium reagent. Those titratons
showed that >80% of the alkyllithium reagent was present even
after 30 min. Surprisingly, up to 50% of the active alkyllithium
remained after standing in open air overnight.
To further examine flammability, we exposed these solutions
to an open flame in the form of a gas torch. As expected, the
hexane immediately ignited on exposure to a gas torch. The PAO
solutions of the alkyllithium reagents also ignited immediately on
exposure to a gas torch and in all of these experiments, the
solutions burned until the solution was completely consumed.
However, PAO432 that did not contain an alkyllithium reagent was
much less flammable. It could be heated with a gas torch for 30
sec without igniting. Further heating did cause the PAO432 to
smoke (Figure 2) and to eventually ignite though without
continued heating by the gas torch, the flame self-extinguished
within a few seconds. Supporting information includes a video of
these experiments (Figure S1). This behavior was seen in repeated
versions of the same experiment as well as with any of the higher
molecular weight PAO variants. Finally, we also added several 2-
mL samples of n-butyl- and tert-butyllithium in PAO432 to water.
None of these experiments led to an ignition event though a similar
experiment with tert-butyllithium in pentane did lead to ignition.
Results and Discussion
While we have previously described using PAO solvents with
Mn values ranging from 687 Da to 2505 Da as solvents,20 these
PAOs have 50 to 180 carbons and a higher than desired velocity.
Thus, this work used PAOs that were decene dimers or trimers that
have viscosities of 2 and 4 cSt and reported Mn values of 283 and
432 Da, respectively. We first examined these materials’
volatility. In this study, both PAO432 and the previously studied
PAO687 had minimal mass loss on heating from room temperature
to 150 ℃(Figure 1). While PAO283 (not shown) did gradually lose
significant mass at 150 ℃, had a ca. 3% mass loss over 2 h at 100
℃. PAO432 and PAO687 showed no mass loss even at 150 ℃in this
same timeframe. Thus we focused our attention on solutions of
alkyllithium reagents in these two lower viscosity solvents whose
viscosity is more amenable for synthetic chemistry.
100
140
PAO687
Heating
or
80
60
40
20
0
120
100
80
PAO432
Constant
Temperature
(150 oC)
Figure 2. A still picture of (A) hexane immediately and (B) PAO432
after 25 s of contact with a gas torch.
60
40
heptane
To establish the equivalence of alkyllithium reagents in PAO
solvents relative to their commercial analogs in low molecular
weight alkanes in synthesis, we examined polymerizations,
metalation chemistry where the alkyllithium is allowed to react
with an aryl bromide to generate an aryllithium reagent, 1,2-
additions to aldehydes where the alkyllithium reagent serves as a
nucleophile, LDA chemistry where the alkyllithium reagent serves
as a base for formation of LDA that is in turn used to form lithium
enolates, and C-H activation chemistry where the alkyllithium acts
as a strong base to abstract an aryl C-H from a relatively acidic
hydrocarbon or from an aryllithium stabilized by a ligating group.
20
0
20
40
60
80
100
120
Time (min)
Figure 1. TGA analysis of heptane (blue curve), PAO432 (red curve),
and PAO687 (black curve).
The PAO solutions of n-butyl-, sec-butyl-, and tert-butyl-
lithium were prepared by transferring commercial hexane or
cyclohexane solutions of these alkyllithium reagents by forced
syphon to a round-bottomed flask containing a known volume of

3
The first reaction we examined in hexanes versus PAO432 was
the polymerization of styrene (Figure 3). In an example of this
reaction, we added a solution of n-butyllithium to a toluene
effective (Figure 6). In this case, the LDA was prepared at -78
℃from a THF solution of diisopropylamine by addition of the
Figure 6. Methylation of the enolate of acetophenone with methyl
iodide using LDA prepared from n-butyllithium in either
hexanes/THF or PAO432/THF.
Figure 3. Styrene polymerizations using either n-BuLi in hexanes or
PAO432 as an initiator.
alkyllithium reagent. This LDA solution that contained a modest
amount of hexane or PAO283 was then allowed to react with
acetophenone to form a THF solution of the lithium enolate that
was in turn allowed to react with propanal. After warming to room
temperature and acidification with dilute acid, the expected aldol
product was isolated in 92% and 87% yields, respectively.
solution of styrene at 25 ℃ produced a red solution. A MeOH
quench led to a clear solution. Solvent removal at reduced
pressure afforded white solid that was purified by precipitation in
hexane to afford polystyrene in 97% yield (Mn 4100 Da, Ð = 2.5).
A reaction with slightly more styrene that used n-butyllithium in
PAO432 at 25 ℃afforded a similar product (Mn 8300, Ð = 1.8) in
98% isolated yield. Similar experiments were carried out by
adding tert-butyllithium in pentane and PAO432 to a toluene
solution of styrene. In those cases, polystyrene was isolated in a
similar manner with 94 and 96% yield (Mn 3920 Da, Ð = 2.0 and
Mn 5160, Ð = 1.6, respectively.
A final example of the equivalence of volatile alkane solutions
of alkyllithium reagents with PAO solutions of alkyllithium
reagents is their use in metalation of C-H bonds. There are many
examples of this chemistry used both in academic and industrial
settings.2 Scheme 7 showed that n- and tert-butyllithium either in
hexanes or in PAO283 readily deprotonates fluorene. Other
metalation chemistry including formation of an aryllithium
reagent by a TMEDA facilitated ortho-lithiation of N,N-
diethylbenzamide using sec-butyllithium in cyclohexane or
PAO432 as a solvent was equally effective.
The second reaction we examined in hexanes versus PAO432
was a transmetallation (Figure 4). In this case, n-butyllithium in
hexanes was allowed to react with bromobenzene in THF at -78 ℃
for 30 min. Propanal was then added, and the reaction was allowed
to warm to room temperature. After a dilute aqueous acid quench,
the product alcohol was isolated in 89% yield. The same
procedure starting with n-butyllithium in PAO432 afforded the 1-
phenylpropanol product in 85% yield.
Figure 7. Lithiation of fluorene by either n- or tert-butyllithium in
either hexanes/THF or PAO283/THF.
A final aspect of the substitution of PAOs with volatile alkane
solvents is that PAOs are easily removed from the products of the
reactions in Figures 3-7. We previously described how higher
molecular weight and higher viscosity PAOs are separable from
solvents like DMF, MeOH, aqueous EtOH and CH3CN.20 Similar
Figure 4. Transmetalation of bromobenzene to form phenyllithium
using either n-BuLi in hexanes/THF or n-BuLi in PAO283/THF
followed by reaction of the aryllithium reagent with propanal.
behavior is seen for PAO283 and PAO432
. In experiments that
A third example of the comparability of alkyllithiums in
hexanes and PAOs is the 1,2 addition of n-butyllithium to
benzaldehyde (Figure 5). The conventional addition of n-
resemble the batch type liquid/liquid extractions typically used to
workup a reaction, contamination of PAO283 and PAO432 was
consistently small (Table 1). Moreover, even what contamination
of the polar phase that was seen could be reduced ca. 10-fold by
adding 20 vol% water to the polar organic phase.
We further examined PAO432 leaching in an experiment where
PAO432 was continuously extracted by CH3CN for an extended
period. After 1 d the as received PAO432 contaminated the CH3CN
phase to the extent of 700 ppm. A second 4 d of continuous
extraction of this ‘extracted’ PAO432 led to only 200 ppm
contamination of the PAO432 in CH3CN. A further 10 d of
continuous extraction led to essentially no further extraction of the
PAO432 into the CH3CN (i.e. <50 ppm).
Figure 5. 1,2-Addition of n-butyllithium in either hexanes/THF or
PAO283/THF to benzaldehyde.
butyllithium in hexanes to a THF solution of benzaldehyde at -78
℃followed by warming to room temperature and a dilute aqueous
acid quench afforded the expected secondary alcohol product in
82% yield. The same procedure starting with n-butyllithium in
PAO432 afforded the same product in 84% yield.
Table 1. Percent Leaching of PAO into Polar Solvents.a.
DMF aq DMF
MeOH
0.21
aq MeOH
0.007
CH3CN
0.04
PAO283 0.10
PAO432 0.02
0.01
Using either n-butyllithium in hexanes or n-butyllithium in
PAO283 to form LDA to effect an aldol reaction was also equally
0.002
0.015
0.005
0.001

4
Tetrahedron
aLeaching was measured by heating an equivolume mixture of the PAO with
19. J. Garcia-Alvarez, E. Hevia, and V. Capriati Chem. – A Eur. J. 2018,
published online, https://doi.org/10.1002/chem.201802873.
20. M. L. Harrell , T. J. Malinski, C. Torres-Lopez, K. Gonzalez, J.
Suriboot, and D. E. Bergbreiter J. Am. Chem. Soc. 2016, 138, 14650-
16657.
MeOH and DMF until the solvent mixture was miscible and then cooling this
thermomorphic mixture to room temperature with or without addition of 10
vol% water. The experiments with CH3CN involved 24 h stirring of a biphasic
mixture of PAO and CH3CN
21. Exxon Mobil, Base stocks for Lubricants,
https://www.exxonmobilchemical.com/en/products-and-services/base-
stocks-for-lubricants (accessed August 14, 2018).
22. Chevron Philips, Polyalphaolefins.,
Conclusions
The results above show that PAO solvents are comparable as
solvents to conventional alkanes like pentane, cyclohexane or
hexanes in a variety of alkyllithium chemistry. However, because
of their low volatility, n-butyl-, sec-butyl- and tert-butyllithium
PAO solutions do not readily inflame. While replacing a low
molecular weight alkane by PAO does not make these highly
reactive pyrophoric reagents safe, it does mitigate their reactivity.
In contrast to conventional alkanes like hexanes or cyclohexane,
PAO solvents do not catch on fire even when exposed to flame for
minutes. While PAOs are still alkanes and can still burn,
alkyllithium reagents in these solvents do not inflame as readily as
they would when they are dissolved in low molecular weight
http://www.cpchem.com/bl/pao/en-us/pages/default.aspx (accessed
August 14, 2018).
Supplementary Material
Supporting information describing how we made solutions of alkyllithium
reagents in PAO, examples of procedures using them, NMR spectra of crude
products showing the absence of PAO contamination, and a video that
provides an example of the difference in flammability of PAO and low
molecular weight alkanes is available.
alkanes.
This suggests that these PAO solvents merit
consideration as a vehicle for use with these and other reactive
organometallic reagents. Further work to explore other
applications of these sustainable, recyclable and safer solvents in
other applications is currently being pursued.
Acknowledgments
We acknowledge support of the work by the National Science
Foundation (Grant CHE-1362735) and the Robert A. Welch
Foundation (Grant A-0639). We would also like to acknowledge
Prof. Hong-Cai Zhou for instrument access and Angelo Kirchon
for assistance obtaining TGA data.
References and notes
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Braish, Eds.
3.
Carey, Francis A. Advanced Organic Chemistry: Part B: Reaction and
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H. Gilman and J. W. Morton, Jr. Org. Reactions 1954, 8, 259-303 and
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3820.
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6.
7.
See www.FMClithium.com (accessed August 14, 2018).
J. B. Johansen, J. C. Kondrup, M. Hinge, and A. T. Lindhardt Org.
Process Res. Dev. 2018, 22, 903-905.
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J. Schwindeman, C. J. Woltermann, and R. J. Letchford Chem. Health
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powders U.S. Patent 5776369A July 7, 1998.
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11. https://www.youtube.com/watch?v=RfeaffoWajc&feature=youtube.
Accessed August 14 2018. (Note, while this video is impressive in
terms of illustrating the pyrophoricity of neat trialkylaluminum
reagents, its use of plastic syringes for a transfer is not recommended).
12. D. F. Taber and K. J. Frankowski J. Org. Chem. 2003, 68, 6047-6048
13. D. F. Taber and C. G. Nelson J. Org. Chem. 2006. 71, 8973-8974.
14. J. Suriboot, C. E. Hobbs, Y.-C. Yang, and D. E. Bergbreiter J. Polym.
Sci., Part A: Polym. Chem. 2012, 50, 4840-4846.
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Bergbreiter J. Am. Chem. Soc. 2012, 134, 14714-14717.
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Proc. Res. Development 2016, 20, 1709-1716.
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3936.

5
Highlights




Oligomeric hydrocarbons are equivalent to
hexane for alkyllithium chemistry
Alkyllithium reagent solutions can be made less
flammable and safer to handle
Poly(olefin) solvents quantitatively separate
from polar organic solvents
t-BuLi in a poly(-olefin) solvent is more stable
and less flammable than in pentane