Effect of solvent on the lithium-bromine exchange of aryl bromides: Reactions of n-butyllithium and tert-butyllithium with 1-bromo-4-tert- butylbenzene at 0 °C

Article abstract of DOI:10.1021/jo060026u

The outcome of reactions of 1-bromo-4-tert-butylbenzene (1), a representative aryl bromide, with n-BuLi or t-BuLi at 0 °C in a variety of solvent systems has been investigated. The products of reactions of 1 with n-BuLi vary significantly with changes in solvent composition: 1 does not react with n-BuLi in pure heptane; the exchange reaction to give (4-tert-butylphenyl) lithium, which is slow in pure diethyl ether, is virtually quantitative in heptane containing a small quantity of THF; and the reaction of 1 with n-BuLi in THF leads to considerable coupling. Lithium-bromine exchange is the virtually exclusive outcome of reactions of 1 with t-BuLi in every solvent studied except pure heptane: the presence of a small quantity of any of a variety of structurally diverse ethers (Et₂O, THF, THP, MTBE) in the predominantly hydrocarbon medium affords (4-tert-butylphenyl)lithium, assayed as tert-butylbenzene, in yields exceeding 97%. The only side products observed from reactions of 1 with t-BuLi are small amounts of benzyne-derived hydrocarbons.

Full text of DOI:10.1021/jo060026u

Effect of Solvent on the Lithium-Bromine Exchange of Aryl
Bromides: Reactions of n-Butyllithium and tert-Butyllithium with
1-Bromo-4-tert-butylbenzene at 0 °C
William F. Bailey,* Mark R. Luderer, and Kevin P. Jordan
Department of Chemistry, UniVersity of Connecticut, Storrs, Connecticut 06269-3060
william.bailey@uconn.edu
ReceiVed January 5, 2006
The outcome of reactions of 1-bromo-4-tert-butylbenzene (1), a representative aryl bromide, with n-BuLi
or t-BuLi at 0 °C in a variety of solvent systems has been investigated. The products of reactions of 1
with n-BuLi vary significantly with changes in solvent composition: 1 does not react with n-BuLi in
pure heptane; the exchange reaction to give (4-tert-butylphenyl)lithium, which is slow in pure diethyl
ether, is virtually quantitative in heptane containing a small quantity of THF; and the reaction of 1 with
n-BuLi in THF leads to considerable coupling. Lithium-bromine exchange is the virtually exclusive
outcome of reactions of 1 with t-BuLi in every solvent studied except pure heptane: the presence of a
small quantity of any of a variety of structurally diverse ethers (Et2O, THF, THP, MTBE) in the
predominantly hydrocarbon medium affords (4-tert-butylphenyl)lithium, assayed as tert-butylbenzene,
in yields exceeding 97%. The only side products observed from reactions of 1 with t-BuLi are small
amounts of benzyne-derived hydrocarbons.
Introduction
Results and Discussion
The reversible metathesis reaction known as the lithium-
halogen exchange was first observed in reactions of n-BuLi with
aryl bromides,2 and the vast primary literature, detailing both
the synthetic utility and mechanistic vagaries of this reaction,
has been comprehensively reviewed.3 The lithium-halogen
exchange of an aryl bromide or iodide with an alkyllithium is
typically a high-yield process that proceeds rapidly at low
temperature and favors the more stable aryllithium at equilib-
rium.4 However, nettlesome side reactions, including coupling
of the aryllithium with the co-generated alkyl halide and
formation of a benzyne intermediate via ortho-metalation of the
We recently reported the results of a study of the reactions
of 1-iodooctane, a representative primary alkyl iodide, with tert-
butyllithium (t-BuLi) at 0 °C in a variety of solvent systems
composed of heptane and various ethers.1 An optimal ether-
heptane ratio, which varied for each of the ethers studied, was
found to maximize the extent of lithium-iodine exchange and
minimize side reactions such as coupling and elimination.
Prompted by the results of this study, we have extended the
investigation to assess the effect of solvent on the outcome of
the reactions of 1-bromo-4-tert-butylbenzene (1), a representa-
tive aryl bromide, with n-butyllithium (n-BuLi) and t-BuLi at
0 °C. As detailed below, lithium-bromine exchange to give
(4-tert-butylphenyl)lithium may be accomplished in virtually
quantitative yield at 0 °C by appropriate choice of both solvent
and alkyllithium.
(2) (a) Wittig, G.; Pockels, U.; Droge, H. Chem. Ber. 1938, 71, 1903.
(b) Gilman, H.; Langham, W.; Jacoby, A. L. J. Am. Chem. Soc. 1939, 61,
106. (c) It is of some historical interest to note that the lithium-bromine
exchange was observed by Marvel and co-workers at least a decade before
these reports: treatment of m-bromotoluene with n-BuLi at room temper-
ature for 4 d in petroleum ether gave an 87% yield of toluene after quench
with water, but the implications of this observation were not recognized at
the time. See: Marvel, C. S.; Hager, F. D.; Coffman, D. D. J. Am. Chem.
Soc. 1927, 49, 2323.
(1) Bailey, W. F.; Brubaker, J. D.; Jordan, K. P. J. Organomet. Chem.
2003, 681, 210.
10.1021/jo060026u CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/01/2006
J. Org. Chem. 2006, 71, 2825-2828
2825

Bailey et al.
SCHEME 1
TABLE 1. Reaction of 1-Bromo-4-tert-butylbenzene (1) with
n-BuLi at 0 °C in Various Solvents (Scheme 1)
aryl halide,5 are sometimes observed.3 In an effort to probe the
effect of solvent variation on the course of reactions of aryl
bromides with n-BuLi and t-BuLi, 1-bromo-4-tert-butylbenzene
(1) was chosen as a representative substrate: in addition to the
practical matter of decreasing the volatility of potential reaction
products, the 4-t-Bu group serves as a positional marker. We
were particularly interested in exploring whether, by appropriate
choice of experimental conditions, aryllithiums might be
prepared efficiently at 0 °C, a temperature significantly higher
than that commonly employed for the exchange reaction.
products,a %
entry
solvent
heptane
2
3
4
5
recovered 1
1
2
3
0.2
80.1
96.9
tr
0.3
0.8
tr
tr
0.2
tr
tr
0.2
98.8
18.6
tr
Et2O
heptane-THF
(99:1 by vol)
heptane-THF
(9:1 by vol)
THF
4
96.1
2.5
tr
tr
tr
5
58.8
39.9
0.2
0.3
tr
a Yields were determined by capillary GC; tr indicates that a trace (viz.
<0.2%) of material was detected.
Reactions with n-BuLi. Experiments were conducted at 0
°C in solvent systems composed of heptane, diethyl ether, THF,
and heptane-THF in various proportions. As detailed in the
Experimental Section, solutions of 1 in the appropriate solvent
were added at 0 °C over a period of 10 min under an atmosphere
of argon to a slight excess (i.e., 1.2 molar equiv) of n-BuLi in
hexane, and the resulting 0.1 M reaction mixtures were allowed
to stand at 0 °C for an additional 20 min before quench with
methanol. Crude product mixtures were analyzed by both
capillary GC and by GC-MS affording baseline separation of
the four products (2-5), illustrated in Scheme 1, that accounted
for essentially the total material balance.6 The tert-butylbenzene
(2), 1-butyl-4-tert-butylbenzene (3), and 4,4′-di-tert-butylbi-
phenyl (4) products were identified by comparison of their
retention times and mass spectra to those of authentic samples;
3,4′-di-tert-butylbiphenyl (5) was identified on the basis of its
reported retention time and mass spectrum.7 The results of these
experiments are summarized in Table 1.
and tetrameric aggregates in THF.10 It is clear from the results
that the hexameric aggregate of n-BuLi does not react with the
aryl bromide: 99% of 1 is recovered unchanged after treatment
with n-BuLi in pure heptane (Table 1, entry 1). The lithium-
bromine exchange is rather slow in diethyl ether: the yield of
(4-tert-butylphenyl)lithium, assayed as tert-butylbenzene (2), is
only 80%, and a significant quantity of 1 is recovered (Table
1, entry 2). In THF solution, all of the bromide is consumed,
and the products consist primarily of the aryllithium, assayed
as 2, and the coupling product, 3, as well as small amounts of
4 and 5 (Table 1, entry 5). The formation of 3 is undoubtedly
the result, as illustrated below, of lithium-bromine exchange
of 1 with n-BuLi to give (4-tert-butylphenyl)lithium followed
by coupling of the aryllithium with the co-generated 1-bro-
mobutane. The ability of THF, in which phenyllithium exists
as a dimeric aggregate,11 to promote coupling of aryllithiums
with alkyl halides was noted some time ago by Merrill and
Negishi.12
The results presented in Table 1 are likely related to the
degree of association of n-BuLi in the various solvents that were
examined. It is known that n-BuLi exists as a hexameric
aggregate in hydrocarbons,8 a tetrameric aggregate in diethyl
ether,9 and as a temperature-dependent equilibrium of dimeric
(3) (a) Jones, R. G.; Gilman, H. Chem. ReV. 1954, 54, 835. (b) Gilman,
H.; Jones, R. G. Org. React. (NY) 1951, 6, 339. (c) Scho¨lkopf, U. In
Methoden der Organischen Chemie; Georg Thieme: Stuttgart, 1970; Vol.
13/1. (d) Wakefield, B. J. The Chemistry of Organolithium Compounds;
Pergamon Press: New York, 1974. (e) Wardell, J. L. In ComprehensiVe
Organometallic Chemistry; Wilkinson, G., Ed.; Pergamon Press: New York,
1982; Vol. 1, p 43. (f) Wakefield, B. J. Organolithium Methods; Pergamon
Press: New York, 1988. (g) Bailey, W. F.; Patricia, J. J. J. Organomet.
Chem. 1988, 352, 1. (h) Schlosser, M. In Organometallics in Synthesis: A
Manual; Schlosser, M., Ed.; Wiley: New York, 2002; pp 101-137. (i)
Sapse, A. M.; Schleyer, P. v. R. Lithium Chemistry: A Theoretical and
Experimental OVerView; Wiley: New York, 1995. (j) Clayden, J. Orga-
nolithiums: SelectiVity for Synthesis; Pergamon Press: New York, 2002;
pp 111-135.
Given the outcome of reactions conducted in pure heptane
(Table 1, entry 1) and pure THF (Table 1, entry 5), it was
somewhat unexpected that addition of a small quantity of THF
(1% by vol) to a predominantly heptane reaction medium gave
a high yield of 2 (∼97%) accompanied by less than 1% each
of the three side products (Table 1, entry 3). Not surprisingly,
addition of a larger quantity of THF to the heptane medium
(4) Applequist, D. E.; O’Brien, D. F. J. Am. Chem. Soc. 1963, 85, 743.
(5) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967.
(10) (a) McGarrity, J. F.; Ogle, C. A. J. Am. Chem. Soc. 1985, 107,
1805. (b) Bauer, W.; Winchester, W. R.; Schleyer, P. v. R. Organometallics
1987, 6, 2371.
(11) Reich, H. J.; Green, D. P.; Medina, M. A.; Goldenberg, W. S.;
Gudmundsson, B. O.; Dykstra, R. R.; Phillips, N. H. J. Am. Chem. Soc.
1998, 120, 7201 and references therein.
(6) No attempt was made to quantitate the amounts, if any, of butane,
1-butene, 1-bromobutane, or octane that may have been produced from
extraneous reactions of n-BuLi.
(7) Fields, E. K. J. Org. Chem. 1978, 25, 4705.
(8) Brown, T. L. Acc. Chem. Res. 1968, 1, 23.
(9) West, P.; Waack, R. J. Am. Chem. Soc. 1967, 89, 4395.
(12) Merrill, R. E.; Negishi, E. J. Org. Chem. 1974, 39, 3452.
2826 J. Org. Chem., Vol. 71, No. 7, 2006

SolVent Effect on the Lithium-Bromine Exchange
SCHEME 2
TABLE 2. Reaction of 1-Bromo-4-tert-butylbenzene (1) with
t-BuLi at 0 °C in Heptane-Ether Solvent (Scheme 2)
(viz. 10% by vol) leads to an increase in the extent of coupling
of the aryllithium with 1-bromobutane to give 3 (Table 1, entry
4).
products,a %
Reactions with t-BuLi. Experiments involving t-BuLi were
run at 0 °C in solvent systems composed of heptane-dialkyl
ethers in various proportions. The reactions were conducted as
described above for the case of n-BuLi with one significant
difference: 2.2 equiv of t-BuLi in heptane were used per mol
of 1. As illustrated below, the second equivalent of t-BuLi
consumes the t-BuBr generated in the exchange to give
isobutane, isobutylene, and LiBr.13
entry
solvent
heptane
heptane-Et2O
(99:1 by vol)
heptane-Et2O
(19:1 by vol))
heptane-Et2O
(9:1 by vol)
heptane-THF
(99:1 by vol)
heptane-THF
(19:1 by vol)
heptane-THF
(9:1 by vol
2
6
7
4
5
recovered 1
1
2
5.4
tr
tr
93.3
97.7 0.2 tr
0.8 0.5
3
97.2 0.2 tr
0.6 0.4
4
97.6 0.2 0.2 0.5 0.4
5
98.7
0.3 0.4
0.3 0.4
6
98.4
7
96.9
0.3 0.4
GC and GC-MS analysis of product mixtures afforded
baseline separation of the five products (2, 4, 5, 6, and 7),
illustrated in Scheme 2, that accounted for the total material
balance. The 1,4-di-tert-butylbenzene (6) and 1,3-di-tert-butyl-
benzene (7) products were identified by comparison of their
retention times and mass spectra to those of authentic samples.14
The results of these experiments are summarized in Table 2.
The most striking feature of the results presented in Table 2
is their monotony: the yield of the aryllithium, assayed as 2, is
virtually quantitative (>97% yield) in every solvent system
examined except for pure heptane. The failure to observe any
significant exchange in pure heptane (Table 2, entry 1), a solvent
in which t-BuLi is known to exist as a tetrameric aggregate,8,15
was not unexpected.13a However, the acute sensitivity of the
exchange reaction to the presence of very small quantities (1%
by vol) of any of a variety of structurally diverse ethers (Et2O,
THF, tetrahydropyran (THP), or MTBE) was unanticipated. It
is clear from the results summarized in Table 2 that addition of
any of the ethers studied, in any proportion from 1% to 10%
by volume,16 to the predominantly hydrocarbon medium pro-
vides a reactive t-BuLi solvate. Given that t-BuLi exists as a
dimeric aggregate in Et2O17 and primarily as a solvated
monomer in THF,18 the outcome of the exchange reaction
8
heptane-THP
(99:1 by vol)
heptane-THP
(19:1 by vol)
heptane-THP
(9:1 by vol)
heptane-MTBE 97.0 0.2 tr
(99:1 by vol)
heptane-MTBE 97.1 0.2 0.2 0.5 0.3
(19:1 by vol)
97.8 tr
0.2 0.5 0.4
9
97.3 0.2 0.2 0.5 0.7
0.2
10
11
12
13
97.9 0.2 tr
0.4 0.6
0.8 0.5
heptane-MTBE 97.9 tr
(9:1 by vol)
0.2 0.4 0.3
a Yields were determined by capillary GC; tr indicates that a trace (viz.
<0.2%) of material was detected.
between 1 and t-BuLi is apparently indifferent to the aggregation
state of ether-solvated t-BuLi. As a practical matter, to the extent
that 1 is representative of its class, the lithium-bromine
exchange between t-BuLi and an aryl bromide may be conducted
at 0 °C in a predominantly hydrocarbon solvent containing a
small quantity of virtually any ether.
The robust nature of the aryl bromide exchange with t-BuLi
at 0 °C stands in contrast to the more complex behavior of
primary alkyl iodides when treated with t-BuLi under these
conditions. As noted above, the reaction of a primary iodide
with t-BuLi at 0 °C in hydrocarbon-ether solution affords a
mixture of exchange, coupling, and elimination products whose
composition varies with changes in both the quantity and nature
of the ether cosolvent.1 The only side products detected in the
reactions of 1 with t-BuLi are small quantities (i.e., <1%) of 4,
5, 6, and 7 (Scheme 2, Table 2). As illustrated in Scheme 3,
the formation of these hydrocarbons is undoubtedly the result
of ortho-lithiation19 of 1 followed by rapid loss of LiBr to give
a 4-tert-butylbenzyne intermediate5 that then adds either t-BuLi,
to afford 6 and 7, or (4-tert-butylphenyl)lithium to give 4 and
5.
(13) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
(b) Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847.
(14) Okada, T.; Karaki, I.; Mataga, N. J. Am. Chem. Soc. 1982, 104,
7191.
(15) Thomas, R. D.; Clarke, M. T.; Jensen, R. M.; Young, T. C.
Organometallics 1985, 5, 1851.
(16) In light of the fairly rapid consumption of t-BuLi by proton
abstraction from various ethers at 0 °C, the exchange reaction between 1
and t-BuLi in solvent containing more than 10% by volume of an ether
was not investigated. The half-life of t-BuLi in various solvents has been
reported; see: Stanetty, P.; Mihovilovic, M. J. Org. Chem. 1997, 62, 1514.
(17) Bates, T. F.; Clarke, M. T.; Thomas, R. D. J. Am. Chem. Soc. 1988,
110, 5109.
(18) Bauer, W.; Winchester, W. R.; Schleyer, P.v. R. Organometallics
1987, 6, 2371.
(19) Snieckus, V. Chem ReV. 1990, 90, 879 and references therein.
J. Org. Chem, Vol. 71, No. 7, 2006 2827

Bailey et al.
SCHEME 3
A mixture of 1,4-di-tert-butylbenzene (6) and 1,3-di-tert-butylben-
zene (7) was prepared following a literature procedure14 and
analytically pure samples of 6 [mp 77-78 °C (lit.14 mp 77.7 °C)]
and 7 [13C NMR δ 31.7, 35.0, 122.4, 122.6, 127.8, 150.8] were
isolated by preparative gas chromatography on a 10-ft, 20% SE-
30 on Anakrom A (60/80 mesh) column.
Conclusions
The results presented above (Table 2) demonstrate that
lithium-bromine exchange of an aryl bromide may be ac-
complished in high yield at 0 °C, a temperature significantly
higher than that normally used for the process,3 by using 2 molar
equiv of t-BuLi in heptane in a predominantly hydrocarbon
medium containing a small (1% by vol) to modest (10% by
vol) quantity of any of a variety of ethers (Et2O, THF, THP, or
MTBE). The only side products detected from experiments
conducted under these conditions were small amounts of
benzyne-derived hydrocarbons (Scheme 2 and Table 2). The
outcome of reactions of n-BuLi with 1-bromo-4-tert-butylben-
zene (1) 0 °C is rather more sensitive to variation in solvent.
The exchange reaction between 1 and n-BuLi, which is slow in
pure diethyl ether (Table 1, entry 2), proceeds in high yield in
a hydrocarbon medium containing a small amount (1% by vol)
of THF (Table 1, entry 3), but coupling of the aryllithium with
co-generated 1-bromobutane occurs to a significant extent in
pure THF (Table 1, entry 5).
Reactions of 1-Bromo-4-tert-butylbenzene (1) with n-BuLi or
t-BuLi at 0 °C. A flame-dried, septum-capped, 10-mL flask was
kept under a positive pressure of argon and charged with an
accurately weighed quantity (ca. 1 mmol) of 1-bromo-4-tert-
butylbenzene (1). A separate flame-dried, septum-capped, 25-mL
round-bottomed flask was charged under a positive pressure of
argon with either 1.2 molar equiv of n-BuLi in hexane or 2.2 molar
equiv of t-BuLi in heptane. The amount of solvent used for each
reaction was determined by calculating the total amount of heptane
and dialkyl ether needed to make a 0.1 M solution of 1 in the desired
solvent ratio: 1 was dissolved in half of the solvent volume,
including all of the ether and the appropriate amount of heptane,
and the alkyllithium was diluted with the remaining heptane. The
alkyllithium solution was cooled to 0 °C and the solution of 1 in
the appropriate solvent was added dropwise via a Teflon cannula
over a period of 10 min. Upon completion of the addition, the
mixture was allowed to stir at 0 °C for an additional 20 min and
then quenched with MeOH. The organic layer was washed with
water and dried (MgSO4), and the crude products were analyzed
by GC on a 25 m × 0.2 mm × 0.33 µm DB-5 cross-linked 5%
phenyl methyl silicone capillary column and by GC-MS on a 25
m × 0.2 mm × 0.25 µm HP-5 cross-linked 5% phenyl methyl
silicone capillary column. The results of these experiments are
summarized in Tables 1 and 2.
Experimental Section
The concentrations of t-BuLi in heptane (FMC) and n-BuLi in
hexane (FMC) were determined prior to use by the method of
Watson and Eastham.20 A sample of 1-butyl-4-tert-butylbenzene
(3),21 isolated from the coupling of 1-bromobutane with (4-tert-
butylphenyl)lithium in THF (Table 1, entry 5), displayed the
following properties: n23D ) 1.4924 (lit.21 n20D ) 1.4898); 1H NMR
δ 0.92 (t, J ) 4.34 Hz, 3H), 1.28-1.41 (overlapping multiplet and
singlet, 11H), 1.55-1.63 (m, 2H), 2.57 (t, J ) 8.0 Hz, 2H), 7.10
Acknowledgment. We are grateful to Dr. Christopher
Wolterman of FMC, Lithium Division, for generous gifts of
t-BuLi in heptane and n-BuLi in hexane. This work was
supported by a grant from Procter & Gamble Pharmaceuticals,
Mason, Ohio.
(dt, J ) 8.67, J ) 1.96, 2H), 7.29 (dt, J ) 8.32, J ) 2.22, 2H); 13
NMR δ 14.2, 22.7, 31.7, 33.9, 34.5, 35.3, 125.3, 128.3, 140.0, 148.5.
C
(20) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.
(21) Hennion, G. F.; Auspos, L. A. J. Am. Chem. Soc. 1943, 65, 1943.
JO060026U
2828 J. Org. Chem., Vol. 71, No. 7, 2006