Effect of solvent and temperature on the lithium-iodine exchange of primary alkyl iodides: Reaction of t-butyllithium with 1-iodooctane in heptane-ether mixtures

Article abstract of DOI:10.1016/S0022-328X(03)00609-0

The reaction of 1-iodooctane, a representative primary alkyl iodide, with t-BuLi at 0 °C in solvent systems composed of heptane and four dialkyl ethers in various proportions has been investigated. Coupling and elimination are unavoidable side reactions that accompany lithium-iodine exchange when the reactions are conducted at 0 °C. The exchange reaction, which is slow in pure hydrocarbon solvent, is significantly facilitated by the presence of essentially catalytic quantities of an ether co-solvent. An optimal ether-heptane ratio for each of the ethers surveyed maximizes the extent of lithium-iodine exchange between 1-iodooctane and t -BuLi but in no case does the yield of octyllithium, assayed as octane, exceed ～90% when reactions were conduced at 0 °C. At lower temperatures, in a solvent system composed of heptane-MTBE (19:1 by volume), side reactions are suppressed and the yield of octyllithium approaches quantitative.

Full text of DOI:10.1016/S0022-328X(03)00609-0

Journal of Organometallic Chemistry 681 (2003) 210Á214
/
www.elsevier.com/locate/jorganchem
Effect of solvent and temperature on the lithiumÁ
/
iodine exchange of
primary alkyl iodides: reaction of t-butyllithium with 1-iodooctane in
heptaneÁether mixtures
/
William F. Bailey *, Jason D. Brubaker, Kevin P. Jordan
Department of Chemistry, University of Connecticut, 55 North Eagleville Rd., Storrs, CT 06269-3060, USA
Received 5 May 2003; received in revised form 6 June 2003; accepted 6 June 2003
Abstract
The reaction of 1-iodooctane, a representative primary alkyl iodide, with t-BuLi at 0 8C in solvent systems composed of heptane
and four dialkyl ethers in various proportions has been investigated. Coupling and elimination are unavoidable side reactions that
accompany lithiumÁ
hydrocarbon solvent, is significantly facilitated by the presence of essentially catalytic quantities of an ether co-solvent. An optimal
etherÁheptane ratio for each of the ethers surveyed maximizes the extent of lithiumÁiodine exchange between 1-iodooctane and t-
BuLi but in no case does the yield of octyllithium, assayed as octane, exceed Â90% when reactions were conduced at 0 8C. At lower
temperatures, in a solvent system composed of heptaneÁMTBE (19:1 by volume), side reactions are suppressed and the yield of
octyllithium approaches quantitative.
2003 Elsevier B.V. All rights reserved.
/
iodine exchange when the reactions are conducted at 0 8C. The exchange reaction, which is slow in pure
/
/
/
/
#
Keywords: LithiumÁhalogen exchange; Organolithiums; Solvent effects
/
1
. Introduction
lithiums by the low-temperature lithiumÁiodine ex-
/
change reaction between a primary alkyl iodide and
tert-butyllithium (t-BuLi) [7,8].
Since its discovery in the late 1930s by Wittig [1] and
Gilman [2], the remarkably rapid, reversible metathesis
reaction known as the lithiumÁhalogen exchange has
been widely employed for replacement of a bromine or
iodine atom in a substrate with lithium and the vast
primary literature detailing the synthetic utility of this
process for the preparation of aryllithiums, vinyl-
lithiums, cyclopropyllithiums and other relatively stable
The success of the lithiumÁhalogen exchange for the
/
/
preparation of primary alkyllithiums (Scheme 1) is
crucially dependent on the choice of halide, alkyllithium,
and solvent. As noted elsewhere [9], alkyl iodides, rather
than bromides, must be used to ensure that the reaction
proceeds cleanly, most likely via a 10-I-2 ate-complex
intermediate or transition state [10]: addition of t-BuLi
to a primary alkyl bromide often initiates radical-
mediated processes [9]. The use of t-BuLi establishes a
favorable exchange equilibrium [6] and, when 2 M
equivalent of the reagent are employed, the exchange
is rendered essentially irreversible since, as illustrated in
Scheme 1, the second equivalent of the reagent rapidly
consumes the t-BuI co-product [11]. Because the
organolithiums has been extensively reviewed [3Á
However, the preparation of simple alkyllithiums by
lithiumÁhalogen exchange has historically been viewed
/5].
/
as more problematic due to the unfavorable position of
the exchange equilibrium [6] and competing reactions
such as b-elimination and Wurtz-type coupling [3Á
/5].
Indeed, it is only within the past decade or so that it has
proved possible to reliably prepare primary alkyl-
lithiumÁ
t-BuLi solvate [7], the best medium for the preparation
of primary alkyllithiums by lithiumÁiodine exchange is
/iodine exchange appears to involve a dimeric
/
*
Corresponding author. Tel.: ꢀ
981.
E-mail address: bailey@uconn.edu (W.F. Bailey).
/
1-860-486-2163; fax: ꢀ1-860-486-
/
a hydrocarbon solvent system that contains a quantity
of a simple alkyl ether, such as Et O or the like, in which
2
0
2
022-328X/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00609-0

W.F. Bailey et al. / Journal of Organometallic Chemistry 681 (2003) 210Á
/214
211
separation of the four products (2Á/5), illustrated in
Scheme 2, that accounted for the total material balance.
Octane (2), 1-octene (3), and hexadecane (5) were
identified by comparison of their retention times and
mass spectra to those of authentic samples; 2,2-
dimethyldecane (4) was identified on the basis of its
reported mass spectrum [14]. The results of these
experiments are summarized in Table 1.
Scheme 1.
Cursory inspection of the data (Table 1) reveals that
in no case was octane (2) the exclusive reaction product.
Thus, under the conditions surveyed in these experi-
ments, it is not possible to effect clean, quantitative
exchange; elimination and coupling reactions accom-
pany the conversion of 1 to octyllithium. While this
result might have been anticipated on the basis of prior
art [5], what was not expected was the profound effect of
very small quantities of ether on the course of the
reaction of t-BuLi with 1. Comparison of the result of
the reaction of t-BuLi with 1 in pure heptane (Table 1,
entry 1) with that of the reaction conducted in a
predominantly heptane medium containing only 0.5%
the t-BuLi is predominantly dimeric [12]. The overall
process depicted in Scheme 1 is quite exothermic; for
this reason, the exchange is typically conducted at low
temperature to avoid side reactions [7,8].
2
. Results and discussion
It occurred to us that it might be possible to prepare
primary alkyllithiums at temperatures significantly
higher than ꢁ78 8C by attenuation of the reactivity of
t-BuLi through the simple expedient of employing a
predominantly hydrocarbon medium, in which the
reagent is tetrameric [13] and essentially unreactive
toward an alkyl iodide at low temperature [9], contain-
ing a small quantity of an ether co-solvent that would
serve to provide the reactive dimeric t-BuLi solvate. As
demonstrated by the results presented below, the
/
of (i-Pr) O (Table 1, entry 5) reveals that the yield of
2
octane (2) is improved from 52 to 75%. It might be
noted that this small quantity of (i-Pr) O is equivalent
2
to 0.16 mmol of ether per 1 mmol of t-BuLi. Since the
dimeric t-BuLi solvate requires a ratio of two molecules
of ether per molecule of t-BuLi [12], the exchange
reaction is essentially catalytic in ether. Moreover, while
a significant quantity of starting iodide (ca. 18%)
remains after treatment of 1 with t-BuLi in pure heptane
for 20 min at 0 8C (Table 1, entry 1), the presence of
even small amounts of ether co-solvent leads to com-
plete consumption of the iodide.
efficiency of the lithiumÁiodine exchange between t-
/
BuLi and a primary alkyl iodide is strongly dependent
on the quantity of ether in the reaction medium and the
temperature at which the reaction is conducted.
Exploratory experiments were conducted at 0 8C in
For each of the ethers surveyed, the yield of octane (2)
produced in the reaction of t-BuLi with 1 fluctuates in a
surprisingly consistent fashion as the proportion of ether
in the reaction medium is varied. These trends are
perhaps best appreciated by reference to Fig. 1: a
qualitatively similar curve is observed for each ether
solvent systems composed of heptaneÁdialkyl ether in
/
various proportions using 1-iodooctane (1) as a repre-
sentative primary alkyl iodide. Diisopropyl ether, meth-
yl t-butyl ether (MTBE), THF, and tetrahydropyran
(
THP) were surveyed as representative ether co-solvents.
As detailed in Section 4, solutions of 1 in heptaneÁether
/
solvent were added at 0 8C under an atmosphere of
argon to a slight excess (i.e. 2.2 M equivalent) of t-BuLi
in heptane and the resulting 0.1 M reaction mixtures
were allowed to stand at 0 8C for an additional 20 min,
which ensured complete reaction, before quench with
water. Crude product mixtures were analyzed by
when the yield of octane is plotted versus the etherÁ
/
heptane solvent ratio. The shape of the plots can be
understood by consideration of two extreme conditions:
(a) conducting the reaction in pure heptane, and; (b)
conducting the reaction in the presence of a high
proportion of ether. When no ether is present in the
reaction medium, the t-BuLi is predominantly tetra-
capillary GC and by GCÁMS affording base-line
/
Scheme 2.

212
W.F. Bailey et al. / Journal of Organometallic Chemistry 681 (2003) 210Á214
/
Table 1
Reaction of 1-iodooctane (1) with t-BuLi at 0 8C in heptaneÁ
/ether solvent
Entry
Ether
HeptaneÁ
/
ether ratio (by volume)
Products
2
3
4
5
Recovered 1
1
2
3
4
5
6
7
8
9
None
(i-Pr)
52.1
69.2
77.2
83.6
74.9
88.0
90.7
82.1
79.3
87.9
89.3
73.3
90.7
90.4
83.8
3.5
4.3
3.7
5.0
4.5
2.4
2.2
3.3
2.5
5.2
3.0
3.4
3.2
2.7
3.7
20.0
14.2
16.3
8.8
3.8
12.3
2.9
2.6
2.9
17.6
2
O
9:1
19:1
99:1
199:1
9:1
16.4
7.7
MTBE
THF
1.9
1.7
19:1
99:1
9:1
7.1
12.9
4.2
14.0
1.4
1
1
1
1
1
1
0
1
2
3
4
5
19:1
49:1
99:1
9:1
5.5
7.7
7.9
6.0
0.9
0.7
14.5
THP
19:1
99:1
6.9
12.5
studied, there is an optimal etherÁ
maximizes the extent of lithiumÁ
octyllithium. However, in no case does the yield of
octyllithium, assayed as octane, exceed Â90% when
/heptane ratio that
/iodine exchange to give
/
reactions were conduced at 0 8C (Fig. 1 and Table 1).
The large variation in the yield of octane at high ether
concentration for the four heptaneÁether solvent sys-
/
tems surveyed is striking (Fig. 1). The fairly rapid
consumption of t-BuLi by reaction with various ethers
at elevated temperatures is well known [4] and the half-
life of the reagent in a number of ether solvents has been
measured by Stanetty and coworkers [15]. The particu-
larly rapid consumption of t-BuLi at 0 8C by reaction
with THF [15,16] is apparent from the data summarized
Fig. 1. Plot of yield of octane (2) vs. etherÁ
-iodooctane (1) with t-BuLi (Scheme 1). Legend: ", (i-Pr)
MTBE; j, THF; k, THP.
/
heptane ratio in reaction of
1
2
O; ',
in Fig. 1 and (i-Pr) O, although not investigated by
2
Stanetty, appears to react even more quickly with t-
BuLi than does THF. In this connection, it might be
noted, as suggested some time ago by Meyers [17], that
THP is superior to THF as a solvent for reactions
involving organolithium reagents in general and t-BuLi
in particular since it does not react as rapidly as does
THF with these reagents. In the course of the present
study, we observed that the concentration of solutions
meric [13]; consequently, side reactions such as coupling
to give 4 and elimination to give 3 are favored over the
exchange process. Conversely, when the concentration
of ether is high, t-BuLi is likely dimeric, favoring the
exchange process, but the reagent is also more likely to
be consumed by abstraction of a proton from the ether
solvent; consequently, consumption of octyllithium by
coupling with excess 1-iodooctane to give 5 becomes
problematic. Thus, for each of the ethers that were
of t-BuLi in heptaneÁMTBE (19:1 by volume) remain
/
fairly stable for considerable periods of time at 0 8C: the
concentration of such a solution decreases less than 13%
over a period of 70 min and this is consistent with the

W.F. Bailey et al. / Journal of Organometallic Chemistry 681 (2003) 210Á
/214
213
relatively high yield of octane observed in experiments
employing heptaneÁMTBE solvent.
It appears that side reactions such as coupling and
elimination are unavoidable when the lithiumÁiodine
exchange reaction between a primary alkyl iodide such
as 1 and t-BuLi is run at 0 8C. In order to study the
4. Experimental
/
4.1. General
/
Heptane was distilled from a dark blue solution of
sodiumÁbenzophenoneÁtetraglyme; ethers were freshly
distilled from dark blue solutions of sodiumÁbenzophe-
/
/
effect of temperature on the lithiumÁ
the reaction of 1-iodooctane with t-BuLi in heptaneÁ
MTBE (19:1 by volume) was investigated at several
temperatures ranging from ꢀ10 to ꢁ78 8C. The results
/iodine exchange,
/
/
none. The concentration t-BuLi in heptane was deter-
mined prior to use by titration with sec-butanol using
1,10-phenanthroline as an indicator according to the
method of Watson and Eastham [18].
/
/
of these experiments, which are summarized in Table 2,
demonstrate that the yield octyllithium, assayed as
octane, increases monotonically as the temperature of
the reaction is lowered.
4.2. Reaction of 1-iodooctane with t-BuLi at 0 8C
A flame-dried, septum-capped, 10 ml pear-shaped
flask was kept under a positive pressure of argon and
charged with ca. 1 mmol of 1-iodooctane. A separate
flame-dried, septum-capped, 25 ml round-bottomed
flask was kept under a positive pressure of argon and
charged with 2.2 mmol equivalents of t-BuLi in heptane.
The total 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-
iodooctane in the desired solvent ratio. The 1-iodooc-
tane was dissolved in half of the solvent volume
including all of the ether and the appropriate amount
of heptane. The t-BuLi solution was diluted with the
remaining heptane, then cooled to 0 8C in an ice-water
bath, and the 1-iodooctane solution 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 8C for an additional 20 min, then quenched with
water. The organic layer was washed with water, dried
3
. Conclusions
Coupling and elimination are unavoidable side reac-
tions when the lithiumÁiodine exchange reaction be-
/
tween 1-iodooctane (and presumably other primary
alkyl iodides) and t-BuLi is conducted at 0 8C. The
exchange reaction is slow in pure hydrocarbon solvent
but even small quantities of an ether co-solvent leads to
an improvement in the yield. There is an optimal etherÁ
heptane ratio for each of the four ethers surveyed that
maximizes the extent of lithiumÁiodine exchange be-
tween 1-iodooctane and t-BuLi but in no case does the
yield of octyllithium, assayed as octane, exceed Â90%
/
/
/
when reactions were conduced at 0 8C. At temperatures
lower than 0 8C, in a solvent system composed of
heptaneÁ/MTBE (19:1 by volume), side reactions are
(MgSO ), and filtered. The crude reaction product was
4
suppressed and the yield of octyllithium approaches
quantitative.
analyzed by GC on a 25-mꢂ
crosslinked 5%-phenyl methyl silicone capillary column
/
0.2-mmꢂ0.33-mm DB-5
/
Table 2
Reaction of 1-iodooctane (1) with t-BuLi in heptaneÁMTBE (19:1 by volume)
/
Entry
Temperature (8C)
Products
2
3
4
5
Recovered 1
1
2
3
4
5
6
10
0
86.4
90.7
91.7
94.1
96.6
98.5
4.2
2.2
2.3
2.0
1.3
7.1
7.1
5.3
3.9
2.1
1.5
0.5
1.8
ꢁ
/
10
20
40
78
ꢁ
/
ꢁ
/
ꢁ
/
Â/0

214
W.F. Bailey et al. / Journal of Organometallic Chemistry 681 (2003) 210Á214
/
ꢁ
1
[
5] (a) B.J. Wakefield, in: D.H.R. Barton, W.D. Ollis (Eds.),
(
1
2
50 8C for 5 min and 1 8C min
to 58 8C followed by
0 8C min to 250 8C for 5 min) and by GCÁMS on a
5-mꢂ0.2-mmꢂ0.25-mm HP-5 crosslinked 5% phenyl
ꢁ
1
Comprehensive Organic Chemistry, vol. 3, Pergamon Press,
/
Oxford, 1979, pp. 943Á
b) J.L. Wardell, in: G. Wilkinson (Ed.), Comprehensive Orga-
nometallic Chemistry, vol. 1, Pergamon Press, Oxford, 1982, pp.
44Á120;
/967;
/
/
(
methyl silicone capillary column (100 8C for 5 min and
0 8C min to 250 8C for 5 min). Octane (2), 1-octene
3), and hexadecane(5) were identified by comparison of
their retention times and mass spectra to those of
authentic samples; 2,2-dimethyldecane (4) was identified
on the basis of it reported mass spectrum [14].
ꢁ
1
1
(
/
(c) U. Sch o¨ llkopf, in: G. Baehr, P. Burba, H.F. Ebel, A.
Luettringhaus, U. Sch o¨ llkopf (Eds.), Methods of Organic Chem-
istry (Houben-Weyl), vol. 13, 4th ed, Georg Thieme, Stuttgart,
1
970 (Part 1);
d) W.F. Bailey, J.J. Patricia, J. Organomet. Chem. 352 (1988) 1.
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43.
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[
7
[
[
7] W.F. Bailey, E.R. Punzalan, J. Org. Chem. 55 (1990) 5404.
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Acknowledgements
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9] (a) W.F. Bailey, J.J. Patricia, T.T. Nurmi, W. Wang, Tetrahedron
This work was supported by Pfizer, Inc., Groton, CT
in the form of an Undergraduate Summer Research
Fellowship to J.D.B. We are grateful to Dr. James
Schwindeman of FMC, Lithium Division, for a gener-
ous gift of t-BuLi in heptane.
[
Lett. 27 (1986) 1861;
(b) W.F. Bailey, J.J. Patricia, T.T. Nurmi, Tetrahedron Lett. 27
(
(
1986) 1865;
c) E.C. Ashby, T.N. Pham, J. Org. Chem. 52 (1987)
1
291.
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