Reaction of lithium diethylamide with an alkyl bromide and alkyl benzenesulfonate: Origins of alkylation, elimination, and sulfonation

Article abstract of DOI:10.1021/jo101505x

A combination of NMR, kinetic, and computational methods are used to examine reactions of lithium diethylamide in tetrahydrofuran (THF) with n-dodecyl bromide and n-octyl benzenesulfonate. The alkyl bromide undergoes competitive S_N2 substitution and E2 elimination in proportions independent of all concentrations except for a minor medium effect. Rate studies show that both reactions occur via trisolvated-monomer-based transition structures. The alkyl benzenesulfonate undergoes competitive S_N2 substitution (minor) and N-sulfonation (major) with N-sulfonation promoted at low THF concentrations. The S_N2 substitution is shown to proceed via a disolvated monomer suggested computationally to involve a cyclic transition structure. The dominant N-sulfonation follows a disolvated-dimer-based transition structure suggested computationally to be a bicyclo[3.1.1] form. The differing THF and lithium diethylamide orders for the two reactions explain the observed concentration-dependent chemoselectivities.

Full text of DOI:10.1021/jo101505x

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Reaction of Lithium Diethylamide with an Alkyl Bromide and Alkyl
Benzenesulfonate: Origins of Alkylation, Elimination, and Sulfonation
Lekha Gupta, Antonio Ramırez, and David B. Collum*
´
Department of Chemistry and Chemical Biology Baker Laboratory, Cornell University Ithaca,
New York 14853-1301, United States
dbc6@cornell.edu
Received July 30, 2010
A combination of NMR, kinetic, and computational methods are used to examine reactions of
lithium diethylamide in tetrahydrofuran (THF) with n-dodecyl bromide and n-octyl benzenesulfo-
nate. The alkyl bromide undergoes competitive S 2 substitution and E2 elimination in proportions
N
independent of all concentrations except for a minor medium effect. Rate studies show that both
reactions occur via trisolvated-monomer-based transition structures. The alkyl benzenesulfonate
undergoes competitive S 2 substitution (minor) and N-sulfonation (major) with N-sulfonation
N
promoted at low THF concentrations. The S 2 substitution is shown to proceed via a disolvated monomer
N
suggested computationally to involve a cyclic transition structure. The dominant N-sulfonation follows a
disolvated-dimer-based transition structure suggested computationally to be a bicyclo[3.1.1] form.
The differing THF and lithium diethylamide orders for the two reactions explain the observed
concentration-dependent chemoselectivities.
2
underlying substitutions and eliminations, the efforts of
Streitwieser and co-workers are prominent.
Introduction
3
Many may remember being confounded by the substitution-
elimination dichotomy presented in our first course on
1
organic chemistry (eq 1). It was difficult to grasp why a
given electrophile-nucleophile-solvent combination causes
the prevalence of substitution over elimination (or vice
versa), despite support from an enormous body of empirical
observations. In our opinion, the confusion stems from the
incomplete picture of how solvation and aggregation influ-
ence nucleophilicity and basicity. The nomenclature based
on “ion pairing” prevalent in the older literature is too
inflexible to describe underlying aggregation effects. Simi-
larly, using terms such as “polarity” to explain solvent-
dependent reactivities and selectivities is inadequate to de-
scribe inherently molecular solvation events. Amid the few
studies designed to untangle the coordination chemistry
Understanding the S 2-E2 dichotomy is more than an
N
aging academic problem. One is struck, for example, by the
profound importance of C-N bond formation in pharma-
4
ceutical syntheses and the role played by S 2 substitutions.
N
5
Given the scope of the applications and their scales, even
incremental improvements in simple N-alkylations of mono-
and dialkylamines could prove significant.
We describe herein reactions of lithium diethylamide
Et NLi) in tetrahydrofuran (THF) with an n-alkyl bromide
2
eq 2) and an n-alkyl sulfonate (eq 3). The competing
(
(
(2) (a) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
rd ed.; VCH: Weinheim, 2003; Chapter 5 . (b) Hiraoka, M. Crown Com-
3
pounds: Their Characteristics and Application; Elsevier: Amsterdam, 1982.
(c) Atwood, J. L., Steed, J. W., Eds. Encyclopedia of Supramolecular
Chemistry; CRC Press: Boca Raton, FL, 2004; pp 940-949.
(3) (a) Wang, D. Z.; Streitwieser, A. J. Org. Chem. 2003, 68, 8936.
(b) Harder, S.; Streitwieser, A.; Petty, J. T.; Schleyer, P. v. R. J. Am. Chem.
Soc. 1995, 117, 3253. (c) Streitwieser, A.; Choy, G. S. C.; Abu-Hasanayn, F.
J. Am. Chem. Soc. 1997, 119, 5013. (d) Streitwieser, A. Proc. Natl. Acad. Sci.
U.S.A. 1985, 82, 8288–8290. See also ref 19. (e) Streitwieser, A.; Jayasree,
E. G. J. Org. Chem. 2007, 72, 1785.
(
1) (a) Smith, M.; March, J. March’s Advanced Organic Chemistry: Reac-
tions, Mechanisms, and Structure, 6th ed.; Wiley-Interscience: New York, 2007;
Chapters 10,17 . (b) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry,
th ed.; Springer: New York, 2007; Chapters 4,5. (c) Saunders, W. H., Jr.;
Cockerill, A. F. Mechanisms of Elimination Reactions; John Wiley & Sons:
New York, 1973; Vol. II, pp 60-68. (d) Baciocchi, E. In The Chemistry of
Halides, Pseudo Halides and Azides, Supplement D; Patai, S., Rappoport, Z.,
Eds.; Wiley: Chichester, U.K., 1983.
5
8
392 J. Org. Chem. 2010, 75, 8392–8399
Published on Web 11/16/2010
DOI: 10.1021/jo101505x
r 2010 American Chemical Society

Gupta et al.
JOCArticle
FIGURE 1. Plot of [3]:[2] vs [THF] in toluene cosolvent for the
FIGURE 3. Plot of [5]:[7] vs [THF] in toluene cosolvent for the reaction
2
reaction of 0.004 M 1-bromododecane (1) withEt NLi (0.10 M) at 0 °C.
of 0.004 M 1-octyl benzenesulfonate (4) withEt NLi (0.10 M) at -30 °C.
2
FIGURE 2. Plot of [3]:[2] vs [Et
cosolvent for the reaction of 0.004 M 1-bromododecane (1) with
Et
NLi at 0 °C.
2
NLi] in THF (3.9 M) and toluene
FIGURE 4. Plot of [5]:[7] vs [Et
cosolvent for the reaction of 0.004 M 1-octyl benzenesulfonate (4)
with Et
NLi at -30 °C.
2
NLi] in THF (6.0 M) and toluene
2
2
N-substitution, elimination, and N-sulfonation (O-desulfo-
nation) pathways are traced to specific solvation and aggre-
gation events.
concentrations were measured and are depicted graphically
in Figures 1-4. The notable feature is that n-alkyl bromide
1
dence (Figures 1 and 2), whereas the relative proportions of
6
affords ratios of 2 and 3 displaying a minor THF depen-
N-sulfonation (5) and N-alkylation (7) show both a depen-
dence on the Et NLi concentration and a striking THF
2
concentration dependence (Figures 3 and 4). The product
ratios allow us to deconvolute the mechanistic contributions
to each pathway.
6
15
Structure of Lithium Diethylamide. Previous Li and
6
N
NMR spectroscopic investigations have shown that [ Li, N]-
15
7
Et NLi is a dimer in THF (9). Computational studies
2
suggest that dimer 9 is disolvated (see Supporting Informa-
tion). At low THF concentrations (<2.0 M), minor amounts
of 3- and 4-rung ladders are observed.
Results
7
,8
Concentration-Dependent Selectivities. Using protocols
and conditions described below, the selectivities of N-alkylation,
elimination, and N-sulfonation versus Et NLi and THF
2
(4) (i) For a survey of chemical syntheses within the process chemistry
R&D departments of GlaxoSmithKline, AstraZeneca and Pfizer, see: (a) Carey,
J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4,
2
337. (b) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res. Dev.
005, 9, 253. (ii) For examples of N-alkylation of lithium dialkylamides, see:
c) Smith, J. K.; Bergbreiter, D. E.; Newcomb, M. J. Org. Chem. 1985, 50,
2
(
General Protocols. Pseudo-first-order rate constants (kobsd)
were determined using excess Et NLi (0.030-0.40 M) and
4549. (d) Sard, H.; Duffley, R. P.; Razdan, R. K. Synth. Commun. 1983, 13,
813. (iii) For representative reactions of lithium dialkylamides with sulfo-
2
nates, see: (e) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.;
Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700. (f) Andersen,
K. K.; Gowda, G.; Jewell, L.; McGraw, P.; Phillips, B. T. J. Org. Chem. 1982,
(5) Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.; Gillmore,
A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W. Chem. Rev. 2006,
106, 3002.
4
7, 1884.
J. Org. Chem. Vol. 75, No. 24, 2010 8393

Gupta et al.
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2
TABLE 1. Summary of Rate Studies for the Et NLi-Mediated Reactions (eqs 2 and 3)
d
e
entry
substrate
product(s)
THF order
a
Et
2
NLi order
b
k
H
/k
D
H D
k /k
1
2
3
4
5
6
a
1
2þ3
2
3
2.0 ( 0.1
0.54 ( 0.03
0.52 ( 0.03
0.57 ( 0.03c
0.98 ( 0.05
0.99 ( 0.04c
0.59 ( 0.04
1.1 ( 0.1
1.1 ( 0.1
1.1 ( 0.1
1.22 ( 0.05
1.12 ( 0.05
3.02 ( 0.04
a
b
2.0 ( 0.1
a
b
2.5 ( 0.1
a
4
5þ7
0
a
c
5
0
a
7
1.29 ( 0.05
b
c
d
NLi] = 0.10 M. [THF] = 3.9 M in toluene cosolvent. [THF] = 6.0 M in toluene cosolvent. Measured using 1 and 1,1-1-d
e
. Measured using 1
[
Et
2
2
and 2,2-1-d
2
.
limiting substrate concentrations (0.004 M). THF was re-
stricted to >2.0 M to avoid the larger aggregates observed at
7
,8
low THF concentrations. The disappearance of the sub-
strate (1 or 4), and the formation of products were monitored
relative to an internal n-decane standard using gas chroma-
tographic (GC) analysis of quenched aliquots; they displayed
clean first-order decays. Measured values of kobsd are inde-
pendent of the initial concentrations of the substrate ((10%),
consistent with first-order dependencies on the substrates. The
product ratios allow kobsd to be partitioned into the rate
constants for the parallel pathways as described below.
Results from the rate studies are summarized in Table 1.
Additional data are archived in Supporting Information.
N-Alkylation and Elimination of 1-Bromododecane. Reac-
tion of Et NLi with 1-bromododecane (1) in THF/toluene
2
FIGURE 5. Representative plot of the time-dependent decay of
(curve A) and formation of 2 (curve B) and 3 (curve C) relative to
an n-decane internal standard (relative area under the curve, AUC)
9
yields N,N-diethyldodecylamine (2) and 1-dodecene (3) as
shown in eq 2 and Figure 5. n-Dodecane that resulted from
1
1
reduction was also detected, but the concentrations were
0
for sequentially quenched samples of a reaction mixture containing
Et
2
NLi (0.10 M), THF (9.90 M), 1 (0.004 M), and toluene cosolvent
1
erratic and very low (<2%). Plots of kobsd versus THF
1
-bx
at 0 °C. The curves depict least-squares fit to: (A) y=ae (a=1.022 (
-
2
-bx
concentration (Figure 6) and kobsd versus Et NLi concentra-
2
0.005, b=k
=(2.11 ( 0.02) ꢀ 10 ); (B) y={a(1 - e )} (a=
- -bx
alk
obsd
2
tion (Figure 7) furnish orders of 2.0 ( 0.1 and 0.54 ( 0.03,
respectively. Replacing toluene cosolvent with 2,2,4,4-tetra-
methyltetrahydrofuran revealed no measurable cosolvent
dependence, arguing against long-range medium effects as
1.199 ( 0.006, b=k =(2.71 ( 0.06) ꢀ 10 ); (C) y={a(1 - e )}
- -2
1
(a=(1.648 ( 0.003) ꢀ 10 , b=kelim=(2.25 ( 0.02) ꢀ 10 ).
6
b,12
the source of second-order THF dependence.
(
6) (a) DePue, J. S.; Collum, D. B. J. Am. Chem. Soc. 1988, 110, 5518.
b) DePue, J. S.; Collum, D. B. J. Am. Chem. Soc. 1988, 110, 5524.
7) (a) Rutherford, J. L.; Collum, D. B. J. Am. Chem. Soc. 1999, 121,
0198. For recent computational studies of Et NLi aggregation and solva-
(
(
1
2
tion states, see: (b) Pratt, L. M. THEOCHEM 2007, 811, 191.
8) (a) Gardiner, M. G.; Raston, C. L. Inorg. Chem. 1996, 35, 4162.
b) Gardiner, M. G.; Raston, C. L. Inorg. Chem. 1996, 35, 4047. (c) Gardiner,
M. G.; Raston, C. L. Inorg. Chem. 1995, 34, 4206. (d) Boche, G.; Langlotz, I.;
Marsch, M.; Harms, K.; Nudelman, N. E. S. Angew. Chem., Int. Ed. Engl.
(
(
FIGURE 6. Plot of kobsd vs [THF] in toluene cosolvent for the
reaction of 1 (0.004 M) with Et
NLi (0.10 M) at 0 °C. The curve
depicts an unweighted least-squares fit to kobsd = k[THF] (k =
2
n
1
992, 31, 1205. (e) Barr, D.; Clegg, W.; Hodgson, S. M.; Lamming, G. R.;
-4
(
1.6 ( 0.4) ꢀ 10 , n = 2.0 ( 0.1).
Mulvey, R. E.; Scott, A. J.; Snaith, R.; Wright, D. S. Angew. Chem., Int. Ed.
Engl. 1989, 28, 1241. (f) Armstrong, D. R.; Barr, D.; Clegg, W.; Hodgson,
S. M.; Mulvey, R. E.; Reed, D.; Snaith, R.; Wright, D. S. J. Am. Chem. Soc.
To separate contributions from the two pathways one
and [2]/[3] = kalk/kelim
1
989, 111, 4719.
9) Ceruti, M.; Balliano, G.; Viola, F.; Cattel, L.; Gerst, N.; Shuber, F.
Eur. J. Med. Chem. 1987, 22, 199.
10) (a) Majewski, M.; Gleave, D. M. J. Organomet. Chem. 1994, 470, 1.
b) Newcomb, M.; Reeder, R. A. J. Org. Chem. 1980, 45, 1489. (c) Newcomb,
simply notes that kobsd = kalk þ k
elim
(
such that kalk and kelim correspond to the pseudo-first-order
rate constants for N-alkylation and elimination, respectively.
The task was simple because the product ratios were nearly
independent of all concentrations (see Figures 1 and 2); the
rate laws for substitution and elimination are identical. (A slight
preference for the formation of 3 at elevated THF concentra-
tions is reflected by the slightly higher order; Table 1, entry 3.)
(
(
M.; Burchill, M. T. J. Am. Chem. Soc. 1984, 106, 8276. (d) Newcomb, M.;
Burchill, M. T. J. Am. Chem. Soc. 1984, 106, 2450.
(
11) We do note, however, that the highest levels of n-dodecane loosely
correlated with higher THF concentrations.
12) Galiano-Roth, A. S.; Collum, D. B. J. Am. Chem. Soc. 1989, 111,
772.
(
6
8
394 J. Org. Chem. Vol. 75, No. 24, 2010

Gupta et al.
JOCArticle
CHART 1
FIGURE 7. Plot of kobsd vs [Et
2
NLi] in THF (3.9 M) and toluene
NLi at 0 °C. The
cosolvent for the reaction of 1 (0.004 M) with Et
curve depicts an unweighted least-squares fit to kobsd=k[Et
2
n
2
NLi]
-3
(
k=(8.7 ( 0.4) ꢀ 10 , n=0.54 ( 0.03).
1
3
Thus, the idealized rate law is described by eq 4. The prod-
uct ratios are sensitive to isotopic substitution. The measured
isotope effects using 1,1-1-d2 and 2,2-1-d (Table 1) are
CHART 2
2
1
4
15
consistent with an S 2 substitution and E2 elimination.
N
GC-MS analyses also confirmed β- rather than R-elimina-
tions. The stereochemistries of N-alkylation and elimina-
1
6
1
7
tion were not addressed experimentally.
1=2
2
-
d½1ꢁ=dt ¼ ðkalk þ kelimÞ½Et2NLiꢁ ½THFꢁ ½1ꢁ ð4Þ
A variety of seemingly plausible transition structures for
substitution and elimination are shown in Chart 1. Density
functional theory (DFT) calculations using the SVP basis set
1
8
for Br and 6-31G(d) for the rest of the atoms afforded
‡
20
enthalpies of activation (ΔH , kcal/mol) that include thermal
In contrast, we failed to locate structures akin to II. Optimi-
zations of β-eliminations III-VI afforded only 11 and 12 (types
III and V), both containing N-Li contacts. No structures of
corrections at 298.15 K. 1-Bromododecane, Et NLi, and
THF were modeled using EtBr, Me NLi and Me O, respec-
2
2
2
21
tively, to restrict the number of conformers. Calculated
activation free energies were ridiculously high even with
MP2/6-31G*//B3LYP/6-31G(d) single-point calculations.
Enthalpies of activation are reported according to eq 5. Al-
though absolute energies are not terribly informative, the
relative values and calculated geometries are.
type IV or VI displaying Br-Li contacts could be found.
(
18) All calculations were executed using Gaussian 03, revision B.04;
Gaussian, Inc.: Pittsburgh, PA, 2003. See Supporting Information for the
full list of authors. The combination of the Ahlrichs all-electron SVP basis set
for second-row atoms and 6-31G* for the rest is denoted as 631A and has
been previously applied to mechanistic studies on organolithium-mediated
reactions: Nakamura, E.; Yamanaka, M.; Yoshikai, N.; Mori, S. Angew.
Chem., Int. Ed. 2001, 40, 1935. Mori, J.; Nakamura, E.; Morokuma, K.
J. Am. Chem. Soc. 2000, 122, 7294 and references therein.
(19) Recent theoretical studies on S 2 reactions involving lithium-
N
containing species: (i) No solvent: (a) Ren, Y.; Gai, J.-G.; Xiong, Y.; Lee,
K.-H.; Chu, S.-Y. J. Phys. Chem. A 2007, 111, 6615. (b) Streitwieser, A.;
Jayasree, E. G.; Leung, S. S.-H; Choy, G. S.-C. J. Org. Chem. 2005, 70, 8486.
ΔH‡
q
1
=2ðEt2NLiÞ ðSÞ þ RX þ 2S
f ½ðEt2NLiÞðSÞ ðRXÞꢁ
2
2
3
ðS ¼ Me2OÞ
ð5Þ
(
4
2
c) Pratt, L. M.; Nguyen, N. V.; Ramachandran, B. J. Org. Chem. 2005, 70,
279. (d) Pomelli, C. S.; Bianucci, A. M.; Crotti, P.; Favero, L. J. Org. Chem.
004, 69, 150. (e) Ren, Y.; Chu, S. Y. J. Comput. Chem. 2004, 25, 461.
The results of the DFT computations (B3LYP/6-31G(d)) are
illustrated in Chart 2. Optimization of type I structures resulted
in legitimate transition structure 10 displaying an N-Li inter-
(
f) Xiong, Y.; Zhu, H.; Ren, Y. J. Mol. Struct. 2003, 664-665, 279. (g) Leung,
S. S.-H.; Streitwieser, A. J. Comput. Chem. 1998, 19, 1325. (ii) Dielectric
solvation models: (h) Streitwieser, A.; Jayasree, E. G.; Hasanayn, F.; Leung,
S. S.-H. J. Org. Chem. 2008, 73, 9426. (i) Ren, Y.; Li, M.; Wong, N.-B.; Chu,
S.-Y. J. Mol. Model. 2006, 12, 182. (j) Ren, Y.; Chu, S. Y. J. Phys. Chem. A
2004, 108, 7079. (k) Zhu, H.; Ren, Y.; Ren, J. J. Mol. Struct. 2004, 686, 65.
(iii) Microsolvation models: (l) Streitwieser, A.; Jayasree, E. G. J. Org. Chem.
2007, 72, 1785. (m) Ando, K. J. Org. Chem. 2006, 71, 1837. (n) Ando, K. J.
Am. Chem. Soc. 2005, 127, 3964. See also reference 20a.
(20) RBr-Li interactions do not appear to be stabilizing: (a) Zuend, S. J.;
Ramirez, A.; Lobkovsky, E.; Collum, D. B. J. Am. Chem. Soc. 2006, 128,
5939. (b) Ikuta, Y.; Tomoda, S. Org. Lett. 2004, 6, 189.
(21) For additional examples showing that Br leaving groups do not
require metal assistance during the alkylation of lithium-based nucleophiles,
see: (a) Zuend, S. J.; Ramirez, A.; Lobkovsky, E.; Collum, D. B. J. Am.
Chem. Soc. 2006, 128, 5939. (b) Ikuta, Y.; Tomoda, S. Org. Lett. 2004, 6, 189.
(c) For a general discussion of lithium-assisted departure of the leaving
group, see: Reich, H. J.; Sanders, A. W.; Fiedler, A. T.; Bevan, M. J. J. Am.
Chem. Soc. 2002, 124, 13386.
1
9
action and a highly bent N-C-Br bond angle (155°).
(
13) We define the idealized rate law as that obtained by rounding the
observed reaction orders to the nearest rational order.
14) (a) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
(
Chemistry; University Science, 2006; Chapter 11 . (b) Fang, Y.-R.; Westaway,
K. C. Can. J. Chem. 1991, 69, 1017. (c) Westaway, K. C.; Lai, Z.-G. Can.
J. Chem. 1989, 67, 345.
(
15) (a) Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 4081.
b) Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1997, 119, 5573.
16) Dehydrobrominations of 2,2-1-d -dodecane afforded exclusively
-dodecene, whereas dehydrobrominations of 1,1-1-d -dodecane yielded
-dodecene .
(
(
2
1
1
-d
-d
1
2
2
(
17) (a) Bock, P. L.; Whitesides, G. M. J. Am. Chem. Soc. 1974, 96, 2826.
b) Whitesides, G. M.; Fischer, W. F., Jr.; San Filippo, J., Jr.; Bashe, R. W.;
House, H. O. J. Am. Chem. Soc. 1969, 91, 4871.
(
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Gupta et al.
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FIGURE 10. Plot of kalk vs [Et
solvent for the N-alkylation of 4 (0.004 M) with Et
2
NLi] in THF (6.0 M) and toluene co-
FIGURE 8. Plot of kalk vs [THF] in toluene cosolvent for the
2
NLi at -30 °Cn.
N-alkylation of 4 (0.004 M) with Et
curve depicts an unweighted least-squares fit to kalk=k[THF] (k=
2
NLi (0.10 M) at -30 °C. The
n
2
The curve depicts an unweighted least-squares fit to kalk=k[Et NLi]
-4
-
6
(k=(2.4 ( 0.1) ꢀ 10 , n=0.59 ( 0.04).
(
5.5 ( 0.7) ꢀ 10 , n=1.29 ( 0.05).
2
FIGURE 11. Plot of ksulf vs [Et NLi] in THF (6.0 M) and toluene
cosolvent for the N-sulfonation of 4 (0.004 M) with Et NLi at -30 °C.
2
FIGURE 9. Plot of ksulf vs [THF] in toluene cosolvent for the
N-sulfonation of 4 (0.004 M) with Et
n
2
The curve depicts an unweighted least-squares fit to ksulf=k[Et NLi]
2
NLi (0.10 M) at -30 °C.
-2
(
k=(1.26 ( 0.07) ꢀ 10 , n=0.99 ( 0.04).
Plots of kalk and ksulf versus THF concentration (Figures 8
The curve depicts an unweighted least-squares fit to ksulf=) .c [THF] þ
0
-4
0
-3
k (c=(-1.07 ( 0.08) ꢀ 10 , k =(1.99 ( 0.06) ꢀ 10
and 9) reveal first- and zeroth-order dependencies, respec-
tively. The linear and slightly inverse THF concentration
dependence observed for ksulf is consistent with secondary
shell (medium) effects accompanying the increasing THF
Efforts to find structure VII corresponding to a hypothetical
unobserved) R-elimination failed, possibly because the tri-
solvation implicated by the rate studies precludes a Br-Li
(
2
2
interaction. The relative enthalpies of transition structures
6b,12
concentration.
Figures 10 and 11 illustrate the dependence
10, 11 and 12 indicate that the nucleophilic substitution (10)
is enthalpically favored.
N-Alkylation and N-Sulfonation of n-Octyl benzenesulfonate.
The reaction of 1-octyl benzenesulfonate (4) with 0.10 M
of kalk and ksulf on the Et NLi concentration (0.03-0.40 M) in
2
0
.59(0.04
6
.0 M THF. The fractional order (k µ [Et NLi]
) and
) are consistent with
alk
.99(0.04
2
0
first order (ksulf µ [Et NLi]
2
monomer- and dimer-based pathways, respectively. The
data support the idealized rate law in eq 6 and the generic
mechanisms in eqs 7 and 8.
Et NLi in THF/toluene mixtures at -30 °C affords products
2
derived from N-sulfonation (5and 6) and N-alkylation (7and 8)
to the exclusion of 1-octene expected from elimination (eq 3).
Figure 3 shows the THF dependence on the ratio of sub-
stitution and elimination (5/7). In contrast to the reaction of
1=2
1
1
0
-d½4ꢁ=dt ¼ kalk½Et2NLiꢁ ½THFꢁ ½4ꢁ þ ksulf ½Et2NLiꢁ ½THFꢁ ½4ꢁ
ð6Þ
1
-bromododecane, the selectivity is highly sensitive to the
kalk½THFꢁ
proportion of THF. By monitoring the 5/7 ratio (vide supra),
kobsd can be deconvoluted to give the rate constants for the
N-sulfonation (ksulf) and N-alkylation (kalk).
q
1
=2ðEt2NLiÞ ðTHFÞ þ 4
f
½ðEt2NLiÞðTHFÞ ð4Þꢁ
2
2
2
ð9Þ
ð7Þ
ð8Þ
(
22) (i) Basic nucleophiles tend to generate Nuc-HR complexes upon
ksulf
s
f
q
unrestricted geometry optimizations (a) Yi, R.; Basch, H.; Hoz, S. J. Org.
Chem. 2002, 67, 5891. (b) Buhl, M.; Schaefer, H. F. J. Am. Chem. Soc. 1993,
15, 9143. (ii) Nu-CR
technique to circumvent this limitation in the study of S
S.; Basch, H.; Wolk, J. L.; Hoz, T.; Rozental, E. J. Am. Chem. Soc. 1999, 121,
724.
ðEt2NLiÞ ðTHFÞ þ 4
½ðEt2NLiÞ ðTHFÞ ð4Þꢁ
2
ð9Þ
2
2
2
1
3
-X angle restriction to collinearity is a common
N
2 reactions: (c) Hoz,
Rate data indicate that N-alkylation occurs via disolvated
Et NLi monomer, possibly with a minor contribution from
7
2
8
396 J. Org. Chem. Vol. 75, No. 24, 2010

Gupta et al.
JOCArticle
at the external and internal Li atoms. Optimization of
CHART 3
proximally solvated forms (types X and XI) led to desolv-
2
6,27
ation.
ring system with coordination of each SdO moiety to one
Transition structure 15 displays a bicyclo[3.1.1]
lithium atom of the Me NLi dimer. The sulfur atom adopts
2
trigonal bipyramidal hybridization with the attacking nitro-
gen and the leaving RO group in apical positions. IRC
2
8
calculations support a stepwise addition-elimination.
The computations qualitatively support a preference for
N-sulfonation over N-alkylation.
Cursory searches of hypothetical (unobserved) monomer-
based β-eliminations afford 16 and 17. Activation enthalpies
suggest that eliminations will not compete with alkylation
and sulfonation.
Discussion
CHART 4
We introduced this paper with the assertion that nucleo-
philic substitutions and eliminations can be confounding
because of a limited understanding of how aggregation
and solvation;two inherently molecular phenomena;
influence the mechanisms. A combination of kinetic and compu-
tational methods was used to study reactions of Et NLi in
2
THF with n-alkyl bromide 1 and n-alkyl benzenesulfonate 4
(eqs 2 and 3). The resulting mechanistic scenario summarized
in Scheme 1 is discussed in the context of several long-
standing issues.
SN2-E2 Dichotomy. We intended to study the mechanistic
basis underlying competing substitutions and eliminations.
Such an analysis of sulfonate 4 was precluded by its failure to
undergo detectable elimination, which is somewhat surpris-
29
ing given the pronounced Br o€ nsted basicity of Et NLi.
2
Focusing on n-alkyl bromide 1, we found that both substi-
tution and elimination proceed via isomeric trisolvated-
monomer-based pathways. One of the most obvious and
practical consequences is that concentration changes provide
no means of controlling selectivity (Figures 1 and 2). The
drifting selectivity with increasing THF concentration
shown in Figure 1 derives from secondary shell solvation
effects; vide infra.
trisolvated monomer, whereas N-sulfonation takes place via
disolvated Et NLi dimer. The generic transition structures in
Chart 3 seem plausible, yet a much smaller subset proved
computationally viable (Chart 4). Attempts to optimize
parent geometries VIII and IX for the nucleophilic substitu-
2
S 2 Substitutions: RBr versus ROSO Ph. Inspection of
N
2
transition structure 18 (or the structurally simpler computed
analog 10) reveals pronounced steric interactions between
tion (using PhSO OEt as a model) converged on hybrid
2
isomer 13, which displays a 6-membered ring and a tetra-
23
coordinate lithium that interacts with the sulfonyl leaving
2
group. Transition structure 13 corresponds to a 6-endotet
4
(26) (a) Fressign ꢀe , C.; Lautrette, A.; Maddaluno, J. J. Org. Chem. 2005,
0, 7816. (b) Pomelli, C. S.; Bianucci, A. M.; Crotti, P.; Favero, L. J. Org.
7
closure, which is considered to be geometrically implausible
2
5
Chem. 2004, 69, 150. (c) Gillies, M. B.; Tønder, J. E.; Tanner, D.; Norrby, P.
J. Org. Chem. 2002, 67, 7378. (d) Fressign ꢀe , C.; Maddaluno, J.; Marquez, A.;
Giessner-Prettre, C. J. Org. Chem. 2000, 65, 8899.
in many settings. Transition structure 14, a trisolvated
analog of 13, lacks an SdO-Li contact.
Searches for disolvated-dimer-based transition structures
(27) (a) Ramirez, A.; Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2006, 128,
0326. (b) Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1995, 117,
166. Searches for structures disolvated at the external Li led to severe
1
2
for N-sulfonation afforded only structure 15 (type XII), solvated
transannular interactions involving the solvent and the SdO-Li bridge.
28) For discussions of S 2 mechanism versus that with a discrete
(
N
(
23) Schlosser, M. In Organometallics in Synthesis: A Manual; Schlosser,
M., Ed.; 2nd ed.; John Wiley & Sons: Chichester, 2002; Chapter 1 .
24) (i) For reports on R SO -Li complexation, see: (a) Linnert, M.;
Bruhn, C.; Wagner, C.; Steinborn, D. J. Organomet. Chem. 2006, 689, 2358.
b) Rhodes, C. P.; Frech, R. Macromolecules 2001, 34, 2660. (c) Pregel, M. J.;
tetrahedral intermediate, see: (a) Erdik, E.; Eroglu, F. Cent. Eur. J. Chem.
2008, 6, 237. (b) Fox, J. M.; Dmitrenko, O.; Liao, L.; Bach, R. D. J. Org.
Chem. 2004, 69, 7317. (c) Weiner, H.; Sneen, R. A. J. Am. Chem. Soc. 1965,
87, 292. (d) Chang, F. C. Tetrahedron Lett. 1964, 6, 305.
(
2
2
(
2
(29) (i) For studies on the acidity of Et NH in THF, see: (a) Furlong,
Dunn, E. J.; Buncel, E. J. Am. Chem. Soc. 1991, 113, 3545. (d) Eisch, J. J.;
Galle, J. E. J. Org. Chem. 1980, 45, 4536. (ii) The nucleophilic substitutions
of arylsulfonates with lithium halides occur with inversion of configuration:
Braddock, D. C.; Pouwer, R. H.; Burton, J. W.; Broadwith, P. J. Org. Chem.
J. J. P.; Lewkowicz, E. S.; Nudelman, N. S. J. Chem. Soc., Perkin Trans. 2
1990, 1461. (ii) For selective substitutions of sulfonates with organolithiums,
see: (b) Nelson, T. D.; Rosen, J. D.; Smitrovich, J. H.; Payack, J.; Craig, B.;
Matty, L.; Huffman, M. A.; McNamara, J. Org. Lett. 2005, 7, 55. (c) Kusumoto,
T.; Ichikawa, S.; Asaka, K.; Sato, K.-I.; Hiyama, T. Tetrahedron Lett. 1995,
36, 1071. (iii) For a recent discussion on β-eliminations of benzenesulfonates,
see: (d) Mohrig, J. R.; Alberg, D. G.; Cartwright, C. H.; Pflum, M. K. H.;
Aldrich, J. S.; Anderson, J. K.; Anderson, S. R.; Fimmen, R. L.; Snover,
A. K. Org. Biomol. Chem. 2008, 6, 1641.
2
009, 74, 6042.
25) (a) Beak, P. Acc. Chem. Res. 1992, 25, 215. (b) Baldwin, J. E. J. Chem.
(
Soc., Chem. Commun. 1976, 734. (c) Baldwin, J. E. Further Perspectives in
Organic Chemistry; A Ciba Foundation Symposium; Elsevier: Amsterdam,
1
978, 736. (d) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
J. Org. Chem. Vol. 75, No. 24, 2010 8397

Gupta et al.
JOCArticle
SCHEME 1
the CH -Br moiety and the THF ligands. Now imagine an
and consider the displacement of a secondary alkyl sulfonate
0
2
analogous substitution of a secondary alkyl bromide via
transition structure 22. The vast literature suggests that it
would be markedly slower (possibly orders of magnitude)
ester. The additional alkyl moiety (R ) in cyclic transition
structure 23 would likely render the reaction untenable
because of acute interactions between the sulfonyl moiety
and the alkyl group of the sulfonate ester. The reaction
would be forced to proceed through a noncyclic form, which
is suggested by the rate studies to be less viable. The inter-
actions within the sulfonate ester moiety are quite prominent
due to destabilizing Et N-RBr contacts. It appears, however,
2
that solvent-substrate interactions are pronounced and that
focusing on Et N-RBr interactions may be misleading. The
2
literature also suggests that highly ionizing conditions can
2
1c,30
markedly promote the S 2 substitution,
N
which would
whereas those with the Et N moiety almost seem to be of
2
logically stem from both the increasing charge on the nucleo-
phile as well as dissociation of the lithium cation and, with it, the
solvent-substrate contacts. This scenario is very unlikely to
secondary importance. Although this description is certainly
an oversimplification, most conventional discussions of SN2
displacements of sulfonate esters do not consider interac-
tions between the sulfonyl moiety and the alkyl substituents
as potentially dominant.
SN2 Substitution versus N-Sulfonation. The reaction of
occur, however, for Et NLi even under highly ionizing con-
2
3
3
ditions. The conclusion is a recurring theme: steric demands of
solvation are an important determinant of aggregate struc-
3
1
ture and reactivity.
Et NLi with sulfonate 4 in THF affords products of sub-
2
stitution and N-sulfonation. The name N-sulfonation, how-
ever, is a lithium amide-centric view. It would be equally
valid to call it O-desulfonation. Such desulfonations are con-
sequential side reactions during displacements of tosylates
3
4
and related sulfonate esters. In contrast to the substitution-
elimination selectivity observed for n-alkyl bromide 1, the
alkylation-sulfonation selectivity is sensitive to both THF
and Et NLi concentrations (Figures 3 and 4). The dominant
2
Comparing the mechanism for S 2 substitutions of
N
sulfonation (120:1) becomes less so (<5:1) at low Et NLi
2
n-alkyl bromide 1 and benzenesulfonate 4 reveals that the
sulfonate ester undergoes substitution via a disolvated rather
than a trisolvated monomer. Computational studies show
that transition structure 20 (Scheme 1), in which a THF
ligand has been replaced by chelation of the sulfonate, is
quite plausible with a 25° distortion of the N-C-O angle
from the optimal 180°, a distortion comparable to that
and high THF concentrations. The concentration dependen-
cies derive from differential solvation and aggregation num-
bers in transition structures 20 and 21. The sulfonation
appears to benefit from multidentate contacts with lithium
as well as from conservation of the Et NLi dimer structure.
2
IRC calculations revealed a two-step (addition-elimination)
mechanism.
Primary Shell versus Secondary Shell Solvation. Both
N-alkylation and β-elimination of 1-bromododecane show
approximate second-order THF dependencies, which we attri-
bute to monomer-based pathways in THF/toluene mixtures.
The THF order for the elimination pathway is actually 2.5 ( 0.1
3
2
observed for the alkyl bromide. Those who use Baldwin’s
ring closure rules categorically may find transition structure
20 disquieting. Let us return to the hypothetical displacements
(
30) (a) Humeres, E.; Nunes, R. J.; Machado, V. G.; Gasques, M. D. G.;
Machado, C. J. Org. Chem. 2001, 66, 1163. (b) Westaway, K. C.; Lai, Z. Can.
J. Chem. 1988, 66, 1263. (c) Reichardt, C. Solvents and Solvent Effects in
Organic Chemistry, 2nd ed.; VCH: Weinheim, 1988; Chapter 7 . (d) Arnett,
E. M.; Maroldo, S. G.; Schriver, G. W.; Schilling, S. L.; Troughton, E. B.
J. Am. Chem. Soc. 1985, 107, 2091. (e) Doolitle, R. E. Org. Prep. Proceed. Int.
(33) (a) Bentley, T. W.; Bowen, C. T.; Morten, D. H.; Schleyer, P. v. R.
J. Am. Chem. Soc. 1981, 103, 5466. (b) Bentley, T. W.; Bowen, C. T.; Parker,
W.; Watt, C. I. F. J. Am. Chem. Soc. 1979, 101, 2486. (c) Bentley, T. W.;
Bowen, C. T. J. Chem. Soc., Perkin Trans. 2 1978, 557. (d) Mori, A.;
Nagayama, M.; Mandai, H. Bull. Chem. Soc. Jpn. 1971, 44, 1669.
1980, 12, 1. (f) Parker, A. J.; Mayer, U.; Schmid, R.; Gutmann, V. J. Org.
Chem. 1978, 43, 1843. (g) Sam, D. J.; Simmons, H. E. J. Am. Chem. Soc. 1974,
9
6, 2252.
(
31) Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed.
(34) Studies on nucleophilic displacements at sulfonate sulfur: (a) Holterman,
H. A. J.; Engberts, B. F. N. J. Org. Chem. 1977, 42, 2792. (b) Van de
Langkruis, G. B.; Engberts, J. B. F. N. J. Org. Chem. 1984, 49, 4152. (c) Mori,
A.; Nagayama, M.; Mandai, H. Bull. Chem. Soc. Jpn. 1971, 44, 1669.
(d) Weiner, H.; Sneen, R. A. Tetrahedron Lett. 1963, 1309.
2
007, 46, 3002.
N
(32) For challenges to the reputed linear trajectory of ideal S 2 reactions,
see: Sato, M.; Yamataka, H.; Komeiji, Y.; Mochizuki, Y.; Ishikawa, T.;
Nakano, T. J. Am. Chem. Soc. 2008, 130, 2396 and references cited therein.
8
398 J. Org. Chem. Vol. 75, No. 24, 2010

Gupta et al.
Table 1, entry 3). One consequence is that the selectivity
JOCArticle
(
the coordination chemistry of lithium, not vague notions of
polarity and ionicity.
shows a preference for elimination at elevated THF concentra-
tions (Figure 1). By using 2,2,5,5-tetramethyltetrahydrofuran, a
cosolvent with a polarity akin to that of THF but no capacity
to coordinate competitively to lithium, the THF order for the
Experimental Section
Reagents and Solvents. THF and toluene were distilled from
blue or purple solutions containing sodium benzophenone ketyl.
The toluene still contained 1% tetraglyme to dissolve the ketyl.
3
5
β-elimination drops to 2.1 ( 0.1. Thus, there is a medium
effect of marginal practical consequence. The N-sulfonation
using sulfonate 4 shows an analogous medium effect, except
that a slight rate reduction occurs at elevated THF con-
centrations. Similar secondary shell effects contributing to
solvent-dependent rates have been documented previous-
6
6
15
[
Li]Et NLi and [ Li, N]Et NLi were prepared as insoluble
2 2
1
5
white solids by metalating Et NH 37and [ N]Et NH
2
2
6
(respectively) with [ Li]n-BuLi in pentane. Recrystallization
from hexane/diethyl ether as the etherate and subsequent evac-
uation afforded solvent-free Et NLi. Air- and moisture-sensitive
materials were manipulated under argon or nitrogen using
standard glovebox, vacuum line, and syringe techniques. Solu-
7
6
,36
ly.
Moreover, they are known to cause both modest
2
accelerations and decelerations, depending on the specific
reaction. Although it may be tempting to focus on how and
why the medium influences reaction rates, we find that the
medium effects are surprisingly minor given that lithium
amides are often viewed as highly polar species. The chem-
istry of lithium amides in particular, and probably organo-
lithium reagents in general, is dominated by ligands in the
primary coordination shell.
2
tions of n-BuLi and Et NLi were titrated for active base using a
38
literature method.
Kinetics. For a kinetic run corresponding to a single rate
constant, a stock solution of Et
2
NLi (0.03-0.4 M) in a THF-
toluene solution was prepared. A series of oven-dried, nitrogen-
flushed 5 mL serum vials (10 per rate constant) fitted with stir
2
bars were charged with the Et NLi stock solution and brought
to the desired temperature ((0.2 °C) using a constant-temperature
bath fitted with a thermometer. The substrate (1 or 4) was
added as a 0.08 M stock solution in hexane containing decane
(0.08 M) as a GC standard. The vessels were periodically
Conclusion
Reaction of Et NLi with an n-alkyl bromide reveals
2
competing S 2 substitution and E2 elimination via trisolv-
N
quenched with 1:1 H
adequate sampling of each of the first three half-lives. The
quenched aliquots were extracted into Et O and the extracts
2
O-THF at intervals chosen to ensure an
ated lithium amide monomers in both instances. Within this
sliver of the enormous field of substitution and elimination,
the relative reaction rates and, consequently, the chemo-
selectivity are insensitive to solvent and lithium amide con-
2
analyzed using GC. The reactions were monitored by following
the decrease of substrates 1 or 4 and the formation of products 2
and 3 or 5 and 7 (eqs 2 and 3) relative to the internal decane
standard. Following the formation of the corresponding prod-
ucts afforded equivalent rate constants within (10%. Rate
constants were determined using nonlinear least-squares fits.
The reported errors correspond to one standard deviation.
The observed rate constants were shown to be reproducible
within (10%.
centrations. Analogous reaction of Et NLi with an n-alkyl
2
arylsulfonate affords low levels of substitution and substan-
tial N-sulfonation to the exclusion of elimination. Because
the N-alkylation proceeds via disolvated monomers and the
N-sulfonation via disolvated dimers, the selectivity is con-
trollable by adjusting concentrations, although the N-sulfo-
nation remains dominant under all conditions. Whereas
primary shell solvation is of profound importance, secondary-
shell solvation (medium effects) has marginally detectable
influence on rates and selectivities. We are reminded that to
understand organolithium reaction mechanism is to understand
Acknowledgment. We thank the National Institutes of
Health (GM39764) for direct support of this work.
Supporting Information Available: NMR, rate, and compu-
tational data, experimental protocols, and complete list of
authors for ref 18. This material is available free of charge via
the Internet at http://pubs.acs.org.
(35) The dielectric constants of substituted THFs are only slightly lower
than THFs. Harada, Y.; Salomon, M.; Petrucci., S. J. Phys. Chem. 1985, 89,
2
8
006. Carvajal, C.; Tolle, K. J.; Smid, J.; Szwarc, M. J. Am. Chem. Soc. 1965,
7, 5548.
(
36) Related secondary shell effects: (a) Ma, Y.; Collum, D. B. J. Am.
(37) (a) Rennels, R. A.; Maliakal, A. J.; Collum, D. B. J. Am. Chem. Soc.
1998, 120, 421. (b) Kottke, T.; Stalke, D. Angew. Chem., Int. Ed. Engl. 1993,
32, 580.
Chem. Soc. 2007, 129, 14818. (b) Ma, Y.; Ramirez, A.; Singh, K. J.;
Keresztes, I.; Collum, D. B. J. Am. Chem. Soc. 2006, 128, 15399. (c) Bordwell,
F. G.; Hughes, D. L. J. Am. Chem. Soc. 1986, 108, 7300.
(38) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
J. Org. Chem. Vol. 75, No. 24, 2010 8399