Lithium diisopropylamide solvated by hexamethylphosphoramide: Substrate-dependent mechanisms for dehydrobrominations

Article abstract of DOI:10.1021/ja060964b

Lithium diisopropylamide-mediated dehydrobrominations of exo-2-bromonorbornane, 1-bromocyclooctene, and cis-4-bromo-tert-butylcyclohexane were studied in THF solutions and THF solutions with added hexamethylphosphoramide (HMPA). Rate studies reveal a diverse array of mechanisms based on mono-, di-, and trisolvated monomers as well as triple ions. The results are contrasted with analogous eliminations in THF in the absence of HMPA.

Full text of DOI:10.1021/ja060964b

Published on Web 11/11/2006
Lithium Diisopropylamide Solvated by
Hexamethylphosphoramide: Substrate-Dependent
Mechanisms for Dehydrobrominations
Yun Ma, Antonio Ramirez, Kanwal Jit Singh, Ivan Keresztes, and David B. Collum*
Contribution from the Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301
Received February 9, 2006; E-mail: dbc6@cornell.edu
Abstract: Lithium diisopropylamide-mediated dehydrobrominations of exo-2-bromonorbornane, 1-bromocy-
clooctene, and cis-4-bromo-tert-butylcyclohexane were studied in THF solutions and THF solutions with
added hexamethylphosphoramide (HMPA). Rate studies reveal a diverse array of mechanisms based on
mono-, di-, and trisolvated monomers as well as triple ions. The results are contrasted with analogous
eliminations in THF in the absence of HMPA.
Introduction
congested lithium salts. Although HMPA coordinates tena-
ciously to dimeric LDA compared with standard ethereal
Adding hexamethylphosphoramide (HMPA) to ethereal solu-
tions of organolithiums often elicits dramatic improvements in
reaction rates, yields, and selectivities.1,2 Although most dis-
cussions of how HMPA influences reactivity are highly con-
jectural, H. J. Reich and co-workers have made great progress
toward filling this void.3 Their investigations of a wide range
of organolithium derivatives confirm the consensus that HMPA
is a strongly coordinating ligand4 capable of promoting de-
aggregation and ion-pair separation. Of particular importance,
their spectroscopic studies in the limit of slow solvent exchange
of free and coordinated HMPA provide a rare glimpse of
lithium-ion solvation at a molecular level of resolution.5
solvents such as THF, we detect no measurable deaggregation
(eq 1).7a Even more surprising, adding HMPA to monomer-
dimer mixtures of either lithium hexamethyldisilazide (Li-
HMDS) or lithium N,N,N′,N′-tetramethylpiperidide (LiTMP)7b
results in ionization of the dimers to form triple ions,7a,8 yet
further deaggregations are still not observed (Scheme 1).9 In
short, HMPA does not fully live up to its reputation as a
deaggregating agent in the context of hindered lithium amides.
Rate studies of the LDA/HMPA-mediated ester enolization
in eq 2 reveal further anomalies: HMPA fails to match
expectations by serving as only a marginal accelerant,7f,10 yet
Our interest in HMPA stems from studies of lithium diiso-
propylamide (LDA) and related N-lithiated species.6,7 Results
from structural and mechanistic studies of LDA/HMPA/THF
mixtures deviate significantly from those of other less sterically
(1) Dykstra, R. R. Hexamethylphosphoric Triamide. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York,
1995; Vol. 4, pp 2668-2675.
(2) For a particularly interesting treatment of stereo- and regioselectivity
affiliated with organolithium chemistry, see: Clayden, J. Organolithiums:
SelectiVity for Synthesis; Pergamon: New York, 2002.
(3) For additional leading references, see: Reich, H. J.; Sanders, A. W.; Fiedler,
A. T.; Bevan, M. J. J. Am. Chem. Soc. 2002, 124, 13386.
(4) HMPA has been estimated to bind 300 times more strongly than THF in
one case. Reich, H. J.; Kulicke, K. J. J. Am. Chem. Soc. 1996, 118, 273.
(5) (a) Hilmersson, G.; Davidsson, O. J. Org. Chem. 1995, 60, 7660. (b)
Hilmersson, G.; Ahlberg, P.; Davidsson, O. J. Am. Chem. Soc. 1996, 118,
3539. (c) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 6009.
(d) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1995, 117, 9863.
(6) Structural studies of N-lithiated species have been reviewed. Lucht, B. L.;
Collum, D. B. Acc. Chem. Res. 1999, 32, 1035. Collum, D. B. Acc. Chem.
Res. 1993, 26, 227. Gregory, K.; Schleyer, P. v. R.; Snaith, R. AdV. Inorg.
Chem. 1991, 37, 47. Mulvey, R. E. Chem. Soc. ReV. 1991, 20, 167.
(7) (a) Romesberg, F. E.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum,
D. B. J. Am. Chem. Soc. 1991, 113, 5751. (b) Romesberg, F. E.; Bernstein,
M. P.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B. J. Am.
Chem. Soc. 1993, 115, 3475. (c) Romesberg, F. E.; Collum, D. B. J. Am.
Chem. Soc. 1994, 116, 9198. (d) Sakuma, K.; Gilchrist, J. H.; Romesberg,
F. E.; Cajthaml, C. E.; Collum, D. B. Tetrahedron Lett. 1993, 34, 5213.
(e) Aubrecht, K. B.; Collum, D. B. J. Org. Chem. 1996, 61, 8674. (f) Sun,
X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2452. (g) Sun, X.; Collum,
D. B. J. Am. Chem. Soc. 2000, 122, 2459.
the nearly solvent-insensitive relative rate constants, krel, belie
deep-seated mechanistic complexities.11 Whereas the LDA/THF-
(8) An extensive bibliography of triple ions is included in the Supporting
Information. Many of the reports cited will not be uncovered using current
algorithms for electronic database searching. Of particular interest are triple
ions derived from N-lithiated species and those based on the +Li(HMPA)4
counterion.
(9) HMPA promotes aggregation in one instance. Jackman, L. M.; Chen, X.
J. Am. Chem. Soc. 1992, 114, 403.
9
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J. AM. CHEM. SOC. 2006, 128, 15399-15404
15399

A R T I C L E S
Scheme 1
Ma et al.
Table 1. Relative Rate Constants for LDA/HMPA-Mediated
Eliminations (Eq 6)
a
substrate
T (°
C)
kHMPA:kTHF
8
10
12
-55
0
-10
3000:1
3:1
30:1
mediated enolization proceeds via disolvated monomer 5, the
analogous enolization with added HMPA appears to proceed
via a combination of monosolvated monomer 6 and tetrasolvated
triple-ion 7.7f These results are surprising on several levels. We
a Eliminations using 0.10 M LDA in 10.0 M THF with no added HMPA
(kTHF) or with 0.60 M HMPA (kHMPA).
such a narrowly focused survey, the influence of HMPA on
the rates and mechanisms proves to be highly substrate
dependent. Moreover, the mechanisms detected in HMPA/THF
solutions are markedly different than those in THF solutions
without added HMPA.
did not anticipate, for example, that HMPA would divert the
monomer-based enolization to a lower solvation number (cf., 5
and 6), although the functional equivalency of two THF ligands
and one HMPA ligand seems logical in retrospect. Moreover,
the second-order dependence on the HMPA concentration and
affiliated ionization follows from HMPA’s reputation as a
strongly coordinating dipolar ligand, yet the affiliation of HMPA
with a dimer-based mechanism12 is at odds with conventional
wisdom.13 We also noted a curious influence of the cosolvent:
Whereas the rate of enolization via monomer 6 is insensitive
to the concentration of THF in HMPA/THF/hexane mixtures,
enolization via putative triple-ion 7 is inhibited by THF. How
does increasing the THF concentration inhibit a putative
ionization-dependent pathway without influencing the monomer-
based pathway? We gingerly suggested that the selective
inhibition derived from the net stabilization of free (uncoordi-
nated) HMPA via THF-HMPA interactions.14 The notion that
solvent-solvent interactions remote from the lithium coordina-
tion spheres can influence organolithium reactivities piqued our
interest.
Results
Substrate-dependent relative rate constants (kHMPA/kTHF) are
summarized in Table 1. Experimentally determined rate laws
for LDA/THF- and LDA/HMPA/THF-mediated eliminations are
summarized in Table 2. Additional figures and data are archived
in the Supporting Information. Putative transition structures
depicting spatial details that are salted throughout the text are
supported by semiempirical and ab initio studies.15
We describe herein investigations of the LDA/HMPA-
mediated dehydrobrominations depicted in eqs 3-5. Even within
General Methods. Pseudo-first-order conditions were estab-
lished using low concentrations of the alkyl bromides (0.004
M). LDA, HMPA, and THF were maintained at high, yet
adjustable, concentrations with hexane as the cosolvent.17 The
losses of the alkyl bromides were monitored by gas chroma-
tography relative to an internal dodecane standard. All reactions
(10) HMPA can also decelerate organolithium reactions. Reich, H. J.; Green,
D. P.; Phillips, N. H. J. Am. Chem. Soc. 1989, 111, 3444. Reich, H. J.;
Phillips, N. H.; Reich, I. L. J. Am. Chem. Soc. 1985, 107, 4101. Reich, H.
J.; Dykstra, R. R. Angew. Chem., Int. Ed. Engl. 1993, 32, 1469. Reich, H.
J.; Sikorski, W. H. J. Org. Chem. 1999, 64, 14.
(11) For a discussion of the limitations of using relative rate constants as
mechanistic probes, see: Bernstein, M. P.; Collum, D. B. J. Am. Chem.
Soc. 1993, 115, 8008.
(12) Behavior of triple ions as one rather than two fragments is a consequence
of the extremely low dissociation constants of even the most stabilized ion
pairs. Bhattacharyya, D. N.; Lee, C. L.; Smid, J.; Szwarc, M. J. Phys. Chem.
1965, 69, 608. Wong, M. K.; Popov, A. I. J. Inorg. Nucl. Chem. Lett. 1972,
34, 3615.
(15) (a) Armstrong, D. R.; Mulvey, R. E.; Walker, G. T.; Barr, D.; Snaith, R.;
Clegg, W.; Reed, D. J. Chem. Soc., Dalton Trans. 1988, 617. (b) Armstrong,
D. R.; Barr, D.; Brooker, A. T.; Clegg, W.; Gregory, K.; Hodgson, S. M.;
Snaith, R.; Wright, D. S. Angew. Chem., Int. Ed. Engl. 1990, 29, 443. (c)
Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1992, 114, 2112. (d)
Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 9187. (e)
Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1995, 117, 2166. (f)
Liao, S.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 15114. (g) Pratt, L.;
Robbins, S. J. Mol. Struct. (THEOCHEM) 1999, 466, 95. (h) Also, see ref
7.
(16) (a) Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1997, 119, 5573. (b)
Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 4081.
(17) The concentration of the LDA, although expressed in units of molarity,
refers to the concentration of the monomer unit (normality). The concentra-
tions of ethereal solvent and HMPA are expressed as total concentration
of free (uncoordinated) ligand.
(13) Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
(14) For discussions of solvent-solvent interactions in solutions of HMPA,
see: Masaguer, J. R.; Casas, J. S.; Sousa Fernandez, A.; Sordo, J. An.
Quim. 1973, 69, 199. Michou-Saucet, M. A.; Jose, J.; Michou-Saucet, C.;
Merlin, J. C. Thermochim. Acta 1984, 75, 85. Vandyshev, V. N.;
Serebryakova, A. L. Russ. J. Gen. Chem. 1997, 67, 540. Kulikov, M. V.
Russ. Chem. Bull. 1997, 46, 274. Mehta, S. K.; Sharma, A. K.; Bhasin, K.
K.; Parkash, R. Fluid Phase Equilib. 2002, 201, 203. Izutsu, K.; Kobayashi,
N. J. Electroanal. Chem. 2005, 574, 197. Prado-Gotor, R.; Ayala, A.;
Tejeda, A. B.; Suarez, M. B.; Mariscal, C.; Sanchez, M. D.; Hierro, G.;
Lama, A.; Aldea, A.; Jimenez, R. Int. J. Chem. Kinet. 2003, 35, 367.
Salomon, M. J. Power Sources 1989, 26, 9.
9
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Lithium Diisopropylamide Solvated by HMPA
A R T I C L E S
Table 2. Summary of Rate Studies for the LDA-Mediated Dehydrobrominations (Eq 6)
entry
substrate
T (
°C)
ligand
ligand order
LDA order
kH/kD
1
2
3
8
8
10
20
-55
20
THF
HMPA
THF
2.24 ( 0.03a
1.9 ( 0.2b,d
0
0.50 ( 0.02b
0.96 ( 0.09e
0.39 ( 0.02g
0.48 ( 0.01g
0.54 ( 0.04h
0.53 ( 0.05i
0.50 ( 0.03
0.61 ( 0.04h
0.57 ( 0.04i
4.0 ( 0.1c,g
9.8 ( 0.1c
1.9 ( 0.1f
1.17 ( 0.08g
0
4
10
0
HMPA
1.74 ( 0.04b,d,f
2.0 ( 0.2b,d
0.93 ( 0.05d
0
5
6
12
12
0
-10
THF
HMPA
1.75 ( 0.02
2.6 ( 0.1
1.4 ( 0.1b,d
a [LDA] ) 0.30 M. b [THF] ) 10.0 M in hexane cosolvent. c Measured using 8 and 8-d4. d [LDA] ) 0.10 M. e [HMPA] ) 0.30 M in 10.0 M THF/
hexane. f Measured using 10 and 10-d1. g See ref 16. h [HMPA] ) 0.10 M in 10.0 M THF/hexane. i [HMPA] ) 0.50 M in 10.0 M THF/hexane.
follow clean first-order decays, affording pseudo-first-order rate
constants (kobsd) that are independent of the initial concentrations
of substrate ((10%). Isotope effects (kH/kD) determined using
deuterated analogues 8-d1, 8-d4, 10-d1,16a and 12-d1 (Table 2)
are consistent with rate-limiting proton transfers and vicinal
dehydrobrominations (rather than carbene-based R-elimina-
tions).18 For expediency, we note at the outset that none of the
LDA/HMPA-mediated dehydrobrominations displays a signifi-
cant dependence on the THF concentration in HMPA/THF/
hexane mixtures.
Anti-Dehydrobromination of cis-4-Bromo-tert-butylcyclo-
hexane (8). Treatment of a cis/trans mixture of 4-bromo-tert-
butylcyclohexane with LDA/HMPA at -55 °C affords 4-tert-
butylcyclohexene (9) owing to elimination of exclusively the
cis (axial) isomer, 8. Detailed rate studies and mechanistic
investigations were carried out using 8 (eq 3) that was purified
by selective recrystallization from hexane at -96 °C.
A suspected diaxial elimination of 8 was supported through
deuterium-labeling studies.19 We compromised precision for ease
of synthesis by monitoring the loss of the 4:1 mixture of
trideuterated cyclohexylbromides 8a-d3 and 8b-d3. The axial
Figure 1. Plot of kobsd versus [THF] for the dehydrobromination of cis-
1-bromo-4-tert-butylcyclohexane (8, 0.004 M) by LDA (0.30 M) in hexane
at 20 °C. The curve depicts an unweighted least-squares fit to kobsd
)
k[THF]n + k′ (k ) 1.0 ( 0.2 × 10-6, k′ ) 3.0 ( 0.3 × 10-7, n ) 2.2 (
0.1).
ingly, reaction of the 8a-d3/8b-d3 mixture was followed by GC
analysis of quenched samples to determine the percent conver-
sion. Each sample was then purified using flash chromatography,
and the mixtures were analyzed with 1H NMR spectroscopy to
determine the 8a-d3/8b-d3 ratio. Combination of the two
analytical methods afforded rate constants for the loss of 8a-d3
and 8b-d3. Qualitatively, 8a-d3 disappeared substantially faster
than 8b-d3. By accounting for the relatively slow competing
abstraction of the R′-deuterium labels at the doubly labeled six
position that cause distortions in the apparent axial-equatorial
preference, we measured the preference for axial proton
abstraction to be g20:1 both with and without added HMPA.20
Reaction of cyclohexyl bromide 8 with LDA/THF in the
absence of HMPA at 20 °C reveals a second-order THF
dependence (Figure 1) and a half-order LDA dependence (Figure
2). The rate law (eq 7) and generic mechanism (eq 8) are
consistent with transition structure 14. This is the first docu-
mented example of a trisolvated-monomer-based reaction of
LDA. We surmise that the high solvation number derives from
the lack of Li-Br interaction demanded by the trans-diaxial
alignment (vide infra).
proton resonance of 8a-d3 and the equatorial proton resonance
of 8b-d3 were identified using standard 1H NMR spectroscopy
aided by single-frequency decouplings (Supporting Information).
Although, in principle, the loss of 8a-d3 and 8b-d3 could be
monitored in situ by H NMR spectroscopy, THF resonances
at approximately 1.7 ppm proved to be problematic. Accord-
1
(18) Ashby, E. C.; Park, B. Acta Chem. Scand. 1990, 44, 291. Ashby, E. C.;
Park, B.; Patil, G. S.; Gadru, K.; Gurumurthy, R. J. Org. Chem. 1993, 58,
424. Ashby, E. C.; Deshpande, A. K.; Patil, G. S. J. Org. Chem. 1995, 60,
663. Taber, D. F.; Christos, T. E.; Neubert, T. D.; Batra, D. J. Org. Chem.
1999, 64, 9673. For a review of lithium carbenoids, see: Boche, G.;
Lohrenz, J. C. W. Chem. ReV. 2001, 101, 697.
(19) Baciocchi, E. Acc. Chem. Res. 1979, 12, 430. Bartsch, R. A.; Zavada, J.
Chem. ReV. 1980, 80, 453. Zavada, J.; Pankova, M.; Sicher, J. J. Chem.
Soc., Chem. Commun. 1968, 1145. Koning, L. J.; Nibbering, N. M. M. J.
Am. Chem. Soc. 1987, 109, 1715. Schlosser, M.; Lehmann, R.; Jenny, T.
J. Organomet. Chem. 1990, 389, 149.
-d[RBr]/dt ) ki[(i-Pr2NLi)2(THF)2]1/2[THF]2[RBr] (7)
(20) The derivations and experimental details are included in the Supporting
Information.
9
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A R T I C L E S
Ma et al.
Figure 3. Plot of kobsd versus [HMPA]23 for the dehydrobromination of
cis-1-bromo-4-tert-butylcyclohexane (8, 0.004 M) by LDA (0.10 M) in THF
(10.0 M)/hexane at -55 °C. The curve depicts an unweighted least-squares
fit to kobsd ) k[HMPA]n + k′ (k ) 4.8 ( 0.7 × 10-3, k′ ) 1.0 ( 0.7 ×
10-4, n ) 1.9 ( 0.2).
Figure 2. Plot of kobsd versus [LDA] for the dehydrobromination of cis-
1-bromo-4-tert-butylcyclohexane (8, 0.004 M) in THF (10.0 M)/hexane at
20 °C. The curve depicts an unweighted least-squares fit to kobsd ) k[LDA]n
(k ) 2.7 ( 0.1 × 10-4, n ) 0.50 ( 0.02).
ki
1/2(i-Pr2NLi)2(THF)2 + 2THF + RBr 98
[(i-Pr2NLi)(THF)3(RBr)]q (8)
The LDA/HMPA-mediated elimination of 8 is very fast
compared with HMPA-free conditions (Table 1). A plot of kobsd
versus HMPA concentration reveals a second-order HMPA
Figure 4. Plot of kobsd versus [LDA] for the dehydrobromination of cis-
1-bromo-4-tert-butylcyclohexane (8, 0.004 M) in HMPA (0.40 M)23/THF
(10.0 M)/hexane at -55 °C. The curve depicts an unweighted least-squares
dependence and an insignificant nonzero intercept (Figure 3),
consistent with a single pathway. A plot of kobsd versus LDA
concentration reveals a first-order dependence (Figure 4). The
idealized rate law (eq 9) and generic mechanism (eq 10) are
consistent with a reaction via tetrasolvated dimers. Because of
the excessive congestion of a tetrasolvated cyclic dimer,6,15 we
invoke triple-ion-based transition structure 15. Experimental and
theoretical support for triple ions of hindered lithium amides is
considerable.8 Of special note in the context of the rate studies
of enolization,7g no THF concentration dependence was ob-
served at either low or high HMPA concentration despite a
perceived similarity with the enolization mechanism.
fit to kobsd ) k[LDA]n + k′ (k ) 6.7 ( 0.8 × 10-3, k′ ) 4.5 ( 0.3 × 10-4
n ) 0.96 ( 0.09).
,
accelerations (Table 1) accompanied by significant changes in
mechanism. A plot of kobsd versus HMPA concentration displays
-d[RBr]/dt ) kii[(i-Pr2NLi)2(HMPA)2][HMPA]2[RBr] (9)
kii
(i-Pr2NLi)2(HMPA)2 + 2HMPA + RBr
98
[(i-Pr2NLi)2(HMPA)4(RBr)]q (10)
a second-order dependence and a substantial nonzero intercept
(Figure 5), consistent with competing HMPA-concentration-
independent and HMPA-concentration-dependent pathways. A
plot of kobsd versus LDA concentration reveals half-order
dependencies when measured at both low and high HMPA
concentrations. Overall, the data are consistent with eliminations
Syn-Dehydrobromination of exo-2-Bromonorbornane (10).
Previous studies of LDA/THF-mediated elimination of 10
implicated mono- and disolvated monomers (16 and 17,
respectively; Table 2).16a Addition of HMPA elicits moderate
9
15402 J. AM. CHEM. SOC. VOL. 128, NO. 48, 2006

Lithium Diisopropylamide Solvated by HMPA
A R T I C L E S
Figure 5. Plot of kobsd versus [HMPA]23 for the dehydrobromination of
(()-2-exo-bromonorbornane (10, 0.004 M) by LDA (0.10 M) in THF (10.0
M)/hexane at 0 °C. The curve depicts an unweighted least-squares fit to
kobsd ) k[HMPA]n + k′ (k ) 1.4 ( 0.1 × 10-3, k′ ) 2.3 ( 0.1 × 10-4, n
) 2.0 ( 0.1).
Figure 6. Plot of kobsd versus [THF] for the elimination of 1-bromocy-
clooctene (12, 0.004 M) in hexane at 0 °C. The curve depicts an unweighted
least-squares fit to kobsd ) k[THF]n + k′ (k ) 1.8 ( 0.2 × 10-5, k′ ) 3.6
( 0.2 × 10-5, n ) 0.93 ( 0.05).
kv
1/2(i-Pr2NLi)2(THF)2 + THF + RBr
98
via mono- and trisolvated monomer-based pathways (eqs 12
and 13) for which we proffer transition structures 18 and 20.
Evidence of disolvated monomer 19 is absent. Perhaps a Li-
Br interaction and the sterically demanding second HMPA
ligand are incompatible.
[(i-Pr2NLi)(THF)2(RBr)]q (15)
Elimination of 12 by LDA/HMPA/THF appears to be the
most mechanistically complex of the three cases studied. A plot
of kobsd versus HMPA concentration displays a nonzero intercept
and a noninteger dependence (n ) 1.4 ( 0.1), suggesting that
-d[RBr]/dt ) kiii[(i-Pr2NLi)2(HMPA)2]1/2[HMPA]0[RBr] +
kiv[(i-Pr2NLi)2(HMPA)2]1/2[HMPA]2[RBr] (11)
kiii
98
1/2(i-Pr2NLi)2(HMPA)2 + RBr
[(i-Pr2NLi)(HMPA)(RBr)]q (12)
kiv
98
1/2(i-Pr2NLi)2(HMPA)2 + 2HMPA + RBr
[(i-Pr2NLi)(HMPA)3(RBr)]q (13)
there is an HMPA-concentration-independent pathway and
possibly two HMPA-concentration-dependent pathways. LDA
orders measured at both low and high HMPA concentration
show half-order dependencies. Overall, the rate law (eq 16) and
generic mechanisms (eqs 17-19) are consistent with monomer-
based transition structures such as 21, 23, and 24. Although we
have no reason to doubt the veracity of the results, such a
complex hypothesis seems unusually vulnerable to minor
systematic errors.
d[RBr]/dt ) kvi[(i-Pr2NLi)2(HMPA)2]1/2[HMPA]0[RBr] +
kvii[(i-Pr2NLi)2(HMPA)2]1/2[HMPA][RBr] +
Syn-Dehydrobromination of 1-Bromocyclooctene (12). A
plot of kobsd versus THF concentration for the elimination of
12 to form cyclooctyne (13)21 reveals a linear dependence
(Figure 6). A half-order LDA dependence at both low and high
THF concentration implicates a mechanism based on disolvated
monomer (eqs 14 and 15) via transition structure 22.16a Thus,
the LDA/THF-mediated syn eliminations of 10 and 12 in the
absence of HMPA show some differences.
kviii[(i-Pr2NLi)2(HMPA)2]1/2[HMPA]2[RBr] (16)
kvi
98
1/2(i-Pr2NLi)2(HMPA)2 + RBr
[(i-Pr2NLi)(HMPA)(RBr)]q (17)
kvii
98
1/2(i-Pr2NLi)2(HMPA)2 + HMPA + RBr
-d[RBr]/dt ) kv[(i-Pr2NLi)2(THF)2]1/2[THF][RBr]
(14)
[(i-Pr2NLi)(HMPA)2(RBr)]q (18)
(21) Cyclooctynes in organic synthesis. Heber, D.; Roesner, P.; Tochtermann,
W. Eur. J. Org. Chem. 2005, 20, 4231.
9
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A R T I C L E S
Ma et al.
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8
We were particularly interested at the outset in determining
the role of THF in LDA/HMPA-mediated eliminations. Recall
that the ester enolization in eq 2 is inhibited by THF, and this
inhibition was tentatively attributed to THF-HMPA interactions
remote from the lithium coordination sphere.7g,14 The attenuated
Lewis basicity would represent a net stabilization of the ground
state relative to a transition state and should influence all
reactions demanding coordination of additional HMPA ligands.
In short, we observed no evidence whatsoever to support this
hypothesis. Even elimination of 8 manifesting a second-order
dependence on HMPA concentration via putative triple-ion 15
showed no cosolvent effect. We went so far as to reproduce
the rate studies of the enolization of ester 3 to confirm the rate-
retarding effects of THF. Inhibition of the enolization in eq 1
is for now unsupported by a tenable mechanistic hypothesis.
1/2(i-Pr2NLi)2(HMPA)2 + 2HMPA + RBr
[(i-Pr2NLi)(HMPA)3(RBr)]q (19)
Discussion
Addition of HMPA to LDA/THF-mediated dehydrobromi-
nations causes accelerations by as little as 3-fold or as much as
3000-fold (Table 1.) Using rate studies to peer beneath the
surface, a reasonably self-consistent mechanistic picture emerges.
The trans-diaxial elimination of 8 (eq 3) offers no provision
for a Li-Br interaction. Consequently, the LDA/THF-mediated
elimination proceeds slowly via a trisolvated monomer 14
unprecedented for LDA. The marked acceleration imparted by
adding the strongly coordinating HMPA is fully in accord with
conventional wisdom, yet rate studies implicate triple-ion-based
transition structure 15. Although many might be surprised that
the second-order HMPA dependence is affiliated with a dimer-
based pathway, putative triple-ion 15 is well founded on
previous structural, rate, and computational studies.7,8,15c-e We
have long suspected that reactions requiring ionization may be
based on triple ions.
The syn-dehydrobrominations of 10 and 12 by LDA at low
HMPA concentrations proceed via monosolvated monomer-
based transition structures for which we submit 18 and 21. The
muted advantages offered by HMPA relative to THF may derive
from stabilization in the transition state that is largely offset by
stabilization in the ground state. Dehydrobrominations of 10
and 12 at higher HMPA concentrations proceed via more highly
solvated monomer-based transition structures bearing as many
as three coordinated HMPA ligands. We suspect that the most
highly solvated monomer-based transition structures (20 and
24) has no Li-Br interaction, although this conclusion is based
on intuition rather than direct evidence. We were somewhat
surprised that 10 did not R-eliminate by a carbenoid intermedi-
ate18 (although limited contributions from additional mechanisms
could lurk beneath the error limits of the rate laws.)
Conclusion
LDA/HMPA-mediated dehydrobrominations proceed via
surprisingly variable reaction mechanisms. We suspect that this
derives from two opposing effects: the profound dipolarity,
promoting solvation of lithium ion, and the severe steric
demands of the HMPA ligand, inhibiting solvation. It is clear
that an empirically observed acceleration cannot necessarily be
ascribed to a deaggregation-based mechanism as is often the
case; triple-ion-based reactions are prevalent. In settings where
selectivity is at issue, subtle changes in rate with added HMPA
could still be affiliated with marked changes in selectivity. Even
small changes in the concentration of added HMPA can cause
mechanistic reversals, which, in turn, would alter product
distributions.
Acknowledgment. We thank the National Institutes of Health
for direct support of this work and Merck, Pfizer, Boehringer
Ingelheim, R. W. Johnson, Aventis, Schering-Plough, and
DuPont Pharmaceuticals (Bristol-Myers Squibb) for indirect
support.
Supporting Information Available: NMR spectra, rate data,
experimental protocols, and a bibliography of triple ions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
One might ask why there is so much variation in the number
of coordinated HMPA ligands for monomer-based syn elimina-
tions. We do not, however, find this to be an acutely vexing
question. Replacing the putatively weak Li-Br interaction22 with
a strong Li-HMPA interaction could account for some varia-
tion. Moreover, given that steric congestion about the lithium
coordination sphere appears to be a major determinant of
solvation,15c,23,24 it is not surprising that subtle changes in the
substrate influence the solvation numbers in the transition
structures. Ongoing investigations of other reactions mediated
by LDA/HMPA suggest that such variations can become acute.25
JA060964B
(23) For early discussions of steric effects on solvation and aggregation, see:
Settle, F. A.; Haggerty, M.; Eastham, J. F. J. Am. Chem. Soc. 1964, 86,
2076. Lewis, H. L.; Brown, T. L. J. Am. Chem. Soc. 1970, 92, 4664. Brown,
T. L.; Gerteis, R. L.; Rafus, D. A.; Ladd, J. A. J. Am. Chem. Soc. 1964,
86, 2135. For more recent discussions and leading references, see: Lucht,
B. L.; Collum, D. B. J. Am. Chem. Soc. 1996, 118, 2217.
(24) For discussions of the role of steric effects on lithium-ion solvation by
HMPA, see: Ishiguro, S. Pure Appl. Chem. 1994, 66, 393. Dack, M. R. J.;
Bird, K. J.; Parker, A. J. Aust. J. Chem. 1975, 28, 955. Ishiguro, S. Bull.
Chem. Soc. Jpn. 1997, 70, 1465. Also, see ref 21c.
(22) Substitution of one THF ligand on (i-Pr)2NLi(THF)3 by MeBr is calculated
to be endergonic by 10.6 kcal/mol using B3LYP/6-31G(d).
(25) Yun, M.; Collum, D. B. Unpublished results.
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15404 J. AM. CHEM. SOC. VOL. 128, NO. 48, 2006