The barrier to enantiomerization of N-Boc-2-lithiopyrrolidine: The effect of chiral and achiral diamines

Article abstract of DOI:10.1039/b714302h

(-)-Sparteine and TMEDA dramatically lower both enthalpy and entropy of activation for the barrier to enantiomerization of N-Boc-2-lithiopyrrolidine in diethyl ether, whereas N,N′-diisopropylbispidine has little effect; the entropy of activation for enantiomerization is zero in the presence of TMEDA and slightly negative in the presence of sparteine; these data suggest a subtle change in mechanism of enantiomerization in the presence of TMEDA and sparteine. The Royal Society of Chemistry.

Full text of DOI:10.1039/b714302h

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The barrier to enantiomerization of N-Boc-2-lithiopyrrolidine: the
effect of chiral and achiral diamines{
Taher I. Yousaf,a Roger L. Williams,ab Iain Coldhamc and Robert E. Gawley*a
Received (in Bloomington, IN, USA) 20th September 2007, Accepted 3rd November 2007
First published as an Advance Article on the web 15th November 2007
DOI: 10.1039/b714302h
(2)-Sparteine and TMEDA dramatically lower both enthalpy
and entropy of activation for the barrier to enantiomerization
of N-Boc-2-lithiopyrrolidine in diethyl ether, whereas
N,N9-diisopropylbispidine has little effect; the entropy of
activation for enantiomerization is zero in the presence of
TMEDA and slightly negative in the presence of sparteine;
these data suggest a subtle change in mechanism of enantio-
merization in the presence of TMEDA and sparteine.
Table 1 Activation parameters for the equilibrium in Scheme 1 (in
diethyl ethera
Entry
Diamine
DH{/kcal mol21
DS{/cal mol21 K21
1
2
3
4
a
Noneb
Bispidine 3
TMEDA, 2
(2)-Sparteine, 1
29 ¡ 2
28 ¡ 1
19 ¡ 1
18 ¡ 1
40 ¡ 8
32 ¡ 2
0 ¡ 2
26 ¡ 2
b
Errors expressed at two standard deviations. Taken from ref. 8.
The role of (2)-sparteine (1) in promoting asymmetric deprotona-
tion with lithium alkyls is legendary,1 as is the role of TMEDA (2)
in ‘‘activating’’ alkyllithiums in diethyl ether.2 Several bispidines
were studied by Beak et al. in the context of seeking alternatives to
sparteine as a lithium ligand in asymmetric deprotonations,3 and
N,N9-diisopropyl bispidine, 3, has recently been championed by
O’Brien as an exchangeable ligand in asymmetric deprotonations,
so that chiral ligands can be used in substoichiometric quantities.4
N-Boc-2-lithiopyrrolidine, 4. This organolithium is particularly
appealing for study due to the extraordinarily high entropy of
activation for enantiomerization of 4 in the absence of any ligands
(Table 1, entry 1).8
Diamines 2 and 3 are achiral, so the enantiomer ratio (er) of
Scheme 1 is 50 : 50 for these ligands (i.e., K = 1). Somewhat
surprisingly, K = 1 for (2)-sparteine as well, over a wide
temperature range.6
The effect of TMEDA, 2, on the rate of inversion of chiral
organolithiums is not straightforward. TMEDA accelerates the
epimerization of diastereomeric oxazolidinones and imidazolidi-
nones,9 whereas in N-alkylpiperidines and pyrrolidines,10 and in
N,N-dialkylaminobenzyllithium,11
2
retards racemization.
Previous studies on the effect of diamines such as (2)-sparteine,
1, or bispidine 3 on the barrier to enantiomerization of chiral
organolithiums are rare.12
One of the more interesting developments in organolithium
chemistry over the past decade has been the emergence of dynamic
resolution of racemic organolithiums as a means of asymmetric
synthesis.5,6 Central to both asymmetric deprotonations and
dynamic resolutions is the issue of enantiomerization: in an
asymmetric deprotonation, it must be minimized, while in a
dynamic resolution it must be controlled. Although the dynamics
of enantiomerization of several rapidly inverting organolithiums
have been determined (usually by dynamic NMR),7 there is
relatively little data on enantiomerization dynamics in systems with
high barriers. As part of an investigation into the structure and
dynamic properties of chiral organolithiums,8 and on the dynamics
of the resolution process in lithiated heterocycles, we have studied
the effect of ligands 1–3 on the barrier to enantiomerization of
Starting with (S)-N-Boc-2-lithiopyrrolidine, the progress of
racemization was followed by quenching the organolithiums with
trimethylsilyl chloride and determination of the er by chiral
stationary phase gas chromatography.{ From these data, the
enthalpic and entropic barriers to enantiomerization were
determined as described previously.8
Table 1 gives activation parameters for the enantiomerization
illustrated in Scheme 1, determined over the temperature range 25
to 233 uC. Excellent fit of the data to first-order kinetic plots was
observed in all runs.
aDepartment of Chemistry and Biochemistry, University of Arkansas,
Fayetteville, AR, 72701, USA. E-mail: bgawley@uark.edu;
Fax: +1 479 575 5178; Tel: +1 479 575 6933
bEastern New Mexico University, Portales, NM, 88130, USA
cDepartment of Chemistry, University of Sheffield, Brook Hill,
Sheffield, UK S3 7HF. E-mail: i.coldham@sheffield.ac.uk;
Fax: +44 (0)114 222 9346; Tel: +44 (0)114 222 9428
{ Electronic supplementary information (ESI) available: First-order rate
plots, Eyring plots, and a representative chromatogram of the chiral
silanes. See DOI: 10.1039/b714302h
Scheme 1
Both the enthalpy and entropy of activation for the enantio-
merization of N-Boc-2-lithiopyrrolidine are high in the absence of
amine ligands (entry 1).8 In contrast, thermodynamic enantiomer-
ization parameters for twenty different chiral organolithiums,
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Table 2 Calculated barriers for the enantiomerization of Scheme 1
DG{/kcal mol21
Notes and references
{ Typical experiment: A stock solution of N-Boc-2-(tributylstannyl)pyrro-
lidine, typically 0.04 M, was prepared in diethyl ether and 2 mL transferred
to each of six 10 mL tubes via septum seal (N2 atmosphere). The tubes were
cooled to 278 uC, and 0.1 mL of a 2.5 M solution of ligand in diethyl ether
were added to each tube followed by 0.1 mL of a 2.5 M solution of n-BuLi
in hexane. The dull yellow color of the organolithium was seen within
seconds. The tubes were thermostatted at the reaction temperature, and a
stopwatch was started. Internal temperature was monitored in a separate
tube in the same bath. Tubes were removed at various times, cooled to
278 uC, and quenched with 0.2 mL of a 2.5 M solution of TMS-Cl in
hexane for ca. 16 h. Water (2 mL) was added to each tube, and the organics
extracted into diethyl ether which was then dried (MgSO4) and
concentrated to ca. 0.3 mL, and purified by preparative TLC (2%
EtOAc–hexane). The silanes (Rf = 0.65 ) were scraped off, extracted from
silica into diethyl ether and then concentrated to one drop, of which 0.1 mL
was subjected to CSP-GC analysis (b-cyclodextrin stationary phase). The
column temperature was programmed as follows: T = 70 uC for 5 min, then
5 uC min21 to T = 200 uC, then maintained for 10 min. Rt = 14.3 and
16.1 min for 4-(S)- and 4-(R)-N-Boc-2-(trimethylsilyl)pyrrolidine,
respectively.
Diamine
calculated at 195 K (278 uC)
None (Et2O)
21 ¡ 6
21 ¡ 3
21 ¡ 2
19 ¡ 1
19 ¡ 2
None (Et2O–hexane)
Bispidine 3 (Et2O)
TMEDA, 2 (Et2O)
(2)-Sparteine, 1 (Et2O)
summarized in a recent review,7 are revealing: eighteen had
negative DS{ values, and only two had small positive values (+2
and +3 cal mol21 K21). This is expected, since charge separation
should require additional solvation in the transition state. The
enantiomerization parameters of 4 were rationalized8 by invoking
a conducted tour mechanism, in which the lithium atom is escorted
between enantiomeric faces of the carbanion by the carbonyl
oxygen. This movement is necessarily accompanied by the
movement of the bulky tert-butoxy group, which would disrupt
the solvent cage. Another contributing factor could be that binding
of the carbonyl oxygen to the lithium restricts conformational
motion in the ground state which is then restored in going to the
TS.
In the presence of 3, which O’Brien4 employs as a ligand that
can readily exchange with 1, DH{ or DS{ for enantiomerization
(Table 1, entry 2) are changed only slightly from entry 1. The
enthalpy of activation is lowered dramatically in the presence of
TMEDA (entry 3) or sparteine (entry 4), and the entropic benefit is
completely erased. One possible explanation is that these diamines
weaken the C–Li bond, perhaps by coordinating strongly to the
lithium, and that the conducted tour mechanism may no longer be
operative in the presence of 1 and 2.
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Bispidine 3 has virtually no effect on the enthalpy of activation,
perhaps because it is only weakly coordinated to the lithium,
consistent with O’Brien’s observation that excess bispidine
readily exchanges Li+ with sparteine.4 Further, 3 induces only
a slight lowering of the entropy term, consistent with weak
binding of 3 to the lithium and more important involvement of the
solvent.
Free energies of activation for inversion of 4 at 278 uC are
calculated from the parameters of Table 1, and listed in Table 2.
These data suggest that 3 would have no effect on the
enantiomerization barrier of 4, but predict that both 1 and 2
would lower the barrier to inversion, consistent with the early low
temperature observations of Beak.13
11 H. Ahlbrecht, J. Harbach, R. W. Hoffmann and T. Ruhland, Liebigs
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116, 3231–3239; (b) K. M. Bertini Gross and P. Beak, J. Am. Chem.
Soc., 2001, 123, 315–321.
We thank the US National Science Foundation (CHE 0616352)
for support of this work, and the Royal Society of Chemistry
for a Travel Grant in support of our collaboration. R. L. W.
was supported as a summer REU student under NSF CHE-
0552947.
98 | Chem. Commun., 2008, 97–98
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