Nucleophilicities and carbon basicities of DBU and DBN

Article abstract of DOI:10.1039/b801811a

The nucleophilicity and Lewis basicity of DBU and DBN toward C _sp2 centers have been measured: nucleophilicities increase in the series DMAP < DBU < DBN < DABCO while Lewis basicities are DABCO < DMAP < DBU < DBN. The Royal Society of Chemistry

Full text of DOI:10.1039/b801811a

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Nucleophilicities and carbon basicities of DBU and DBNwz
M. Baidya and Herbert Mayr*
Received (in Cambridge, UK) 7th February 2008, Accepted 19th February 2008
First published as an Advance Article on the web 13th March 2008
DOI: 10.1039/b801811a
The nucleophilicity and Lewis basicity of DBU and DBN toward
Csp2 centers have been measured: nucleophilicities increase in the
series DMAP o DBU o DBN o DABCO while Lewis
basicities are DABCO o DMAP o DBU o DBN.
eqn (2), where k (L molꢀ1 ꢀ1) is the second-order rate
s
constant, E is the electrophilicity parameter, N is the nucleo-
philicity parameter, and s is a nucleophile specific slope
parameter.7
log k20 1C = s(N + E)
(2)
Bicyclic amidines, such as DBU (1,8-diazabicyclo[5.4.0]undec-
7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene), are useful
reagents for dehydrohalogenation reactions and have been
termed ‘nonnucleophilic strong bases’.1 On the other hand,
numerous examples have been reported which demonstrate
that DBU and DBN can also act as nucleophiles.2,3 Aggarwal
even claimed that DBU is the optimum catalyst for
Baylis–Hillman reactions, providing adducts at much faster
rates than using DABCO (1,4-diazabicyclo[2.2.2]octane).4 The
great interest in the use of DBU and DBN as organocatalysts
prompted us to investigate the nucleophilicity of these
amidines quantitatively.
We will now describe the determination of the nucleophilicity
parameters of the title compounds and demonstrate that with
these parameters rate constants for the reactions of DBU and
DBN with ordinary Michael acceptors can be predicted.
ð3Þ
Addition of DBU to the ꢀblue solutions of the benzhydrylium
tetrafluoroborates 1–BF4 in acetonitrile leads to decoloriza-
tion due to formation of adducts (eqn (3)), which have been
characterized by NMR spectroscopy (see ESIz).
Because much of the controversy about the properties of the
title compounds arises from the synonymous use of the terms
‘nucleophilicity’ and ‘Lewis basicity towards carbon centers’,
we want to recall that, according to IUPAC, ‘nucleophilicity
of a Lewis base is measured by relative rate constants of
different nucleophilic reagents towards a common substrate,
most commonly involving formation of a bond to carbon’
(eqn (1)).5
The reactions, which were monitored photometrically
by using the stopped-flow technique described previously,7
followed second-order kinetics. Details are given in the
ESI.z Table 1 shows that DBU generally reacts 2 to 3 times
faster than DMAP (4-dimethylaminopyridine, Steglich’s
base), whereas DBN is 6 to 7 times more reactive than DMAP.
When the second-order rate constants are plotted against
the electrophilicity parameters E, linear correlations are ob-
tained (Fig. 1), as required by eqn (2), from which the
nucleophile specific parameters N = 15.29, s = 0.70 for
DBU and N = 16.28, s = 0.67 for DBN were obtained.
Comparison with the nucleophilicities of other tertiary
amines and phosphanes (Scheme 1) shows that DBN and
DBU are somewhat more nucleophilic than DMAP and
considerably less nucleophilic than DABCO and quinucli-
dine.8,9 The rate constants of the reactions of DBU, DBN,
and DMAP with the colored Michael acceptors 2a–g (eqn (4))
have been determined analogously, and Table 2 shows that the
experimental rate constants generally deviate by less than a
factor of 10 from those calculated by eqn (2); only 2b reacts 14
times more slowly, and 2c reacts 10–24 times faster than
calculated.
ð1Þ
The kinetic term ‘nucleophilicity’ has to be differentiated from
the thermodynamic term ‘Lewis basicity’ which compares the
equilibrium constants for Lewis adduct formation for a series
of Lewis bases with a common reference Lewis acid (eqn (1)).5
Hine introduced the term ‘carbon basicity’ to express relative
Lewis basicities with respect to a carbon centered Lewis acid.6
Relative nucleophilicities as well as relative Lewis basicities
depend on the choice of the reference Lewis acid.
The most comprehensive nucleophilicity scales presently
available have been developed with respect to benzhydrylium
ions (diarylcarbenium ions) as reference electrophiles. We
have shown that the rates of the reactions of s-, n-, and
p-nucleophiles with benzhydrylium ions can be described by
Department Chemie und Biochemie, Ludwig-Maximilians-Universitat
¨
Munchen, Butenandtstr. 5-13 (Haus F), 81377 Munchen, Germany.
¨
¨
E-mail: herbert.mayr@cup.lmu.de; Fax: +49-89-218077717
w Dedicated to Professor Wolfgang Steglich on the occasion of his
75th birthday.
z Electronic supplementary information (ESI) available: Details of the
kinetic and thermodynamic experiments, NMR spectroscopic char-
acterization of products. See DOI: 10.1039/b801811a
ð4Þ
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Table 1 Second-order rate constants for the reactions of DBU, DBN
and DMAP with the benzhydrylium ions 1a–f (CH3CN, 20 1C)
k/L molꢀ1 sꢀ1
Ar2CH+
DBU
DBN
DMAPb
Ea
c
1a
ꢀ7.02 5.67 ꢂ 105
—
2.31 ꢂ 105
c
1b
1c
ꢀ7.69 2.33 ꢂ 105
—
ꢀ8.22 8.43 ꢂ 104 2.43 ꢂ 105 3.32 ꢂ 104
Scheme 1 Comparison of the nucleophile specific reactivity para-
meters (N, s) for different organocatalysts in acetonitrile.
aN parameters refer to CH2Cl2.
1d
ꢀ8.76 3.17 ꢂ 104 9.44 ꢂ 104 1.29 ꢂ 104
be used to roughly predict the rates of the initial steps of
Baylis–Hillman and related reactions.
1e
1f
ꢀ9.45 1.36 ꢂ 104 3.98 ꢂ 104 5.30 ꢂ 103
However, in previous work,8 we have discussed that nucleo-
philicity, i.e., the rate of a reaction with a certain electrophile,
is not the only factor controlling the efficiency of nucleophilic
organocatalysts. Of even greater importance is the Lewis
basicity towards an electron deficient carbon center, i.e.,
ꢀ10.04 4.46 ꢂ 103 1.38 ꢂ 104 2.11 ꢂ 103
Table 2 Comparison of experimental and calculated (eqn (1)) sec-
ond-order rate constants k for the reactions of various Michael
acceptors 2 with DBU, DBN, and DMAP in acetonitrile at 20 1C
kb/L molꢀ1 sꢀ1
a
b
Electrophilicity parameters from ref. 7. Second-order rate constants for the
c
reactions of DMAP are from ref. 8a. Reactions of DBN with 1a and 1b were
Ea
Michael acceptor
DBU
DBN
DMAP
too fast to be measured with the stopped-flow technique.
2a
ꢀ10.11 7.39 ꢂ 103 2.31 ꢂ 104
4.23 ꢂ 103 1.36 ꢂ 104
This agreement in a reactivity scale covering more than 30
orders of magnitude is impressive, considering the fact that the
N and s parameters for DBU, DBN, and DMAP have been
derived from the rates of their reactions with benzhydrylium
ions in CH3CN, and the E parameters for the Michael
acceptors 2 have been calculated from the rates of their
reactions with carbanions in DMSO.10 It is thus demonstrated
that the N and s parameters of DBU, DBN, and DMAP can
2b
2c
2d
2e
ꢀ11.32 4.42 ꢂ 101
6.01 ꢂ 102
ꢀ10.28 3.26 ꢂ 104 1.28 ꢂ 105 3.20 ꢂ 104
3.21 ꢂ 103 1.05 ꢂ 104 1.35 ꢂ 103
ꢀ12.76 8.65 ꢂ 101
5.90 ꢂ 101
ꢀ10.37 1.62 ꢂ 104 4.43 ꢂ 104 1.09 ꢂ 104
2.78 ꢂ 103 9.11 ꢂ 103 1.17 ꢂ 103
2f
1.28 ꢂ 105
8.80 ꢂ 104
5.92 ꢂ 104c
2g
ꢀ11.89 2.61 ꢂ 102c
2.40 ꢂ 102
Fig. 1 Plots of log k versus E parameters for the reactions of
DBU (K) and DBN (’) with benzhydrylium ions Ar2CH+
(CH3CN, 20 1C).
a
b
c
Electrophilicity parameters from ref. 10. Calculated values in italics. Rate
constants in CH2Cl2.
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Table 3 Equilibrium constants (K) and intrinsic barriers (DG0z) for
the reactions of DBU, DBN and DMAP with some Michael acceptors
2 in acetonitrile at 20 1C
superior carbon basicity combined with a nucleophilicity
comparable to that of DMAP. It cannot be the low nucleo-
philicity of DBU and DBN which limits their use as organo-
catalysts in Baylis–Hillman reactions, but rather their low
nucleofugality, which is responsible for the formation of
products which include DBU or DBN as building blocks.3
Another limitation of the use of these amidines as nucleophilic
catalysts is their high Brønsted basicity,13 which triggers
reactions via initial deprotonation of the substrates.14
Support by the Deutsche Forschungsgemeinschaft (Ma673/
21-2) and the Fonds der Chemischen Industrie is gratefully
acknowledged. We thank Dr A. R. Ofial for performing the
correlation analysis.
K/Mꢀ1
DG0z/kJ molꢀ1
DMAP
DBU
DBN
DMAP
2a
2c
2e
2f
(2–20) ꢂ 103
(1–7) ꢂ 104
(2–8) ꢂ 104
Large
(1–2) ꢂ 105
Small
Large
Large
Large
1.96 ꢂ 102
2.41 ꢂ 102
7.58 ꢂ 104
52.7
55.6
56.8
carbon basicity (for definition see above). By comparing
equilibrium constants for the reactions of DABCO and
DMAP with benzhydrylium ions we have found that DMAP
possesses a 650-fold higher carbon basicity despite its 103-fold
lower nucleophilicity.8 Attempts to employ benzhydrylium
ions also for determining the carbon basicity of DBU and
DBN were unsuccessful, however, because even the least
electrophilic benzhydrylium ions 1e and 1f reacted quantita-
tively with DBU and DBN.
Notes and references
1 For reviews see: D. Basavaiah, A. J. Rao and T. Satyanarayana,
Chem. Rev., 2003, 103, 811; N. Ghosh, Synlett, 2004, 574; H.
Oediger, F. Moller and K. Eiter, Synthesis, 1972, 591; I. Hermecz,
Adv. Heterocycl. Chem., 1987, 42, 83.
Therefore, we tried to determine the equilibrium constants
K of eqn (4) for comparing the carbon basicities of DBU,
DBN, and DMAP. While DBU and DBN showed a much
higher Lewis basicity than DMAP towards the Michael ac-
ceptors 2 (Table 3), only the reactions of DMAP with 2 could
accurately be described by the simple Lewis acid–Lewis base
coordination shown in eqn (4). With DBU and DBN as Lewis
bases, the equilibrium ‘constants’ calculated as K = [20]/([2]-
[amine]) were found to depend on the concentrations of the
reactants. Because we were not able to formulate an alter-
native relationship which yields concentration-independent
equilibrium constants, approximate values of K according to
eqn (4) are given in Table 3.
2 R. Reed, R. Reau, F. Dahan and G. Bertrand, Angew. Chem., Int. Ed.
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Because rate and equilibrium constants could be determined
for the reactions of DMAP with 2c, 2e and 2f, it was possible
3 H. Lammers, P. Cohen-Fernandes and C. L. Habraken, Tetrahe-
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z
to calculate the intrinsic barriers DG0 (Table 3) for these
reactions by substituting DGz and DrG0 = ꢀRT ln K into the
Marcus eqn (5), where the work term has been neglected.11
4 V. K. Aggarwal and A. Mereu, Chem. Commun., 1999, 2311.
5 P. Muller, Pure Appl. Chem., 1994, 66, 1077.
z
z
DGz = DG0 + 0.5DrG0 + (DrG0)2/16DG0
(5)
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One can see that the intrinsic barriers, i.e., the barriers in the
absence of a thermodynamic driving force, are approximately 10
kJ molꢀ1 smaller for the reactions of DMAP with these Michael
acceptors than with the benzhydrylium ions 1d–f in the same
solvent (CH3CN).8 None of the Michael acceptors 2a–f yields
measurable amounts of adducts with the considerably stronger
nucleophiles quinuclidine and DABCO (Scheme 1), in accor-
dance with our previous conclusion that these bicyclic amines are
much weaker carbon bases than DMAP. In line with this
observation, an equilibrium constant K = 35 Mꢀ1 (25 1C,
CH3CN) has been reported for the reaction of quinuclidine with
the unsubstituted benzylidene-N,N0-dimethylbarbituric acid
which must be a stronger Lewis acid than its p-methoxy-deriva-
tive 2e.12 Despite our failure to derive accurate equilibrium
constants for the reactions of DBU and DBN with carbon
centered Lewis acids, the semiquantitative order of carbon
basicities DABCO o DMAP o DBU o DBN is unambiguous.
Aggarwal’s observation that DBU is a superior catalyst in
Baylis–Hillman reactions4 can, therefore, be explained by its
12 B. Schreiber, H. Martinek, P. Wolschann and P. Schuster, J. Am.
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V. V. L. Gowriswari, Synth. Commun., 1987, 17, 587; P. Auvray, P.
Knochel and J. F. Normant, Tetrahedron, 1988, 44, 6095.
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This journal is The Royal Society of Chemistry 2008
1794 | Chem. Commun., 2008, 1792–1794