Highlights
Organocatalysis
Nucleophilic Catalysis by 4-(Dialkylamino)pyridines
Revisited—The Search for Optimal Reactivity and
Selectivity
Alan C. Spivey* and Stellios Arseniyadis
Keywords:
asymmetric catalysis · esterification · N ligands ·
nucleophilic catalysis · organocatalysis
4-(Dimethylamino)pyridine (4-DMAP,
1) is well known as a catalyst for the
esterification of alcohols by acid anhy-
drides and for various other syntheti-
cally useful transformations involving
acyl transfer.[1, 2] Its catalytic potential
was first discovered by the groups of
Litvinenko and Steglich in the late
1960s[3, 4] and its synthetic utility and
that of its congeners, including polymer-
ic variants,[5] have been reviewed.[6–9]
Recently, attention has been focused
on the development of enantiomerically
pure chiral 4-(dialkylamino)pyridines
for the kinetic resolution of alcohols
and related enantioselective transfor-
mations.[10, 11] As a result of this interest,
the detailed mechanism of catalysis by
4-(dialkylamino)pyridines and the fac-
tors that influence their reactivity have
come under renewed scrutiny. In partic-
ular, Steglich and co-workers[12] report-
ed pyridonaphthyridine 3 as being the
most catalytically active 4-DMAP ana-
logue yet prepared for the acetylation of
tertiary alcohols, and work by Kattnig
and Albert[13] has illustrated the key role
of the anion and general base catalysis in
regulating the rate and regioselectivity
of polyol acetylation by 1 (Scheme 1).
Herein, the detailed mechanism of
catalysis of esterification by 4-(dialkyl-
amino)pyridines is reexamined in light
of these findings, and the complexity
[*] Dr. A. C. Spivey, S. Arseniyadis
Department of Chemistry
South Kensington Campus
Imperial College
London SW7 2AZ (UK)
Fax: (+ 44) 20-7594-5841
E-mail: a.c.spivey@imperial.ac.uk
5436
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
associated with this apparently straight-
forward process is highlighted.
That pyridine and 4-substituted de-
rivatives act primarily as nucleophilic
rather than general base catalysts for
alcohol esterification follows from the
dramatic loss of activity that accompa-
nies 2-alkyl substitution despite the
relatively marginal effect that this sub-
stitution has on the pKa value of these
derivatives. Such steric inhibition of
catalysis was first shown to be character-
istic of nucleophilic catalysis in work by
Gold and Jefferson in the early 1950s on
the hydrolysis of Ac2O with a series of
methyl-substituted pyridines.[14, 15] The
effect was quantified by Litvinenko
and co-workers in 1981 for the catalysis
of benzoylation of benzyl alcohol with
BzCl.[16] In addition to confirming the
nucleophilic nature of the catalysis, this
work also highlighted the particularly
high catalytic activity of 1, which exhib-
its a rate of 3.4 ; 108 relative to the
uncatalyzed reaction (Scheme 2).
The high catalytic reactivity of 1 had
previously been noted by Litvinenko
and co-workers in the benzoylation of 3-
chloroaniline[3] and subsequently, but
independently, 1 was shown by Steglich
and co-workers to enable esterification
of even hindered tertiary alcohols with
Ac2O.[4] Esterification reactions of ter-
tiary alcohols are relatively slow and
particularly susceptible to steric factors
and therefore proved to be useful for
exploring structure–activity relations for
catalysis by 4-DMAP analogues. Ac-
cordingly, Hassner et al. found that 4-
pyrrolidinopyridine (4-PPY, 2) was the
most efficient of a series of 4-amino-
pyridine derivatives, including 1, for the
DOI: 10.1002/anie.200460373
acetylation of 1-methylcyclohexanol
with Ac2O (Scheme 3).[17]
Hassner et al. noted the lack of
correlation between the pKa value and
the catalytic activity; they suggested that
the relative efficiencies of the various
catalysts reflected the stabilities of the
respective derived acyl pyridinium in-
termediates in a mechanistic scenario
involving equilibrium formation of these
salts followed by rate-determining reac-
tion with the alcohol (Scheme 4).
Additionally, Hassner et al. noted
that the order of catalytic activity of 4-
aminopyridine derivatives [4-pyrrolidi-
no (2) > 4-dimethylamino (1) > 4-piper-
idino (5) > 4-morpholino (7)] mirrored
the order of reactivity of cyclohexa-
none-derived enamines towards electro-
philes.[18–24] This order has been ration-
alized as a balance of stereoelectronic
(nN !p*C=C) and steric effects (A1,3
strain) which dictates the efficiency with
which the lone pair of electrons on the
enamine nitrogen atom interacts with
the CC double bond. By analogy with
the enamine series,[19] Hassner et al.
noted that there was a qualitative corre-
lation between the degree of shielding of
the pyridyl b-hydrogen atoms in the
1
H NMR spectra of the catalytically
active 4-aminopyridine derivatives and
their catalytic efficiency (see
Scheme 3).[17] They inferred that the
extent of electronic communication be-
tween the lone pair of electrons of the
exocyclic nitrogen atom and the carbon-
yl function through the pyridyl ring was
a key factor in stabilizing the acyl
pyridinium intermediate.
The design of pyridonaphthyridine 3
(Scheme 1), recently disclosed by Steg-
Angew. Chem. Int. Ed. 2004, 43, 5436 –5441
 Angewandte
Chemie

Scheme 1. Relative rates of acetylation of 1-ethynylcyclohexanol with Ac2O catalyzed by 4-DMAP (1), 4-pyrrolidinopyridine (4-PPY, 2), or pyrido-
naphthyridine 3;[12] and the regioselectivity of acetylation of octyl b-d-glucopyranoside with AcCl/pyridine versus Ac2O/pyridine catalyzed by 4-
DMAP (1).[13]

dimethylamino or pyrrolidi-
no analogues (i.e. 21 or 22)
as judged by their relative
reactivities towards, for ex-
ample, the Danishefsky di-
ene (Scheme 5).[25, 26]
As the tricyclic scaffold
found in derivative 24 allows
Scheme 2. Catalysis of benzoylation of benzyl alcohol with the most efficient electronic
BzCl by substituted pyridines.[16] communication between the
lone pair of electrons of the
amine and the cation, pyri-
donaphthyridine 3 was pre-
lich and co-workers,[12] evolved from this dicted to form highly stabilized acyl Scheme 4. Mechanism of nucleophilic cataly-
analysis. Prior studies by Mayr et al. had pyridinium salts and consequently to sis of alcohol esterification according to Hass-
ner et al.[17] rds = rate-determining step.
established a quantitative framework be a particularly efficacious nucleophilic
for comparing the influence of 4-dial- acylation catalyst. Moreover, density
kylamino substitution on benzhydryl functional theory calculations of the
cation reactivity and specifically had reaction enthalpies for acetyl transfer be the most catalytically active 4-
shown that “conformationally fixed” from pyridine to 3 corroborated the DMAP analogue yet prepared, display-
cations such as 23 and 24 are signifi- expected stability of the acetylpyridini- ing a rate of  6 relative to 1 for the
cantly more stabilized than either the um salt of 3. In the event, 3 was shown to acetylation of 1-ethynylcyclohexanol

Scheme 3. Catalysis of acetylation of 1-methylcyclohexanol with Ac2O by substituted pyridines and related azines.[17]

Angew. Chem. Int. Ed. 2004, 43, 5436 –5441 www.angewandte.org
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5437
Highlights
Scheme 5. Relative reactivities of various
benzhydryl cations towards the Danishefsky
diene as a measure of the ability of the 4-dial-
kylamino group to participate in nN !p*C=C
overlap.[26]
with Ac2O and with Et3N as auxiliary
base (Scheme 1).
These results clearly have practical
synthetic significance for the esterifica-
tion of highly hindered alcohols and
lend support to the notion that the
efficiency of nucleophilic catalysis by
this class of compound is closely related
to the stability of the intermediate
acylpyridinium salt. However, the mech-
anistic framework represented in
Scheme 4 is simplistic. Although the
kinetics of the esterification by 1 under
standard conditions in a low-polarity
solvent are broadly consistent with the
steady-state formation of N-acylpyridi-
nium salt followed by the rate-determin-
ing reaction of this salt with the alco-
hol,[27] this analysis fails, at least explic-
itly, to account for a number of impor-
tant features of the catalysis, such as the
significant differences in the rate of
catalysis when employing acid chlorides
versus anhydrides and when varying the
auxiliary base.[9, 12, 13] To facilitate a dis-
cussion that encompasses these features,
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
a more detailed catalytic cycle is pre-
sented below (Scheme 6).
In this four-step cycle, reversible
formation of N-acylpyridinium salt II
by the addition of 1 to the acyl donor
via the tetrahedral intermediate I
Scheme 6. Proposed catalytic cycle for alcohol esterification with 4-DMAP (1).
(steps 1 and 2) is followed by irreversi-
ble nucleophilic addition of the alcohol
to salt II (step 3, !III) with concomi-
tant proton transfer (through transition
state III#) and finally elimination to
regenerate 1 (step 4).
The position of the equilibrium to
form salt II is dictated by the relative
affinities of the anion X and 1 for the
acyl group in the reaction solvent.
Because of the aforementioned influ-
ence of steric effects and conjugation
(IIa$IIb$IIc, Scheme 6)[28, 29] these
“acyl affinities” will not mirror pKa
values,[30] but the equilibrium will be
shifted in favor of N-acylpyridinium salt
formation for:
* pyridines that have high nucleophi-
licity and impart stabilization of the
acyl group by conjugation (e.g. 1 >
pyridine),
* anions that have high nucleofugacity
(e.g. Cl > OAc), and
* polar solvents that can solvate the
charge-separated salt more efficient-
ly than the neutral starting materials
www.angewandte.org
(e.g. H2O > hexane). This is partic-
ularly pronounced because in sol-
vents of low polarity a solvated ion
pair is expected, with a high propen-
sity to return in a quasi-unimolecular
fashion to starting materials, where-
as in highly polar solvents the dis-
sociated ions will experience a sig-
nificant activation entropy for re-
turn.
Evidence to support these expect-
ations has been summarized previous-
ly.[9] Of particular note were VT-NMR
spectroscopy experiments (VT = varia-
ble temperature), which showed that
mixtures of 2 and Ac2O (1:1.5) in CDCl3
consist of 5–10 % acetylpyridinium ace-
tate at room temperature, whereas
equivalent mixtures of 2 and AcCl
consist of  100 % acetylpyridinium
chloride. Parallel experiments with pyr-
idine resulted in no detectable forma-
tion of N-acetylpyridinium acetate and
precipitation of insoluble N-acetylpyri-
dinium chloride respectively. Solubility
is an important factor that affects the
concentration of reactive N-acylpyridi-
nium salts in solution: N-Acyl 4-(di-
alkylamino)pyridinium salts II tend to
be significantly more soluble in non-
polar organic solvents than the corre-
Angew. Chem. Int. Ed. 2004, 43, 5436 –5441

sponding unsubstituted pyridinium salts.
Loss to competing reaction manifolds,
such as elimination to form ketenes, also
has an impact on the concentration of
salt.[31, 32] Ketene formation is only pos-
sible when the acyl function has b-
hydrogen atoms and is retarded by
conjugation between the carbonyl group
and the 4-dialkylamino substituent. Sus-
ceptibility to ketene formation increases
with the basicity of the auxiliary base.
The rate of esterification through this
pathway is slow relative to that through
nucleophilic catalysis.[33]
The overall rate of the catalyzed
reaction clearly depends not only on the
concentration of the N-acylpyridinium
salt II (and of the alcohol) in solution
but also the reactivity of the salt towards
addition under the reaction conditions.
That a favorable balance between these
two factors is required is apparent from
the comparison between AcCl-mediat-
ed acetylation of alcohols catalyzed by
pyridine and 1 in nonpolar solvents: the
carbonyl group in N-acetylpyridinium
chloride itself is “intrinsically” more
activated than in the corresponding 4-
DMAP-derived salt (IR: ñ(C=O) 1800
vs. 1755 cm1, respectively)[9] but pyri-
dine fails to mediate efficient catalysis
primarily because its N-acylpyridinium
salt is not present in a kinetically mean-
ingful concentration.
A confounding factor in the above
analysis, however, is that the observed
reactivities of N-acylpyridinium salts do
not correlate well with their intrinsic
carbonyl activation as expected from
resonance and spectrochemical proper-
ties. In particular, their reactivity is
highly anion- and solvent-dependent.[9]
The anion dependence is illustrated by
the threefold-greater rate of 4-DMAP-
mediated (3 equiv) acetylation of 1-
ethynylcyclohexanol when using Ac2O
(2 equiv) relative to AcCl (2 equiv)
(Scheme 7).[9]
Considering that < 10 % of the
Ac2O will be present as N-acetyl-4-
(dimethylamino)pyridinium acetate in
one case in contrast to  100 % of the
AcCl as N-acetyl-4-(dimethylamino)-
pyridinium chloride in the other (see
above), this rate difference equates to a
significantly higher reactivity for the
acetate relative to the chloride salt.[9]
The solvent dependence of 4-
DMAP-catalyzed reactions is well docu-
Angew. Chem. Int. Ed. 2004, 43, 5436 –5441
Scheme 7. Relative rates of 4-DMAP-mediated
acetylation of 1-ethynylcyclohexanol with AcCl
and Ac2O.[9]
mented: The highest rates are found in
nonpolar solvents[9] which appears para-
doxical given that such solvents accom-
modate only low concentrations of N-
acylpyridinium salts (see above)!
How then can we account for these
reactivity trends? The key is to examine
solvation and general base catalysis by
the anion as crucial factors in dictating
the reactivity of N-acylpyridinium salts.
Strong solvation by polar solvents leads
to dissociated ions with low reactivity
(whose reactivities do parallel intrinsic
carbonyl activation), whereas weak sol-
vation by nonpolar solvents leads to
highly reactive ion pairs (whose reactiv-
ities are structure-dependent). Conse-
quently, in aqueous solution N-acetyl-
pyridinium chloride hydrolyzes about
2000 times faster than N-acetyl-4-(dime-
thylamino)pyridinium chloride[34] (i.e.
the reverse of their relative reactivities
towards alcohols in nonpolar solvents as
described above). The important struc-
tural parameters that influence the rel-
ative reactivity of N-acylpyridinium ion
pairs towards alcohols in nonpolar sol-
vents are ion mobility and the efficacy of
general base catalysis by the anion.
The mobility of the constituent ions
dictates the ease of access of the alcohol
to the reactive carbonyl carbon.
“Loose” delocalized ion pairs (e.g. ace-
tate/4-(dialkylamino)pyridinium) are
more reactive than “tight” ion pairs
(e.g. chloride/pyridinium).[9] The ability
of the anion to deprotonate the alcohol
nucleophile in the rate-determining
transition state III# will mirror its basic-
ity (e.g. acetate > chloride). This general
base catalysis has long been mooted as
being important during nucleophilic
catalysis,[35] but the recent experiments
of Kattnig and Albert[13] provide the first
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Angewandte
Chemie
strong evidence for the case of 4-DMAP
(1) catalysis. They found that when using
K2CO3 (4 equiv) as auxiliary base, the 4-
DMAP-catalyzed (5 mol %) acetylation
of 2-propanol in CDCl3 at room temper-
ature with Ac2O (2 equiv) proceeded
about 10 times faster than the analogous
reaction with AcCl (t1/2 = 18 min vs.
200 min). In contrast, with pyridine
(2 equiv) as auxiliary base the relative
rates were dramatically reversed
( 700 times rate difference: t1/2 =
120 min vs. < 10 s). Similar results were
obtained with 1-propanol (Scheme 8).
Scheme 8. Relative rates of 4-DMAP-catalyzed
acetylation of 1- and 2-propanol with various
AcCl/Ac2O and K2CO3/pyridine combina-
tions.[13]
They concluded that when using
insoluble K2CO3, the acetate or chloride
anion must act as a general base, where-
as when using pyridine deprotonation
can also be carried out by this auxiliary
base.[36, 37] Their results certainly militate
in favor of deprotonation at the transi-
tion state III# (Scheme 6) being a critical
component of the rate-determining step.
This is also consistent with the observa-
tion by Steglich and co-workers that t1/2
for acetylation of 1-ethynylcyclohexanol
with Ac2O catalyzed by 1 decreased
from 465 to 151 min when triethylamine
was used as auxiliary base rather than
pyridine.[12] Moreover, the results shown
in Scheme 7 may be partially accounted
for by an approximately threefold great-

2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5439
Highlights
er steady-state concentration of free 4-
DMAP (1) available to act as a general
base in the reaction with Ac2O relative
to that with AcCl.
However, since Kattnig and Albert
used just 5 mol % of 4-DMAP (1) it is
unclear why their AcCl–pyridine condi-
tions result in much faster rates than
their Ac2O–pyridine conditions. The
concentrations of free pyridine present
to act as general base must have been
comparable, therefore presumably a
much greater concentration of N-ace-
tyl-4-(dimethylamino)pyridinium chlo-
ride relative to the corresponding acetate
must be responsible. Given that the
former ion pair is less reactive than the
latter (see above),[38] the equilibrium
between 4-DMAP (1) and salt II alone
(Scheme 6) could not be responsible for
such an extreme concentration differ-
ence. A plausible explanation is that the
equilibrium for neutralization of the
acid generated during the reaction con-
tributes to this situation. Usually at least
1 equivalent of a tertiary amine such as
Et3N is used as an auxiliary base for this
purpose and under these conditions 4-
DMAP-catalyzed esterifications are
usually faster with Ac2O than with
AcCl.[17] Being slightly more basic than
4-DMAP (1) (pKa  11 vs.  10) and
present in excess, the tertiary amine
effectively sequesters the acid (HCl or
HOAc) and maintains the 4-DMAP (1)
in the unprotonated form and available
for nucleophilic catalysis. However,
when pyridine (pKa  5) is employed as
the auxiliary base, sequestration of the
acid will be less efficient, and significant
protonation of 4-DMAP (1) may occur.
The findings of Kattnig and Albert
would then be consistent with the extent
of protonation of 4-DMAP (1) versus
pyridine by HOAc exceeding that by
HCl, or proton transfer between pyridi-
ne·HOAc and 4-DMAP·HOAc being
slow relative to that between pyridi-
ne·HCl and 4-DMAP·HCl.[39]
Kattnig and Albert went on to show
that synthetically useful levels of regio-
control can be exerted in 4-DMAP-
catalyzed polyol acetylation by the ap-
propriate choice of conditions. For ex-
ample, the primary alcohol group at C6
of octyl b-d-glucopyranoside is esteri-
fied by using AcCl–pyridine, whereas
the secondary alcohols at C3/C4 are
esterified by using Ac2O–pyridine
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
(Scheme 1). In line with previous work
by Yoshida and co-workers,[40] they at-
tributed the regioselectivity under the
Ac2O–pyridine conditions to noncova-
lent (hydrogen bonding) interactions of
the acetate ion with the substrate.
In summary, the search for optimal
catalytic activity for 4-(dialkylamino)-
pyridine-catalyzed esterification de-
mands balancing a delicate raft of fac-
tors. It is hoped that the foregoing
discussion has illuminated the complex
interplay between catalyst structure,
acylating agent, auxiliary base, and sol-
vent that conspire to set this balance and
that future studies in this area will shed
additional light. In particular, develop-
ments in asymmetric organocatalysis
with chiral 4-(dialkylamino)pyridines
and related systems can be expected to
build upon our understanding and to
provide further information on this
catalytic manifold.
Published Online: September 17, 2004
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[2] A. Hassner in Encyclopedia of Reagents
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[30] For a discussion of the pKa values of
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[32] Unimolecular elimination of the N-acyl-
pyridinium salt to form an acylium ion is
also conceivable but this process would
be expected to be more significant for
the initial acyl donor (Scheme 6).
[33] The intervention of a ketene pathway
during 4-(dialkylamino)pyridine-cata-
lyzed esterification has been proposed
but not substantiated.[15, 17]
[34] M. Wakselman, E. Guibe-Jampel, Tetra-
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[36] Kattnig and Albert obtained values in
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isotope effects (KIEs, kH/kD) for the
Angew. Chem. Int. Ed. 2004, 43, 5436 –5441

reactions shown in Scheme 8. These are
not consistent with a primary KIE of
0.81 for 4-DMAP-mediated acetylation
of tBuOH with Ac2O in CDCl3[37] and do
not provide clear-cut evidence in favor
of general base catalysis.
[37] E. Guibe-Jampel, G. Le Corre, M. Wak-
selman, Tetrahedron Lett. 1975, 16,
1157 – 1160.
[38] Evidence for this comes not only from
the results of Steglich and co-workers
Angew. Chem. Int. Ed. 2004, 43, 5436 –5441
(Scheme 7),[9] but also from studies in
which isolated N-acetyl-4-(dimethylami-
no)pyridinium acetate but NOT the
corresponding chloride, tosylate, or tet-
rafluoroborate was shown to react with
tBuOH in CHCl3.[37]
[39] Ion pair “complexes” of 4-DMAP (1)
with carboxylic acids are relatively sta-
ble and have been characterized by X-
ray diffraction. Higher aggregates (e.g.
1H+·OAc·HOAc) may be the key spe-
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angewandte
Chemie
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[40] T. Kurahashi, T. Mizutani, J.-i. Yoshida,
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473.
5441