The DMAP-catalyzed acetylation of alcohols - A mechanistic study (DMAP = 4-(dimethylamino)pyridine)

Article abstract of DOI:10.1002/chem.200500398

The acetylation of tert-butanol with acetic anhydride catalyzed by 4-(dimethylamino)pyridine (DMAP) has been studied at the Becke3 LYP/6-311+G(d,p)//Becke3LYP/6-31G(d) level of theory. Solvent effects have been estimated through single-point calculations

Full text of DOI:10.1002/chem.200500398

FULL PAPER
The DMAP-Catalyzed Acetylation of Alcohols—A Mechanistic Study
(DMAP=4-(Dimethylamino)pyridine)
Shangjie Xu, Ingmar Held, Bernhard Kempf, Herbert Mayr, Wolfgang Steglich, and
Hendrik Zipse*[a]
Abstract: The acetylation of tert-buta-
nol with acetic anhydride catalyzed by
action of this ion pair with the alcohol
substrate yields the final product, tert-
butylacetate. The competing base-cata-
lyzed reaction pathway can either pro-
ceed in a concerted or in a stepwise
manner. In both cases the reaction bar-
rier far exceeds that of the nucleophilic
catalysis mechanism. The reaction
mechanism has also been studied ex-
perimentally in dichloromethane
4-(dimethylamino)pyridine
(DMAP)
through analysis of the reaction kinet-
ics for the acetylation of cyclohexanol
with acetic anhydride, in the presence
of DMAP as catalyst and triethylamine
as the auxiliary base. The reaction is
found to be first-order with respect to
acetic anhydride, cyclohexanol, and
DMAP, and zero-order with respect to
triethyl amine. Both the theoretical as
well as the experimental studies strong-
ly support the nucleophilic catalysis
pathway.
has been studied at the Becke3LYP/6-
311+G(d,p)//Becke3LYP/6-31G(d)
level of theory. Solvent effects have
been estimated through single-point
calculations with the PCM/UAHF sol-
vation model. The energetically most
favorable pathway proceeds through
nucleophilic attack of DMAP at the
anhydride carbonyl group and subse-
quent formation of the corresponding
acetylpyridinium/acetate ion pair. Re-
Keywords: acylation · density func-
tional calculations · dimethylamino-
pyridine · kinetics · nucleophilic
catalysis
Introduction
reaction of DMAP with the acyl donor (Scheme 1). The al-
cohol then reacts with the acylated catalyst in the rate-deter-
mining second step to form the ester product together with
the deactivated (protonated) catalyst. Regeneration of the
latter requires an auxiliary base such as triethylamine. An
alternative mechanism, the deprotonation of the alcohol by
DMAP and subsequent attack of the alkoxide at the acyl
4-(Dimethylamino)pyridine (DMAP, 1) is a catalyst of out-
standing utility in a variety of group-transfer reactions, such
as the acylation of alcohols and amines.[1–5] Despite the fre-
quent use of DMAP itself and the recent development of
chiral DMAP derivatives for applications in stereoselective
catalysis,[6–13] the mechanisms of even the most simple
DMAP-catalyzed reactions, such as the acetylation of alco-
hols with acetic anhydride, have not yet been studied in
detail. A recent review of the mechanistic characteristics of
this reaction highlighted the importance of the deprotona-
tion step as well as the influence of the auxiliary base on the
catalytic activity of DMAP.[3f] The currently accepted mech-
anism for acylation reactions of alcohols involves the pre-
equilibrium formation of an acylpyridinium cation through
[a] Dr. S. Xu, Dipl.-Chem. I. Held, Dr. B. Kempf, Prof. H. Mayr,
Prof. Dr. W. Steglich, Prof. Dr. H. Zipse
Department Chemie und Biochemie, LMU München
Butenandtstrasse 5–13, 81377 München (Germany)
Fax : (+49)89-2180-77738
E-mail: zipse@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Scheme 1.
Chem. Eur. J. 2005, 11, 4751 –4757
DOI: 10.1002/chem.200500398
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4751

donor, has been ruled out because of the lack of correlation
between the catalytic reactivity and the pKa of amines.[3a,5]
One of the open questions in this nucleophilic catalysis
mechanism concerns the base required to deprotonate the
alcohol in the rate-determining step. Possible options in-
clude the acetate counterion, the auxiliary base triethyl-
amine, and the catalytic base DMAP. The involvement of
the acetate counterion has been suggested, based on the low
reactivity of acyl pyridinium salts containing less basic
anions (chloride, tosylate, and tetrafluoroborate).[14–16]
To shed light on the mechanism of this acylation reaction,
we have now studied the reaction mechanism of acetic anhy-
dride with tert-butanol in the presence of DMAP with theo-
retical methods. In how far the model system chosen for the-
oretical study is representative for the situation under exper-
imental conditions has subsequently been verified through
determination of the reaction order for all reactants.
now poised to attack the acetylpyridinium cation. The reac-
tivity of the alcohol is enhanced through hydrogen bonding
to the acetate counterion in this second step of the reaction.
Transition state 9 thus witnesses the concerted cleavage and
ꢀ
formation of overall four bonds: the C N bond connecting
ꢀ
the acetyl and the pyridine moiety in 8a, the C O ester
ꢀ
ꢀ
bond in ester 4, the O H bond in alcohol 3, and the O H
bond in acetic acid (5) (Figure 1). Transition state 9 is locat-
ed +69.9 kJmolꢀ1 above the reactant complex
6 and
+8.8 kJmolꢀ1 above transition state 7. This is in agreement
with the assumption of rate-limiting acyl transfer to the al-
cohol as described in Scheme 1. The surprisingly exothermic
formation of product complex 10 derives from a strong hy-
drogen bond between DMAP and acetic acid 5. Cleavage of
this complex to yield the separate components 1, 4, and 5 is
therefore endothermic by approximately 52 kJmolꢀ1. The
most favorable variant of the competing general base cataly-
sis mechanism leads in one single step from reactant com-
plex 6 to product complex 10. The most favorable transition
Results and Discussion
All stationary points have been
optimized at the B3LYP/6-
31G(d) level of theory and rela-
tive enthalpies have been ob-
tained at the B3LYP/6-311+G-
(d,p)//B3LYP/6-31G(d) level.
The DMAP-catalyzed reac-
tion of acetic anhydride and
tert-butanol is initiated through
formation of a ternary complex
6
of all three components,
which is common to both the
nucleophilic and the general
base
catalysis
pathway
(Scheme 2, Table 1). Along the
former pathway the pyridine-
ring nitrogen atom reacts with
acetic anhydride 2 in a concert-
ed acyl-transfer mechanism
without the intermediacy of a
tetrahedral
intermediate.[17–21]
Expulsion of the acetate leaving
group is facilitated at this stage
through formation of a hydro-
gen bond to the hydroxy group
of alcohol 3 (Figure 1). Passing
through transition state 7, the
system arrives at intermediate
8b, which can best be described
as a loose complex of the ace-
tylpyridinium cation of DMAP
and a complex between acetate
and tert-butanol.[22] Reorienta-
tion of the two components of
this complex yields intermedi-
Scheme 2. Gas-phase enthalpy profile (DH298) for the competing nucleophilic and base catalysis mechanisms in
the DMAP-catalyzed reaction of acetic anhydride with tert-butanol as calculated at the B3LYP/6-311+G-
ate 8a, in which the alcohol is (d,p)//B3LYP/6-31G(d) level of theory.
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Acetylation of Alcohols
FULL PAPER
Table 1. Relative enthalpies [in kJmolꢀ1] for stationary points located on
the potential-energy surface of DMAP (1)+acetic anhydride (2)+tert-
butanol (3). Solvent effects have been estimated through PCM/UAHF/
Becke3LYP/6-31G(d) single-point calculations.
through a six-membered-ring transition state 11b, which is
4.5 kJmolꢀ1 less favorable than the four-membered-ring
transition state 11a. As highlighted in Figure 2 the terms
H298(gas)[a]
H298(CCl4)[a]
H298(CHCl3)[a]
H298(CH2Cl2)[a]
nucleophilic catalysis
1+2+3
6
7
8a
8b
9
10
1+4+5
0.0
-35.1
0.0
+2.7
0.0
+7.8
0.0
+13.3
+54.0
+34.6
+39.0
+60.9
ꢀ56.1
ꢀ45.9
+26.0
+8.03
+6.84
+34.8
ꢀ101.4
ꢀ49.1
+52.2
+32.7
+36.8
+55.1
ꢀ66.4
ꢀ47.4
+51.3
+32.0
+36.5
+57.1
ꢀ61.0
ꢀ46.5
base catalysis (concerted)
1+2+3
6
11a
11b
10
0.0
-35.1
+72.7
+77.2
ꢀ101.4
ꢀ49.1
0.0
+2.7
+91.7
+95.6
ꢀ66.4
ꢀ47.4
0.0
+7.8
+93.5
+96.3
ꢀ61.0
ꢀ46.5
0.0
+13.3
+97.0
+99.1
ꢀ56.1
ꢀ45.9
1+4+5
base catalysis (stepwise)
1+2+3
6
16
15
14
13
12
10
0.0
-35.1
0.0
+2.7
+150.8
+143.6
+169.0
+5.2
+23.5
ꢀ66.4
ꢀ47.4
0.0
+7.8
0.0
+13.3
+157.3
+149.8
+168.7
+25.3
+29.5
ꢀ56.1
Figure 2. Structures of transition states 11a and 11b located along the
base catalysis reaction pathway as calculated at the Becke3LYP/6-31G(d)
level of theory.
+120.5
+113.2
+154.7
ꢀ11.3
+4.4
+152.9
+145.5
+166.9
+20.4
+26.0
ꢀ61.0
“four-membered” and “six-membered” describe the overall
changes in bonding between the reacting centers. However,
the distances included in Figure 2 show that the reactions
are far from synchronous, the deprotonation of tert-butanol
being far advanced, while protonation of acetate is still in a
very early stage. The very unfavorable energies of the transi-
tion states 11a and 11b clearly rule out any participation of
the base-catalyzed pathway at typical reaction temperatures.
The base-catalyzed pathway can also proceed in a stepwise
fashion, involving full deprotonation of the alcohol as the
first (and energetically also most demanding) step
(Scheme 3). The barrier for this deprotonation step as well
ꢀ101.4
1+4+5
ꢀ49.1
ꢀ46.5
ꢀ45.9
[a] B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level.
ꢀ
as its subsequent addition to the C O double bond of acetic
anhydride is, however, even less favorable than that of the
concerted base-catalyzed pathway.
The presence of partially or fully charge-separated zwit-
terionic intermediates described in Schemes 2 and 3 suggests
that solvent effects may potentially have a large influence
on the energetics of these reactions, polar solvents possibly
leading to lower reaction barriers. Experimentally observed
solvent effects indicate, however, that the oppopsite is
true.[3a,5] A larger series of solvents has been tested by Hass-
ner and co-workers in the acetylation of 1,1-diphenylethanol
with triethylamine as the auxiliary base and pyrrolidinopyri-
dine (PPY) as the catalyst.[5] The reaction was found to pro-
ceed most readily in hexane and carbontetrachloride, more
slowly in dichloromethane and diethyl ether, and to no ap-
preciable extent in DMF or acetonitrile. To test the influ-
ence of solvent effects on the three pathways outlined in
Schemes 2 and 3, we have estimated solvent effects for car-
bontetrachloride, chloroform, and dichloromethane through
PCM/UAHF single-point calculations and combined them
with gas-phase enthalpy differences to construct a solution-
phase enthalpy profile (Table 1). The results obtained in this
Figure 1. Structures of transition states 7 and 9 located along the nucleo-
philic catalysis reaction pathway together with the corresponding zwitter-
ionic complexes 8a and 8b as calculated at the Becke3LYP/6-31G(d)
level of theory.
state for this step (11a) is located +107.9 kJmolꢀ1 above re-
actant complex 6 and thus +37.9 kJmolꢀ1 above transition
state 9. The base-catalyzed pathway can also proceed
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H. Zipse et al.
have therefore studied the ki-
netics of the DMAP-catalyzed
reaction of acetic anhydride
with alcohols in dichlorome-
thane at ambient temperature
in the presence of triethylamine
as the auxiliary base. These
studies have been performed
with cyclohexanol (17) as the
alcohol component in order to
allow for a sufficiently large
variation of concentrations
(Scheme 4).[23]
For all concentrations studied
here the reaction rate can be
expressed through a rate law
that contains two terms, one for
the DMAP-catalyzed process
and one for the uncatalyzed
background process [Eq. (1)]. If
one of the two reactants, for ex-
ample, Ac2O, is chosen in large
excess over the other, and
DMAP is accompanied by an
excess of a more basic and cata-
lytically inactive amine, the rate
law can be simplified to that of
a pseudo-first-order reaction as
in Equations (2) and (3).
Scheme 3. Gas-phase enthalpy profile (DH298) for the competing concerted and stepwise base catalysis mecha-
nisms in the DMAP-catalyzed reaction of acetic anhydride with tert-butanol as calculated at the B3LYP/6-
311+G(d,p)//B3LYP/6-31G(d) level of theory.
fashion show that even moderately polar solvents such as di-
chloromethane raise the reaction barrier through solvating
the reactants substantially better than the intermediates or
transition states. In line with the observations made by
Hassner and co-workers, the reaction is predicted to pro-
ceed most readily in the least polar solvent CCl4, while reac-
tion in chloroform is slightly less favorable, and reaction in
dichloromethane even more so. The rate-limiting step is still
predicted to be the same as in the gas phase, as solvent ef-
fects are comparable for transition states 7 and 9. In all
three solvents the base-catalyzed mechanisms are as uncom-
petitive as they are in the gas phase.
Scheme 4. Reaction chosen for kinetic studies.
ꢀd½cyclohexanolŠ
dt
¼k3½Ac2OŠ½cyclohexanolŠ½DMAPŠþ
ð1Þ
k2½Ac2OŠ½cyclohexanolŠ
One remarkable feature of transition state 9 is the con-
certedness of acetyl and proton transfer. This is illustrated
in detail in Figure 1 showing transition states 7 and 9.
ꢀd½cyclohexanolŠ
dt
ð2Þ
ð3Þ
¼ k1Y ½cyclohexanolŠ
k1Y ¼ k3½Ac2OŠ ½DMAPŠ0 þ k2½Ac2OŠ
In case the deprotonation of the alcohol through the ace-
tate anion in transition state 9 is a realistic description of
the rate-limiting step of the overall reaction, one must
expect that deprotonation through auxiliary bases, such as
triethylamine (NEt3) or through a second equivalent of
DMAP, plays no role under preparative conditions. In how
far the reaction rate depends on the concentrations of
DMAP or triethylamine to first or higher order has, howev-
er, not yet been clarified for the acylation of alcohols. We
0
0
Measurement of the reaction rate under appropriately
controlled conditions yields the results shown in Figures 3
and 4. In line with the rate law expressed in Equations (2)
and (3), and the consensus nucleophilic catalysis mechanism,
the rate of reaction depends linearly on the concentration of
DMAP (Figure 3a). This excludes the possibility of a second
molecule of DMAP acting as the catalytic base in the rate-
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Chem. Eur. J. 2005, 11, 4751 –4757

Acetylation of Alcohols
FULL PAPER
Figure 3. Variation of the pseudo-first-order rate constant k1Y as a func-
tion of the reaction conditions (208C, CH2Cl2). a) Dependence of k1Y on
the concentration of DMAP with [Ac2O]0 =0.12m, [cyclohexanol]0 =
0.02m, [NEt3]0 =0.06m. b) Dependence of k1Y on the concentration of
NEt3 with [cyclohexanol]0 =0.02m, [Ac2O]0 =0.20m, [DMAP]0 =0.0004m.
Figure 4. Variation of the pseudo-first-order rate constant k1Y as a func-
tion of the reaction conditions (208C, CH2Cl2). a) Dependence of k1Y on
the concentration of cyclohexanol with [Ac2O]0 =0.02m, [NEt3]0 =0.06m,
[DMAP]0 =0.0004m. b) Dependence of k1Y on the concentration of Ac2O
with [cyclohexanol]0 =0.02m, [NEt3]0 =0.06m, [DMAP]0 =0.0004m.
limiting step of the acylation reaction. No dependence of
the reaction rate on the concentration of the auxiliary base
triethylamine could be found in the concentration range of
0.03–0.08m (Figure 3b). The horizontal line shown in Fig-
ure 3b is only included to guide the eye. This result is in full
support of the consensus mechanism and implies that tri-
ethylamine does not participate in the rate-limiting step of
the acylation reaction.
The reaction rate depends linearly on both reactants, cy-
clohexanol (Figure 4a) and acetic anhydride (Figure 4b), up
to concentrations of 0.32m. Preliminary measurements with
alcohol concentrations exceeding 1m indicate, however, that
higher concentrations of this polar component will lead to a
deviation from the linear dependence predicted by Equa-
tions (2) and (3) towards slower rates. This is in line with
earlier observations of reduced reaction rates in polar sol-
vents and also the continuum solvation calculations de-
scribed above.[3a,5] Fitting all data points to Equation (1)
yields rate constants of k2 =1.42ꢁ0.07”10ꢀ4 Lmolꢀ1 sꢀ1 and
k3 =1.30ꢁ0.07 L2 molꢀ2 sꢀ1. This indicates a rate difference
of 9154 at a DMAP concentration of 1m. At the much lower
concentrations of DMAP used here (mm range), however,
the uncatalyzed background reaction represents up to 10%
of the reaction rate. While this is of no practical conse-
quence for the reaction studied here, the rate ratio of the
catalyzed and the uncatalyzed pathway is highly critical for
kinetic resolutions with chiral DMAP derivatives.
Conclusion
In conclusion the theoretical examination of the nucleophil-
ic and the base catalysis pathways and the experimental
studies of the reaction kinetics of the DMAP-catalyzed acy-
lation of cyclohexanol fully support the consensus mecha-
nism described in Scheme 1. Solvation through organic sol-
vents of moderate polarity is predicted to increase the barri-
er relative to apolar solvents. Based on the kinetic measure-
ments neither the auxiliary base NEt3 nor the catalytic base
DMAP appear to be involved in the deprotonation of the
alcohol during the acylation process. This leaves us with the
acetate counterion contained in the acylpyridinium ion pair
as the most likely base.
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H. Zipse et al.
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General: Dichloromethane was vigorously stirred over concentrated
H2SO4 to remove traces of olefins (3 days), and was then washed with
water, 5% aqueous K2CO3 solution, and water again. After drying over
CaCl2 for 2 days, it was distilled from CaH2. 4-Dimethylaminopyridine
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Kinetic measurements: Reaction solutions were prepared through mixing
stock solutions of DMAP with a calibrated solution containing cyclohex-
anol, acetic anhydride, and triethylamine. Reactions were performed
under a nitrogen atmosphere at 208C. All kinetic measurements were
performed by using gas chromatography (FISONS 8130, Column: SE30)
with nonane as internal standard. Rate measurements were performed
through following the disappearance of the minor reaction component
under pseudo-first-order conditions.
Computational details: All stationary points were optimized at the
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of conformational isomers exist. Only the energetically most favorable
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of the vibrational frequency spectrum. Thermochemical corrections to
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Chem. Eur. J. 2005, 11, 4751 –4757

Acetylation of Alcohols
FULL PAPER
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Received: April 7, 2005
Published online: May 27, 2005
Chem. Eur. J. 2005, 11, 4751 –4757
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4757