Selectivity under microwave irradiation. Benzylation of 2-pyridone: an experimental and theoretical study

Article abstract of DOI:10.1016/j.tet.2008.06.052

The reaction of 2-pyridone with benzyl bromide in the absence of base and under solvent-free conditions has been studied experimentally and by computational methods. This reaction was one of the first reported examples in which modification of selectivity under microwave irradiation was observed. C- and/or N-alkylations were obtained depending on the benzyl halide and the heating system. N-Alkylation through mechanism A (S_N2 mechanism) is kinetically favoured while C-alkylation through an S_N1-type mechanism is thermodynamically favoured and is observed under microwave irradiation. Two S_N1-type mechanisms (mechanisms B and C) have been calculated, mechanism C being a kind of S_Ni. The influence of the pyridone/benzyl bromide ratio was studied. A second molecule of pyridone stabilizes the transition state and assists the leaving of the bromide ion. The occurrence of C-alkylation under microwave irradiation is explained by the predominance of the thermodynamic control in these conditions. Under microwave irradiation N-alkylation through an S_N1-type mechanism (mechanism C) can also occur. The dependence of the outcome of N-alkylation on the benzyl bromide ratio has been explained by a shift in the mechanism from S_N2 to S_N1 under microwave irradiation. Computational calculations have shown to be a useful tool for determination of the origin of the selectivity under microwave irradiation.

Full text of DOI:10.1016/j.tet.2008.06.052

Tetrahedron 64 (2008) 8169–8176
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selectivity under microwave irradiation. Benzylation of 2-pyridone: an
experimental and theoretical study
a
,
a
b
,
a
a
*
*
Antonio de la Hoz , Mar ı´ a Pilar Prieto , Michel Rajzmann , Abel de C o´ zar , Angel D ı´ az-Ortiz ,
a
c
Andr e´ s Moreno , Fernando P. Coss ı´ o
a
Departamento de Qu ´ı mica Org a´ nica, Facultad de Qu ´ı mica, Universidad de Castilla-La Mancha, E-14071 Ciudad Real, Spain
Laboratoire SYMBIO, UMR-CNRS 6178, Facult e´ des Sciences et Techniques, Universit e´ Paul Cezanne Boite D12, 13397 Marseille Cedex 20, France
Kimika Organikoa Saila, Kimika Fakultatea, Universidad del Pa ´ı s VascodEuskal Herriko Unibertsitatea, P.K. 1071, 20080 San Sebasti a´ n-Donostia, Spain
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 May 2008
Received in revised form 9 June 2008
Accepted 12 June 2008
Available online 19 June 2008
The reaction of 2-pyridone with benzyl bromide in the absence of base and under solvent-free conditions
has been studied experimentally and by computational methods. This reaction was one of the first re-
ported examples in which modification of selectivity under microwave irradiation was observed. C- and/
or N-alkylations were obtained depending on the benzyl halide and the heating system. N-Alkylation
through mechanism A (S
mechanism is thermodynamically favoured and is observed under microwave irradiation. Two S
mechanisms (mechanisms B and C) have been calculated, mechanism C being a kind of S
N
2 mechanism) is kinetically favoured while C-alkylation through an S
N
1-type
1-type
N
N
i. The influence
of the pyridone/benzyl bromide ratio was studied. A second molecule of pyridone stabilizes the tran-
sition state and assists the leaving of the bromide ion. The occurrence of C-alkylation under microwave
irradiation is explained by the predominance of the thermodynamic control in these conditions. Under
microwave irradiation N-alkylation through an S
dependence of the outcome of N-alkylation on the benzyl bromide ratio has been explained by a shift in
the mechanism from S 2 to S 1 under microwave irradiation. Computational calculations have shown to
N
1-type mechanism (mechanism C) can also occur. The
N
N
be a useful tool for determination of the origin of the selectivity under microwave irradiation.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
reaction times can be used and many processes can be improved.
Indeed, even reactions that do not occur by conventional heating
Microwave heating is very attractive for chemical applications
and has become a widely accepted non-conventional energy source
for performing organic synthesis.
can be performed using microwaves.
The results obtained cannot always be explained by the effect of
rapid heating alone, and this has led various authors to postulate
the existence of a so-called ‘microwave effect’. Hence, acceleration
or changes in reactivity and selectivity could be explained by
A large number of examples of reactions have been described in
organic synthesis.1 Several reviews have been published on the
2
15
application of microwaves to cycloaddition reactions, heterocyclic
a specific radiation effect and not merely by a thermal effect.
chemistry,3 carbohydrates and natural products, fullerene and
4
Control of the desired selectivity (chemo-, regio-, stereo- and
enantioselectivity) is the most important objective in organic
synthesis: The efficient use of reaction conditions (temperature,
time, solvent, etc.), kinetic versus thermodynamic control, pro-
tecting or activating groups (for example, chiral auxiliaries) and
catalysts (including chiral catalysts) have all been used to obtain the
nanotubes chemistry,5 polymers, the synthesis of radioisotopes,
6
7
8
9
medicinal and combinatorial chemistry, homogeneous and het-
erogeneous catalysis,1 solvent-free reactions, green chemistry
0
11
12
1
3
14
and, more recently, to proteomics and biological chemistry.
Microwave-assisted organic synthesis is characterized by the
spectacular accelerations produced in many reactions as a conse-
quence of the heating rate, which cannot be reproduced by classical
heating. Higher yields, milder reaction conditions and shorter
16
desired isomer.
A large number of examples have been described where mi-
crowave irradiation leads to a different selectivity than conven-
17
tional heating. These are very attractive results because of the
possibility of controlling the selectivity just by changing the mode
of heating, i.e., conventional heating versus microwave irradiation.
Alkylation of 2-pyridone under basic conditions is one of
the most studied and interesting examples of selectivity in ambi-
dent anions where the reactive sites are connected through
*
Corresponding authors. Tel.: þ34 926 295 411; fax: þ34 926 295 318 (A.d.l.H.);
fax: þ33 491 288 841 (M.R.).
E-mail addresses: antonio.hoz@uclm.es (A. de la Hoz), michel.rajzmann@univ-
cezanne.fr (M. Rajzmann).
0
040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.052

8170
A. de la Hoz et al. / Tetrahedron 64 (2008) 8169–8176
N
O
CH2Ph
3
+
PhCH2X
2
N
H
O
CH2Ph PhH2C
PhH2C
CH2Ph
O
1
+
+
N
H
O
N
H
O
N
H
4
5
6
Scheme 1. Benzylation of 2-pyridone under solvent-free conditions and in the absence of base.
mesomerism.18 Alkylation of 2-pyridone salts is very sensitive to
the reaction conditions such as counterion, solvent, alkylation
agent, leaving group and temperature.
We have described the benzylation of 2-pyridone in solvent-free
conditions in the absence of base under conventional heating and
microwave irradiation.19 This reaction produced interesting modi-
fications in the selectivity and these depended on the leaving group
and the mode of heating. Indeed, this was one of the first examples
in which the selectivity of a reaction was modified under micro-
wave irradiation.
performed in closed Teflon vessels in a domestic oven and the
temperature was measured at the end of the reaction. Reactions
involving conventional heating were performed in screw-cap
sealed reaction vessels and heated in a closed aluminium block
2
6
previously heated to the desired temperature.
The selectivity in the benzylation of 2-pyridone under solvent-
free conditions and in the absence of base was found to depend
strongly on the alkylation agent, i.e., the leaving group and the
mode of heating, microwave irradiation or conventional heating,
with N- and C-alkylation products the only observed compounds
(Scheme 1 and Table 1). O-Alkylation was not detected under these
conditions.
With benzyl chloride, N-alkylation was the exclusive process
regardless of the mode of heating. In contrast, with benzyl iodide
the selectivity was found to depend on the mode of heating; with
conventional heating traces of N-alkylation product were detected
while under microwave irradiation C-alkylation was observed ex-
clusively. Finally, with benzyl bromide the selectivity depends
again on the mode of heating and, under microwaves, on the power
applied. Conventional heating again leads to N-alkylation exclu-
sively, while microwave irradiation at 150 W produced N-alkyl-
ation and at 450 W only C-alkylation was observed. As microwave
reactions were performed in a domestic oven that always works at
the maximum power, these results must be a consequence of the
different heating rates and reaction temperatures.
Our research group has maintained an interest in the theoretical
study of reactions carried out under microwave irradiation in order
to rationalize the effects of this energy source in chemical syn-
2
0
thesis. We think that theoretical calculations can be used to
elucidate the reaction mechanisms under conventional heating and
microwave irradiation, to determine the origin of the modification
in the selectivity and to solve the problems encountered with
temperature determination under microwave irradiation.
In the literature there are very few examples of ab initio cal-
culations for full S
molecules, generally tert-butyl chloride. However, calculations
concerning some aspects of S 1 mechanisms have been performed.
N
1 processes and these are only applied to small
N
In these examples two kinds of approaches were used. In the first,
explicit water molecules were introduced in order to simulate
solvent effects in all calculations. With the semi-empirical PM3
QM/MM method the solute molecule was surrounded by 483 water
molecules.21 The Monte Carlo method is also well adapted to
In order to gain a deeper insight into the results of these re-
actions we studied experimentally and theoretically the reaction of
2-pyridone with benzyl bromide under conventional heating and
microwave irradiation. In order to rationalize our previous results
we carried out some new reactions. In these cases, the reactions
were performed in a monomode reactor with 10 mmol of pyridone
for 10 min, under solvent-free conditions and in the absence of
2
2
simulate the hydrolysis of t-BuCl. In addition, a cluster of t-BuCl
and four water molecules was chosen to represent the solvent–
solute complex evolution, and HF and MP2 ab initio calculations
2
3
were performed to obtain a full reaction path. In the second ap-
proach, solvent effects were treated by a dielectric continuum. In
this case, elongation of the C–Cl bond of t-BuCl until full dissocia-
base. At the end of the reaction, the crude mixture was dissolved in
1
tion of ions was used to achieve S
N
1 energy profiles. Water was also
deuterated chloroform and the N/C ratio was determined by
NMR spectroscopy by integration of the benzyl CH
¼3.5–4.0; N–CH ¼5.0–5.5). Reactions under conventional heat-
ing were performed in an aluminium block previously heated to the
H
2
4a
used for AM1 and MNDO semi-empirical calculations
or HF and
Some valence bond calculations were
2 2
group (C–CH
2
4b
MP2 ab initio calculations.
d
2
d
carried out in order to calculate solvent barriers with four organic
solvents.25 With a dielectric continuum model, only C–Cl elonga-
desired temperature.
26
Reactions under microwave irradiation
tion was used to represent the S
N
1 mechanism and so a transition
were performed in a focused PROLABO MAXIDIGEST MX250
state (TS) was not characterized by Hessian eigenvalues.
Within this context, in this paper we present an experimental
and theoretical study on the selectivity in the alkylation of 2-pyr-
idone with benzyl bromide in an attempt to understand the mod-
ification in selectivity observed.
Table 1
Benzylation of 2-pyridone using conventional heating and microwave irradiation,
under solvent-free conditions and in the absence of base19
ꢀ
X
Conditions
Time (min)
Temperature ( C)
N/C ratio
a
198c
176
Cl
Cl
Br
Br
Br
I
MW, 780 W
CH
5
5
5
2.5
5
100:0
100:0
100:0
0:100
100:0
0:100
Traces:0
b
2
. Results
a
c
MW, 150 W
81
180
a
c
MW, 450 W
Reactions were performed by mixing 10 mmol of 2-pyridone
b
CH
196
146
and 20 mmol of benzyl halide and heating the mixture under sol-
vent-free conditions in the absence of base. Under solvent-free
conditions, the influence of microwave irradiation should be more
marked as the radiation is directly absorbed by the reagents and not
by the solvent.1 Under microwave irradiation, reactions were
a
c
MW, 150 W
5
5
b
I
CH
180
a
MW, microwave irradiation.
CH, conventional heating.
Determined at the end of the reaction.
b
c
1a

A. de la Hoz et al. / Tetrahedron 64 (2008) 8169–8176
8171
2
1
1
1
1
1
8
6
4
2
00
80
60
40
20
00
0
0
0
0
0
Table 3
Reaction of 2-pyridone with benzyl bromide under microwave irradiation (pyridone
ꢀ
10 mmol, temperature 180 C, power 150 W)
BrCH Ph (mmol)
2
N (%)
C (%)
Conversion (%)
1
0
28.2
52.7
79
90.1
90
71.8
47.3
20.6
9.9
78.3
79.1
94.3
100
1
5
20
25
30
10
100
30 to 300 W. In all reactions the same N/C ratio was observed. As
0
1
2
3
4
5
Time (min)
6
7
8
9
a consequence it can be concluded that under microwave irradia-
tion the selectivity depends exclusively on the reaction tempera-
ture and not on the irradiation power. On using conventional
heating only N-alkylation was observed, regardless of the temper-
ature used in the reaction.
Secondly, we performed a series of experiments in an effort to
elucidate the possible mechanism of the benzylation. N- and C-
benzylation can occur by S
Figure 1. Temperature profile of a typical reaction under microwave irradiation. Re-
action time 10 min, temperature180 C, power50 W, pyridone/benzyl bromideratio 1:2.
ꢀ
Table 2
Reaction of 2-pyridone with benzyl bromide under microwave irradiation (pyridone
0 mmol, benzyl bromide 20 mmol, power 150 W)
1
N N
1 and S 2 mechanisms and these may
ꢀ
Temperature ( C)
N (%)
C (%)
Conversion (%)
occur by a similar or a different path.
ꢀ
80
95.3
95.4
79.9
58.5
4.7
4.6
20.1
41.5
43.1
51.0
72.4
85.9
Reactions were performed with 10 mmol of pyridone, at 180 C,
irradiation at 150 W for 10 min and a variable ratio of benzyl bro-
mide from 10 to 30 mmol (Table 3 and Fig. 3).
1
10
40
70
1
1
The dependence observed in the N/C ratio with the initial benzyl
bromide/2-pyridone ratio indicates that N- and C-alkylation do not
follow the same mechanism and that N-alkylation must proceed
microwave reactor modified with a stirring system and an IR py-
rometer. The IR pyrometer was calibrated with a fibre optic sensor
in order to give an accurate temperature measurement. Reaction
conditions, temperature, time and power were controlled with
through an S
mechanism.
N N
2 mechanism while C-alkylation must follow an S 1
ꢀ
Once again, under conventional heating conditions (180 C,
27
specially designed software (Fig. 1).
10 min) N-alkylation was always observed regardless of the initial
Firstly, we performed two series of experiments in order to as-
certain if the modification of selectivity was a consequence of the
heating rate, or a consequence of the applied power.
pyridone/benzyl bromide ratio.
Formation of the C-alkylated product must occur by a nucleo-
philic substitution with the pyridone acting as a nucleophile. Other
possibilities were previously ruled out: (i) an N-benzyl to C-benzyl
and an O-benzyl to C-benzyl rearrangements were excluded be-
cause the N-alkyl and O-alkyl derivatives are stable under the
In the first series, reactions were performed with 20 mmol of
benzyl bromide with a fixed irradiation power of 150 W and the
ꢀ
temperature was changed from 80 to 170 C. In each case, the re-
action gave a complex mixture but the C-ratio increased with
temperature (Table 2 and Fig. 2).
100%
In the second series, reactions were performed with a fixed
ꢀ
temperature of 170 C and the irradiation power was changed from
8
6
4
0%
0%
0%
100
N-
C-
8
6
0
0
20%
0%
N-
C-
4
2
0
0
10
15
20
Benzyl bromide (mmol)
25
30
0
1
05%
6
0
110
Temperature (°C)
160
100%
9
9
8
8
7
5%
0%
5%
0%
5%
9
8
7
6
5
4
3
0
0
0
0
0
0
0
70%
65%
6
0
120
Temperature (°C)
180
10
15 20
Benzyl bromide (mmol)
25
30
Figure 2. N/C ratio and conversion in the reaction of 2-pyridone with benzyl bromide
Table 2).
Figure 3. N/C ratio and conversion in the reaction of 2-pyridone with benzyl bromide
(Table 3).
(

8172
A. de la Hoz et al. / Tetrahedron 64 (2008) 8169–8176
reaction conditions, in the presence of benzyl bromide and (ii)
a radical substitution was excluded as reaction takes place in the
19
presence of a radical scavenger.
The use of microwave irradiation, solvent-free conditions (het-
erogeneous conditions), closed vessels and short reaction times
prevented the use of kinetic analysis in this reaction. In conse-
quence, in order to explain the experimental results, to justify the
exclusive formation of the C-alkylation product under microwave
irradiation and to clarify the mechanism of the benzylation, com-
putational studies on this reaction were performed.
3
3
. Computational calculations
.1. Methodology
As Kormos and Cramer28 pointed out all efforts to find solvated
separated ionic transition states with PBE/CPCM were unsuccessful,
so we applied AM1/SM5.2 model, which allowed us to obtain both
N N
S 1 and S 2 full reaction paths. First, we had to verify that AM1/
SM5.2 has a qualitative agreement with PBE/CPCM for S
mechanisms.
N
2
Figure 4. Transition structures of C-alkylation and N-alkylation (S
PBE/6-31G : a, and AM1: b.
N
2) computed at
*
In this exploratory study, most of the calculations reported were
performed with the semi-empirical AM1 method available in the
AMPAC software.29 This method gave reasonable results for organic
chemical reactivity studies. Geometries of stationary points were
determined by energy minimizations with respect to all geometric
parameters. All reaction paths were determined by the fullchn
procedure.29
All transition structures (TS) of full reaction paths were located
by the chain method31 and characterized by one and only one
negative eigenvalue of the Hessian matrix, and the corresponding
vibration was found to be associated with nuclear motions along
the reaction coordinate.
Stationary point connections from TS to minima were obtained
either by a steepest descent if the slope was sufficient, or a poly-
nomial interpolation for nearly flat reaction path regions. This
N
The AM1 with AMSOL/SM5.2 methods allows describing the S 1
mechanism, in which ionic intermediates exist, to be treated as
carbocation and carbanion. In our experiments, the medium was
benzyl bromide, which is less polar than water and, consequently,
we could not use cluster strategies to stabilize ions. Solvent effects
were included in our semi-empirical calculations by means of
a dielectric medium. In this way all full reaction paths were
obtained in a reasonable computing time.
3
0
DFT and AM1 TS structures are similar. However, polarization
atomic orbitals are only included in PBE/6-31G
*
calculations, so it is
not surprising that, for non-linked reactive atoms in both S
N
2
mechanisms, nitrogen–carbon (N-alkylation) or carbon–carbon (C-
alkylation) and carbon–bromide distances are longer for DFT cal-
culations than AM1 calculations (Table 4). With both methods,
N
polynomial interpolation is very useful for S 1 mechanisms. All
a
activation and reaction energies E and Erxn are lower for N-alkyl-
these successive steps are included in the fullchn process. With this
automatic process we obtained a full reaction path in a single run.
Solvent effects were estimated by means of the AMSOL/SM5.2
ation than C-alkylation, even if AM1/SM5.2 activation energies are
overestimated. Therefore, there is a qualitative agreement between
DFT and AM1 calculations. As a consequence, PBE/CPCM calcula-
tions validate AM1/SM5.2 calculations for qualitative studies.
Moreover, the same reactants are also present for all N-alkylation
and C-alkylation mechanisms. AM1 calculations are therefore suf-
ficient to explain our experimental results because we have only
studied different evolutions of the same system.
3
2,33
model.
This non-rigid cavity solvent model can be applied to
chemical reactions involving bond dissociation and full solvent
reaction paths were obtained with the fullchn process. However,
some calculation instabilities can occur when two cavities are very
close, but these difficulties could be overcome by changing some
data. Bromobenzene was chosen as the medium for semi-empirical
Experimental results (Table 3) indicate that N-alkylation and C-
alkylation reactions could occur through different mechanisms.
AM1 with AMSOL/SM5.2 was used to compute all mechanisms
calculations because its dielectric constant (3) is close to that of
benzyl bromide.
In order to check that the AM1/SM5.2 model is adapted for this
study, we performed PBE/CPCM calculations for C- and N-alkylation
S 2 mechanisms. Ab initio calculations were carried out using the
N
for these reactions (N-alkylation S
2, C-alkylation S 1).
For all calculations, we only used the hydroxypyridine tautomer
N N
2, N-alkylation S 1, C-alkylation
S
N
N
3
4
Gaussian 03 series of programs, with the standard 6-31G basis
*
rather than the pyridone tautomer, because: (i) in our experiments,
O-alkylation has never been detected, which means that our re-
actants are the hydroxypyridine tautomer and benzyl bromide for
all alkylation reactions. Intermolecular keto-enolization between
set. Density Functional Theory (DFT)36 was used to include elec-
tron correlation at a reasonable computational cost. In this study,
these calculations were carried out by means of the functional
developed by Perdew et al., which is usually denoted as PBE. All
TS structures and minima were fully characterized by harmonic
analysis. Solvent effects were estimated by means of the polarizable
conductor calculation model CPCM. As we did not have all
physical constants for benzyl bromide, chlorobenzene was used as
the medium given that the dielectric constants of these two com-
pounds are similar. Indeed, with the CPCM model, PBE functional
35
37
Table 4
Geometrical data, distances (Å), activation energies (
D
E
a
, kcal/mol), reaction ener-
2) computed
3
8
gies ( rxn, kcal/mol) of transition structure for C- and N-alkylation (S
DE
N
at PBE/6-31G
*
Entry
d C–C
d C–N
d C–Br
E
a
E
rxn
NAa
1
2
3
4
DFT
AM1
DFT
1.94
1.78
2.59
2.39
2.91
2.67
21.29
55.24
40.42
71.80
ꢁ17.44
ꢁ3.28
and 6-31G
*
basis and solvent cavities are well adapted for optimi-
CAa
1.86
1.84
ꢁ22.98
ꢁ19.53
zation convergences, so we obtained optimized TS and minimum
structures. C- and N-alkylation TS are shown Figure 4 and their
main structural data are collected in Table 4.
AM1
a
NA denotes N-alkylation and CA denotes C-alkylation.

A. de la Hoz et al. / Tetrahedron 64 (2008) 8169–8176
8173
two pyridone molecules occurs easily. Indeed, with PBE/CPCM the
activation energy for the keto-enolization reaction is only
1.08 kcal/mol and 4.25 kcal/mol for the reverse reaction. (ii) For N-
alkylation mechanisms the nitrogen lone pair has to be available.
iii) For C-alkylation mechanisms, the benzyl carbocation has to be
stabilized and benzyl bromide is not sufficiently polar to achieve
this. If a pyridone molecule stabilizes this ion through an oxygen
lone pair, 2-benzyloxypyridine should always be obtained through
this mechanism. As this compound has never been observed in any
of our experiments, pyridone molecules were replaced by
hydroxypyridine molecules in our calculations and, in this way, the
correct compound was obtained. Moreover, the hydroxypyridine–
bromide complex (O/H/Br) is stable enough for the bromide ion
to move in the reaction path, but this complex can easily release the
bromide ion, which catches a hydrogen atom (H9 or H5) (Scheme 2)
to give hydrogen bromide.
Table 6
Activation energies (
moments (debye)
D
E
a
, kcal/mol), reaction energies (
D
E
rxn, kcal/mol) and dipole
1
Entry
Mechanism
m
DE
a
DE
rxn
(
1
2
3
4
5
6
7
8
9
A (NA)
A (CA)
B (NA)-1
B (NA)-2
C (NA)-b-1
C (NA)-b-2
B (CA)-1
B (CA)-2
C (CA)-b-1
12.62
14.07
16.06
25.69
24.23
d
53.26
67.55
56.68
d
ꢁ1.57
ꢁ16.14
ꢁ1.57
a
a
a
55.66
ꢁ1.57
a
a
20.33
20.78
27.77
24.73
d
a
66.45
d
ꢁ16.14
ꢁ16.14
a
a
10
C (CA)-b-2
59.15
Mechanisms determined with two hydroxypyridine molecules.
a
NA denotes N-alkylation and CA denotes C-alkylation.
hydroxypyridine derivative, but all reaction energies are given for
the pyridone derivative (Tables 4–6). Indeed, the last tautomerism
is common for all C-alkylation mechanisms with low activation
energy. Energy profiles are similar for N- and C-alkylation, although
the activation energy for N-alkylation is lower than that for C-al-
kylation (Table 6, entry 1 vs 2). Examination of TS structures shows
that interatomic distances C5–C10 and C10–Br11 are longer in the
TS for C-alkylation than interatomic distances N1–C10 and C10–
Br11 in the TS for N-alkylation (Table 7), a situation that explains
why the activation energy for C-alkylation is 14 kcal/mol higher
than that for N-alkylation (Table 6, entry 1 vs 2). The weak slopes of
these energy profiles are associated with the movement of the
bromide ion. This motion is facilitated by the formation of a bro-
mide–hydroxypyridine complexda situation confirmed by the
short Br11–H17 distance (Table 7), where H17 belongs to the second
hydroxypyridine unit (Figs. 5 and 6)
H12
7
H8
H13
Br 11
0
O
1
16
O
2
14
3
4
1
N
N
H
15
1
7
6
5
H9
Scheme 2. Atom numbering for the two hydroxypyridine and benzyl bromide
molecules.
Activation and reaction energies in solution are collected in
Table 5. It has been proposed that dipole moments play an im-
portant role in reactions induced by microwave irradiation and
these values are also collected in Table 5.
there are generally at least two TS and these are denoted as 1 and 2.
Activation energies are given for higher TS.
15a
N
In S 1 mechanisms
Two possible reactions paths were found for mechanisms B and
C, they are S 1-type mechanisms as benzyl cation is formed in the
N
first step. In both cases assistance of one hydroxypyridine unit is
required for releasing the bromide ion. The fundamental difference
between these mechanisms is in the first step and the attacking
hydroxypyridine unit.
N
In S 1-type mechanisms the ions that form during the process
have to be stabilized. As stabilization by benzyl bromide is weak,
a second molecule of hydroxypyridine, which stabilizes the benzyl
carbocation and the TS, was introduced. Thus we have included two
hydroxypyridine molecules for one benzyl bromide molecule in the
calculations. The main results are collected in Table 6.
In all cases, activation energies were lower when two
hydroxypyridine molecules were introduced into our calculations.
As expected, this decrease in the activation energy is more signif-
3
.2.2. Mechanisms B
In mechanism B, the bromide anion is released from benzyl
bromide and stabilized by a hydroxypyridine molecule. A second
hydroxypyridine is then linked by the other side of the benzyl
carbocation with the N1 atom (N-alkylation) or C5 atom (C-alkyl-
ation). Finally, the bromide ion catches a hydrogen atom (H9) to
give a molecule of hydrogen bromide (Figs. 7 and 8). All fragments
in this mechanism are well separated; as a consequence, in-
teratomic distances cannot explain the difference in the activation
energy between these two mechanisms, i.e., N- and C-alkylation
icant for S
a carbocation is formed, than for S
N
1-type mechanisms (mechanisms B and C), where
2 mechanisms (mechanisms A).
N
As a result, only full reaction path drawings with two hydroxy-
pyridine molecules are included in this study.
3
.2. Description of the calculated mechanisms
3.2.1. Mechanisms A
(Table 6, entry 3 vs 8). A detailed inspection of all TS structures in
N
Mechanisms A are S 2 mechanisms. In order to limit the size of
these mechanisms indicates that the two first TS of each mecha-
nism are similar, where the carbocation is stabilized by two lone
pairsdone from a nitrogen atom and one from an oxygen atom, and
the bromide ion is also stabilized by an OH group (Br11–H17 dis-
tance: 1.99 Å, Table 7). Consequently, the energies are very close.
figures, C-alkylation energy profile drawings are restricted to the
Table 5
Activation energies (
moments (debye)
a
DE , kcal/mol), reaction energies (DErxn, kcal/mol) and dipole
Entry
Mechanism
m
D
E
a
DE
rxn
Table 7
1
2
3
4
5
6
7
8
9
A (NA)
A (CA)
15.26
16.03
16.89
28.10
22.72
23.65
19.31
12.83
18.51
9.46
55.24
71.80
63.42
d
ꢁ3.28
ꢁ19.53
ꢁ3.28
Geometrical data for transition structures
B (NA)-1a
B (NA)-2a
C (NA)-1a
Distances (Å)
S 2
N
S 1
N
SN1-b
TS1
TS
TS1
TS2
TS2
d
a
N-Alkylation
C-Alkylation
N1–C10
1.83
2.40
2.15
1.96
2.88
2.07
3.92
3.70
1.99
5.02
4.78
1.99
2.69
6.18
2.07
2.11
6.19
2.01
3.54
4.01
6.45
5.67
3.74
6.61
C (NA)-2
B (CA)-1
58.15
d
ꢁ3.28
a
C10–Br11
Br11–H17
C5–C10
C10–Br11
Br11–H17
B (CA)-2a
C (CA)-1a
C (CA)-2a
71.98
62.85
d
ꢁ19.53
ꢁ19.53
3.11
6.18
7.95
10
Mechanisms determined with one hydroxypyridine molecule.
a
Mechanisms determined with two hydroxypyridine molecules.
NA denotes N-alkylation and CA denotes C-alkylation.

8174
A. de la Hoz et al. / Tetrahedron 64 (2008) 8169–8176
N
Figure 7. Energy profile for the N-alkylation through mechanism B (S 1).
N
Figure 5. Energy profile for the N-alkylation through mechanism A (S 2).
In contrast, the second TS structures are different. For N-alkyl-
4. Discussion
ation, the carbocation is stabilized by the nitrogen lone pair and the
bromide ion by two OH groups (Br11–H17 distance: 2.07 Å). For C-
alkylation there is no stabilization by the lone pair as the in-
teratomic distance C5–C10 is 2.11 Å (Table 7), which produces only
The reaction of pyridone with benzyl bromide in solvent-free
conditions and in the absence of base follows a complex path. Ex-
perimental results show that under conventional heating N-alkyl-
ation is produced regardless of the reaction conditions,
temperature, time and molar ratio of reagents. Under microwave
irradiation, however, the selectivity N/C-alkylation depends on the
temperature and the benzyl bromide/pyridone ratio, but not on the
power used at a fixed temperature. These results indicate that in
this reaction microwave irradiation favours the thermodynamic
control path.
a weak interaction between the carbocation and the
p system of the
pyridine ring. Moreover, the bromide ion is only stabilized by one
OH group (Br11–H17 distance: 2.01 Å). This structural difference
could explain why the activation energy for C-alkylation is 10 kcal/
mol higher than for N-alkylation (Table 6, entry 3 vs 8).
3.2.3. Mechanisms C
In mechanism C, the bromide ion and a proton (H8) from the
Computational calculations helped to elucidate the reaction
paths and to explain the experimental results. All calculations show
that assistance of a second molecule of 2-hydroxypyridine leads to
a reduction in the free energy of activation of all processes.
Theoretical results indicate that N-alkylation through mecha-
hydroxy group are released to give hydrogen bromide. The
remaining reactive groups, i.e., the benzyl cation and hydroxypyr-
idine anion, are bonded through the two reactive sites N1 (N-al-
kylation) or C5 (C-alkylation) with C10 in a kind of internal
Nucleophilic Substitution (S
N
i). Nucleophilic attack takes place by
N
nism A (S 2) is the kinetically favourable process because it has the
the same side of the removal of bromide ion. N-Alkylation is
completed at this stage (Fig. 9). For C-alkylation, a hydrogen ex-
change (H8 and H9) from hydrogen bromide occurs with the help of
a second hydroxypyridine unit (Fig. 10). The small difference in the
activation energy (3 kcal/mol) between these two mechanisms
lowest activation energy (Table 6, entry 1). This process is observed
exclusively under conventional heating conditions.
At high temperatures, the process has enough energy to pass the
two energy barriers corresponding to N-alkylation (mechanism A,
N N
S 2) and C-alkylation (mechanism C, S i) (Table 6, entry 1 vs 10).
(
Table 6, entry 5 vs 10) can be explained in terms of the higher TS
This latter process is favoured thermodynamically and is observed
under microwave irradiation.
structures of these mechanisms. Indeed, for N-alkylation the car-
bocation is further stabilized in the TS by two nitrogen lone pairs,
while for C-alkylation one lone pair can be used for such stabili-
zation. In these mechanisms bromide is always linked and, as such,
stabilization of hydroxypyridine is not necessary, meaning that the
Br11–H17 distance is greater than 6 Å (Table 7).
The acceleration of reactions by microwave exposure may be
a result of the interaction of the radiation with matter. Dielectric
heating results from dipolar polarization as a consequence of di-
pole–dipole interactions between polar molecules and the elec-
tromagnetic field. These interactions lead to a dissipation of energy
Figure 6. Energy profile for the C-alkylation through mechanism A (S
N
2).
N
Figure 8. Energy profile for the C-alkylation through mechanism B (S 1).

A. de la Hoz et al. / Tetrahedron 64 (2008) 8169–8176
8175
in the selectivity to favour N-alkylation (Table 3). To simulate this
effect we performed calculations with one molecule of hydroxy-
pyridine, which represents a higher concentration of benzyl
bromide.
Our results (Table 5) reveal that N-alkylation through mecha-
N
nism C (S i) now has not only a lower activation energy
(ꢁ4.70 kcal/mol) but also a higher dipole moment (þ5.14 D) than
the C-alkylation through mechanism C (Table 5, entry 6 vs 9). In
contrast, with 2 equiv of hydroxypyridine the N-alkylation through
mechanism C has still a lower activation energy (ꢁ3.49 kcal/mol)
but a similar dipole moment (ꢁ0.50 D) to the C-alkylation through
mechanism C (Table 6, entry 5 vs 10). As a consequence, the in-
crease in the proportion of benzyl bromide produces a modification
of the mechanism, from C-alkylation to N-alkylation, under mi-
crowave irradiation in good agreement with the experimentally
observed inversion of the selectivity.
N
Figure 9. Energy profile for the N-alkylation through mechanism C (S i).
5
. Conclusion
as heat. This energy dissipation in the core of the material allows
a much more regular repartition in the temperature when com-
pared to classical heating. In this way thermodynamically con-
trolled processes are favoured under microwave irradiation. In our
case, the reaction energy is 14.57 kcal/mol lower for C-alkylation
than that for N-alkylation (Table 6, entries 2, 8, 10 vs 1, 3, 5).
In our process, the TS corresponding to C-alkylation are also
much more polar (15.15 D) than the TS corresponding to N-alkyl-
The mechanism of the benzylation of 2-pyridone in solvent-free
conditions and in the absence of base has been elucidated by
computational calculations.
Computational calculations showed that modification on se-
lectivity can be explained through thermal effects that lead to
thermodynamic control under microwave irradiation. N-Alkylation
occurs through mechanism A (S
mechanism C (S i). Microwave irradiation also induces a shift from
C- to N-alkylation (mechanism C) with an excess of benzyl bromide.
It should be noted that mechanisms C (S i) were determined for
the first time, thanks to fullchn calculations, which represent
a powerful research tool.
Finally, we performed calculations exclusively with benzyl bro-
mide because the most dramatic modifications were observed with
this alkylation agent. Results obtained with benzyl chloride and
benzyl iodide can be rationalized by considering the modifications
expected in the mechanism according to the nature of the leaving
3
9,40
N
2), and C-Alkylation through
ation (Table 6, entry 1 vs 9).
N
Therefore, under microwave irradiation C-alkylation occurs
because this process is thermodynamically favourable. The reaction
rate for C-alkylation is enhanced at high temperatures. C-Alkylation
N
is produced by a kind of S
N
i mechanism (mechanism C). This is not
a pure S 1 mechanism as a molecule of 2-hydroxypyridine facili-
N
tates the formation of hydrogen bromide and, in consequence it
participates in the rate determining step.
Experimentally, N-alkylation also occurs under microwave irra-
diation. The small difference in the activation energies between
mechanism C (S
ation) and the high dipole moment for mechanism C (S
N
i, N-alkylation) and mechanism A (S
N
2, N-alkyl-
i, N-alkyl-
group (chloride, S
favourable, exclusive C-alkylation under microwave irradiation).
N N
2 favourable, exclusive N-alkylation; iodide, S 1
N
ation) TS 24.23 D (Table 6, entry 5) indicate that N-alkylation under
microwaves can occur through mechanism C. This behaviour is
The effect of microwave irradiation on chemical synthesis re-
sults from material–wave interactions that lead to thermal effects
that can be proved by temperature measurements. Some authors
have also postulated the existence of non-thermal effects. Many of
these described non-thermal effects have been a consequence of
the use of non-appropriate techniques for temperature measure-
ment. Even using multiple fibre-optic probes, the presence of mi-
croscopic hot spots in heterogeneous reactions cannot be
discarded. In this paper we have shown that theoretical calcula-
tions can be used not only to elucidate the mechanism but to ex-
plain the origin of the modification of selectivity under microwave
irradiation, avoiding possible errors in temperature measurements.
similar to that observed for the mechanism C (S
N
i, C-alkylation)
(Table 6, entry 9), even though the activation energy is 3 kcal/mol
N
higher than that for mechanism B (S 1-type, N-alkylation). Conse-
quently, computational results are consistent with the occurrence of
N-alkylation and C-alkylation under microwave irradiation.
4
.1. Influence of the ratio of benzyl bromide
41
Experimental results show that under microwave irradiation an
increase in the proportion of benzyl bromide produces an inversion
6
6
. Experimental section
.1. General
All reactions were performed under the conditions described in
Section 2 and Tables 2 and 3. The crude products were dissolved in
1
3
CDCl (1 mL) and isomer ratios were determined by H NMR by
integration of the benzyl protons. C- and N-Alkylation products
were isolated by column chromatography on silica gel using hex-
ane/ethyl acetate as the eluent.
6
.1.1. 1-Benzyl-2-pyridone (3)
Bp 230 C/0.01 mmHg; H NMR (500 MHz, CDCl
ꢀ
1
3
): 5.18 (s, 2H, N–
CH
2
), 6.14 (td, 1H, J¼1.4, 6.4 Hz, H-5), 6.62 (ddd, 1H, J¼0.8, 1.4, 9.2 Hz,
13
Figure 10. Energy profile for the C-alkylation through mechanism C (S
N
i).
H-3), 7.25 (ddd, J¼0.8, 2.1, 6.4 Hz, H-6), 7.2–7.4 (m, 6H, Ph, H-4);
C

8176
A. de la Hoz et al. / Tetrahedron 64 (2008) 8169–8176
NMR(125 MHz, CDCl
3
):51.0(N–CH
2
),105.45(C-5),119.83(C-3),127.41
9. Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717–727.
0. Will, H.; Scholz, P.; Ondruschka, B. Chem. Ing. Tech. 2002, 74, 1057–1067.
1. (a) Loupy, A. Solvent-free Reactions in Modern Solvents in Organic Chemistry;
Springer: 1999; Vol. 206, pp 155–207; (b) Varma, R. S. Tetrahedron 2002, 58,
1235–1255.
1
1
(p-C),127.57 (o-C),128.48(m-C),137.40(6-C),139.09(i-C),140.01 (4-C),
161.33 (C]O). IR (KBr):
n
¼3261, 2938, 1641, 1613, 1561, 1490, 1472,
ꢁ
1
1448, 774, 723, 695 cm ; elemental analysis calcd (%) for C12
H11NO
1
2. (a) Bose, A. K.; Manhas, M. S.; Ganguly, S. N.; Sharma, A. H.; Banik, B. K. Syn-
thesis 2002, 1578–1591; (b) Varma, R. S. Advances in Green Chemistry: Chemical
Syntheses Using Microwave Irradiation; AstraZeneca Research Foundation, Ka-
vitha Printers: Bangalore, India, 2002; (c) Roberts, B. A.; Strauss, C. R. Acc. Chem.
Res. 2005, 38, 653–681.
(185.23): C 77.88, H 5.99, N 7.57; found: C 77.91, H 5.80, N 7.30.
6
.1.2. 3-Benzyl-2-pyridone (4)
Mp 144–145 C (ethyl acetate); H NMR (500 MHz, CDCl
ꢀ
1
3
): 3.89
13. Sandoval, W. N.; Pham, V.; Ingle, E. S.; Liu, P. S.; Lill, J. R. Comb. Chem. High
(
6
s, 2H, 3-CH
2
), 6.19 (t, 1H, J¼9.9 Hz, 5-H), 7.06 (d, 1H, J¼9.9 Hz, 4-H),
Throughput Screening 2007, 10, 751–765.
14. Collins, J. M.; Leadbeater, N. E. Org. Biomol. Chem. 2007, 5, 1141–1150.
13
.9–7.3 (m, 6H, Ph, H-6); C NMR (125 MHz, CDCl
3
): 35.80 (3-CH
2
),
1
5. (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223; (b) D ı´ az-Ortiz, A.; de
la Hoz, A.; Moreno, A. Chem. Soc. Rev. 2005, 157–168.
1
1
n
06.71 (5-C), 126.26 (p-C), 128.48 (m-C), 129.29 (o-C), 132.08 (3-C),
32.78 (6-C), 138.83 (4-C), 139.20 (i-C), 164.57 (C]O). IR (KBr):
¼3261, 2938, 1641, 1613, 1561, 1490, 1472, 1448, 774, 723,
16. Ward, R. S. Selectivity in Organic Synthesis; John Wiley and Sons: New York, NY,
1999.
ꢁ
1
1
7. (a) Langa, F.; de la Cruz, P.; de la Hoz, A.; D ı´ az-Ortiz, A.; D ı´ ez-Barra, E. Contemp.
Org. Synth. 1997, 373–386; (b) D ı´ az-Ortiz, A.; de la Hoz, A.; Moreno, A. Curr. Org.
Chem. 2004, 8, 903–918.
695 cm ; elemental analysis calcd (%) for C12H11NO (185.23): C
7
7.88, H 5.99, N 7.57; found: C 77.91, H 5.80, N 7.30.
18. Reutov, O. A.; Beletskaya, I. P.; Kurts, A. L. Ambident Anions; Plenum: New York,
6
.1.3. 5-Benzyl-2-pyridone (5)
Mp 114–115 C (ethyl acetate); H NMR (500 MHz, CDCl
NY, 1983.
ꢀ
1
19. Almena, I.; D ı´ az-Ortiz, A.; D ı´ ez-Barra, E.; de la Hoz, A.; Loupy, A. Chem. Lett.
3
): 3.66
1996, 333–334.
(
s, 2H, CH
2
-5), 6.48 (d, 1H, J¼14.4 Hz, H-3), 7.1 (dd,1H, J¼14.4 Hz, H-
2
0. (a) D ı´ az-Ortiz, A.; Carrillo, J. R.; Coss ı´ o, F. P.; G o´ mez-Escalonilla, M. J.; de la Hoz,
A.; Moreno, A.; Prieto, P. Tetrahedron 2000, 56, 1569–1577; (b) Fraile, J. M.;
Garc ı´ a, J. I.; G o´ mez, M. A.; de la Hoz, A.; Mayoral, J. A.; Moreno, A.; Prieto, P.;
Salvatella, L.; Vazquez, E. Eur. J. Org. Chem. 2001, 2891–2899; (c) Prieto, P.;
Coss ı´ o, F. P.; Carrillo, J. R.; de la Hoz, A.; D ı´ az-Ortiz, A.; Moreno, A. J. Chem. Soc.,
Perkin Trans. 2 2002, 1257–1263; (d) Pinto, D. C. G. A.; Silva, A. M. S.; Brito, C. M.;
Sandulache, A.; Carrillo, J. R.; Prieto, P.; D ı´ az-Ortiz, A.; de la Hoz, A.; Calvaleiro,
J. A. S. Eur. J. Org. Chem. 2005, 2973–2986; (e) Arrieta, A.; Otaegui, D.; Zubia, A.;
Coss ı´ o, F. P.; D ı´ az-Ortiz, A.; de la Hoz, A.; Herrero, M. A.; Prieto, P.; Foces-Foces,
C.; Pizarro, J. L.; Arriortua, M. I. J. Org. Chem. 2007, 72, 4313–4322; (f) Coss ı´ o, F.
P.; D ı´ az, A.; Rivacoba, A.; Lopez, X.; Carrillo, J. R.; de la Hoz, A. J. Am. Chem. Soc.,
submitted for publication.
13
4
), 7.2–7.7 (m, 5H, Ph), 7.40 (d, 1H, J¼2.7 Hz, H-6); C NMR
): 37.44 (5-CH ), 120.09 (3-C), 120.85 (5-C), 126.63
6-C), 128.66 (p-C), 128.70 (m-C), 132.68 (o-C), 139.21 (i-C), 143.93
4-C), 163.08 (C]O); IR (KBr):
(
125 MHz, CDCl
3
2
(
(
n
¼3057, 1654, 1597, 1543, 1490, 802,
ꢁ
1
732, 699 cm ; elemental analysis calcd (%) for C12 11NO (185.23):
H
C 77.88, H 5.99, N 7.57; found: C 78.13, H 5.82, N 7.92.
6.1.4. 3,5-Dibenzyl-2-pyridone (6)
ꢀ
1
Mp 93–94 C (ethyl acetate); H NMR (500 MHz, CDCl
H, CH -5), 3.84 (s, 2H, CH -3), 7.00 (s, 1H, H-4), 7.21 (s, 1H, H-6),
.9–7.4 (m, 10H, Ph); C NMR (125 MHz, CDCl ): 35.82 (3-CH ),
7.65 (5-CH ), 119.46 (5-C), 126.20 (p-C), 126.48 (p-C), 128.43 (6-C),
28.62 (m-C), 128.69 (m-C), 129.16 (o-C), 130.27 (o-C), 132.34 (3-C),
39.30 (i-C), 139.42 (i-C), 140.80 (4-C), 163.86 (C]O). IR (KBr):
3
): 3.65 (s,
2
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ꢁ1
n
¼3021, 1653, 1623, 1558, 1490, 1475, 1450, 737, 696 cm ; ele-
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3
Financial support from the DGICYT of Spain through project
CTQ2007-60037/BQU and from the Consejer ı´ a de Ciencia y Tecno-
log ı´ a JCCM through projects PBI-06-0020 and PCI-08-0040 is
gratefully acknowledged. We are grateful to Professor D.A. Liotard
for AMPAC/SM5.2 program improvements and his invaluable ad-
1
3
3
4. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,
J. V.; Gui, Q.; Baboul, A. G.; Clifford, S.; Gioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonz a´ lez, C.; Pople, J. A. Gaussian 03,
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vice, which allowed us to obtain S
A. Samat for fruitful discussions.
N
1 reactions paths, and Professor
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