Site selective processes: A combined theoretical and experimental investigation of thermally activated tautomerization processes in 2(2,4-dinitrobenzyl) pyridine derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00497-X

The thermally activated NH→CH tautomerization process in crystals of 2(2,4-dinitrobenzyl) pyridine derivatives was investigated. The results indicate the absence of any trivial molecular structure-reactivity correlation, in contrast to what is found for similar systems in solutions. The absence of molecular structure-reactivity correlation in the crystalline state is attributed to the participation of neighboring molecules in the proton transfer process. A combined experimental and theoretical approach is presented and applied to the study of the tautomerization reaction in crystalline environments. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00497-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6753±6771
Site Selective Processes: A Combined Theoretical
and Experimental Investigation of Thermally Activated
Tautomerization Processes in 2(2,4-Dinitrobenzyl)
Pyridine Derivatives
S. Khatib,a S. Tal,a,b O. Godsi,a U. Peskina,c and Y. Eichena,d,
*
aDepartment of Chemistry, TechnionÐIsrael Institute of Technology, Haifa 32000, Israel
bTechnion Excellence Program, TechnionÐIsrael Institute of Technology, Haifa 32000, Israel
cLise Meitner Center for Computational Quantum Chemistry, TechnionÐIsrael Institute of Technology, Haifa 32000, Israel
dSolid State Institute, TechnionÐIsrael Institute of Technology, Haifa 32000, Israel
Received 17 January 2000; revised 23 February 2000; accepted 3 March 2000
AbstractÐThe thermally activated NH!CH tautomerization process in crystals of 2(2,4-dinitrobenzyl) pyridine derivatives was investi-
gated. The results indicate the absence of any trivial molecular structure±reactivity correlation, in contrast to what is found for similar
systems in solutions. The absence of molecular structure±reactivity correlation in the crystalline state is attributed to the participation of
neighboring molecules in the proton transfer process. A combined experimental and theoretical approach is presented and applied to the
study of the tautomerization reaction in crystalline environments. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
and thermodynamics was rationalized in terms of a shell of
rare gas atoms,10 representing Van±der±Vaals interactions
but not including speci®c directional interactions such as
hydrogen bonds. In many other cases, such as in the case
of salicylidene anylides, a straightforward structure±reac-
tivity correlation could not be drawn for reactions in the
solid state.11
Tautomerization and proton-transfer (PT) processes have
been studied extensively in recent years due to their funda-
mental importance in many chemical and biological
processes and their in¯uence on different reaction mecha-
nisms.1 For example, different bacteriorhodopsin systems
having the same ammonium-retinal moiety embedded in
an only slightly different protein shell exhibit considerably
different PT properties.2,3 Evidence for site dependence in
solid-state chemical transformations can be found also in
numerous crystalline systems where a slight variation in
the environment of the reactants results in a signi®cant
change in activity or in mechanism path selection.4 Recent
publications5±7 reported the effect of the site on the determi-
nation of the absolute steric course of a photorearrangement
process in crystals of different ketones and in polyenes.8
In recent publications,12,13 different groups compared the
reactivity of several phototautomers of 2(2,4-dinitrobenzyl)
pyridine derivatives in single crystals and noted the absence
of any simple structure±reactivity correlation. Furthermore,
in recent reports,14 we have reported that the proton transfer
kinetics of the tautomerization process in crystalline phases
of 2(2,4-dinitrobenzyl)-3-methyl pyridine is sensitive to the
molecular packing.
Here we report on an experimental investigation of a
tautomerization process in different derivatives of 2(2,4-
dinitrobenzyl) pyridine and propose a theoretical approach
for modeling the reaction site effect in crystalline systems.
The approach is demonstrated in the study of the proton
transfer mechanism in crystals of 2(2,4-dinitrobenzyl)-3-
methyl pyridine.12
In most cases, rationalization of the experimental results
was restricted to effects at the isolated reacting molecule
level, ignoring its close packing within a solvation shell
or, at most, regarding the environment as simple restriction
to the molecular motion (reaction in a cage approach9). In
other cases the effect of the crystal on the reaction kinetics
Keywords: tautomerization; proton-transfer processes; structure±reactivity
correlation.
Results and Discussion
* Corresponding author. Tel: 1972-4-8293708; fax: 1972-4-8233735;
e-mail: chryoav@tx.technion.ac.il
Crystals of derivatives of 2(2,4-dinitrobenzyl) pyridine
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00497-X

6754
S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
Scheme 1.
present a wealth of crystalline polymorphs of which some
are photoactive while others are photoinert.12c The photo-
active crystals develop a blue color upon UV (l,430 nm)
irradiation due to the formation of two metastable photo-
tautomers.11±13 Scheme 1 outlines the photoinduced and
thermally activated tautomerization processes that take
place in the crystalline state.12 The possible existence of
an unidenti®ed dark metastable state was also reported.12c,d
Typically, the blue color of the NH form decays homo-
geneously in the dark, an indication of the thermally
activated NH!CH tautomerization process. Investigation
of the thermally activated NH!CH process revealed a
strong primary isotope effect, an indication that the proton
transfer process is the rate determining step and that it is
associated with only minor structural reorganization
energy.12 In crystals of 2(2,4-dinitrobenzyl) pyridine.12,13
1, 2(2,4-dinitrobenzyl)-4-methyl pyridine, 2, 2(2,4-dinitro-
benzyl)-5-methyl pyridine, 3, 2(2,4-dinitrobenzyl)-6-
methyl pyridine,12 4, and 1(2,4-dinitrophenyl)-1(2-pyridyl)
ethane, 5, the thermally activated NH!CH tautomerization
process follows a monoexponential decay, while in the case
of 2(2,4-dinitrobenzyl)-3-methyl pyridine,12,14 6, the decay
follows a biexponential curve, indicating the coexistence of
two different types of NH phototautomers. Fig. 1 presents
the Arrhenius plots for the different systems. The resulting
activation energies and pre-exponential factors are summar-
ized in Table 1. Attempts to associate the experimental
activation energies for the different NH!CH tautomeri-
zation processes with molecular properties fail to demon-
strate any obvious correlation between molecular
characteristics and the observed kinetics. Intramolecular
parameters for the different crystals, Table 2, also fail to
reveal any consistent correlation between the molecular
structure and reactivity, as was previously reported for simi-
lar DNBP derivatives in solutions.19 Furthermore, the
signi®cant difference in the experimental activation
energies observed for the NH!CH process in two different
phases of the same molecular specie, 6, Fig. 2, provides
Figure 1. Arrhenius plot of the NH decay constants for the different crystals: (1) 2(2,4-dinitrobenzyl) pyridine,13 (2) 2(2,4-dinitrobenzyl)-4-methyl pyridine,
(3) 2(2,4-dinitrobenzyl)-5-methyl pyridine, (4) 2(2,4-dinitrobenzyl)-6-methyl pyridine,12a (5) 1(2,4-dinitrophenyl)-1(2-pyridyl) ethane, (6a) low temperature
phase of 2(2,4-dinitrobenzyl)-3-methyl pyridine,14a (6b) high temperature phase of 2(2,4-dinitrobenzyl)-3-methyl pyridine.14a

S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
6755
Table 1. Kinetic data for the NH!CH process in the various systems
and gas-phase in two major points. In crystals, the molecular
species usually adopt only one preferred conformation and
this molecular species is con®ned in a well-de®ned static
environment of neighboring molecules. Therefore, our
understanding of chemical processes in solutions cannot
be applied for such processes.
Crystal and phase
Ea (Kcal mol21
)
Log (A)
2(2,4-dinitrobenzyl) pyridinea
2(2,4-dinitrobenzyl)-4- methyl
pyridine
22.0^0.5
19.7^0.4
11.8^0.3
10.0^0.5
2(2,4-dinitrobenzyl)-5- methyl
pyridine
2(2,4-dinitrobenzyl)-6- methyl
pyridinea
1(2,4-dinitrophenyl)-1-(2-
pyridyl) ethane
2(2,4-dinitrobenzyl)-3- methyl
pyridinea (phase A)
15.9^0.3
22.8^0.3
14.5^0.5
27.4^0.8
18.9^0.2
8.9^0.3
12.3^0.3
7.8^0.5
15.2^1.1
10.3^0.3
2(2,4-dinitrobenzyl)-3- methyl
pyridinea (phase B)
a After Ref. 12a
strong evidence that the supramolecular structure (environ-
ment) plays an important role in controlling the tautomeri-
zation process. Chemical processes in crystalline
environments differ from similar processes in solutions
Table 2. Intramolecular parameters in crystals of 2(2,4-dinitrobenzyl) pyridine derivatives
Crystal
1
2
3
4
5aa
5ba
6Ab
6Bb
Pyridine±Phenyl (8)
o-Nitro-phenyl (8)
p-Nitro-phenyl (8)
65.1
31.7
12.3
3.02
3.06
2.35
56.9
41.7
15.3
2.95
3.12
2.35
90.7
161.3
167.52
3.03
3.04
2.40
55.0
40.1
12.32
2.96
3.09
2.43
115.1
44.4
7.1
3.17
±
2.47
114.8
35.7
6.3
3.22
±
2.38
56.10
40.80
14.20
3.12
3.01
2.47
68.31
29.70
8.20
3.12
2.95
2.38
Ê
N1±H1 (A)
Ê
N1±H2 (A)
Ê
O1±H1 (A)
a 5a and 5b are the two nonequivalent molecules 5 in the same unit cell.
b 6A and 6B molecule 6 in phases A and B, respectively.
Figure 2. Crystal structure of the two different phases of 2(2,4-dinitrobenzyl)-3-methyl pyridine, phase A in sticks and phase B in balls and sticks.

6756
S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
atoms (.102) required for the construction of a realistic
model for the molecule embedded in its environment
(vide infra) currently limits our quantum chemical descrip-
tion to semi-empirical Hartree±Fock calculations.15
The theoretical treatment is based on the following scheme.
(a) The crystallographic structure of the product (the
thermally stable tautomer CH) is revealed experimentally
from X-ray crystallography. All computational treatments
are based on this structure. (b) The reactants (the NH
tautomers) are photogenerated in high dilution. Therefore,
they are isolated from one another and are surrounded by a
large number of non reacting molecules. Thus, the pertur-
bation to the crystalline structure during the reaction is
assumed to be nil. (c) Local site effects control the stability
of the reactants. Collective effects such as coupling to
H-bond networks or coupling to ¯oppy global lattice
phonons are ignored within this approximation. (d) Local
site effects can be represented approximately by a compact
model for the reacting molecule in its solvation shell.
Within this model, lattice constraints are represented arti-
®cially by ®xing selected atoms of the molecular skeleton at
their crystallographic coordinates. Naturally, the goal of
such an approach is to minimize the number of geo-
metrically constrained atoms in the reacting molecule in
order to allow molecular motion along the tautomerization
process. (e) The free motion of side groups, which liberate
signi®cantly in the crystal (such as methyl and nitro
groups17), is not restricted arti®cially during the tautomer-
ization process.
Figure 3. Atom labeling in 2(2,4-dinitrobenzyl)-3-methyl pyridine, (6).
In the following, a combined theoretical±experimental
approach is proposed in order to gain better understanding
of chemical processes taking place in such geometrically
restricted environments. As an example the case of
2(2,4-dinitrobenzyl)-3-methyl pyridine, 6, is studied.
The theoretical approach
Two different routes were chosen for dealing with geo-
metrically restricted systems. (a) A common approach
associates the crystal with an inert cage which imposes
well de®ned and rigid geometrical constraints on the react-
ing molecule. This reaction in a cage approach9 is often used
to describe reactions in rare gas matrices. Here, the assump-
tion is that geometrical differences in conformation may
result in different reaction paths and consequently in
different activation energies for the same processes. (b)
The alternative approach assumes that the crystal plays an
active role in the process (an active site). In such a case,
changes in the relative orientation between the reacting
molecule and speci®c functional groups in its solvation
shell may affect the ability of neighboring molecules to
participate in the process. For example, in the case of
2(2,4-dinitrobenzyl)-3-methyl pyridine the neighboring
molecules posses nitro and pyridine groups, that may act
as Lewis bases and affect the proton transfer process.
These groups are situated in close vicinity to the tautomeri-
zation reaction center. It is therefore possible that changes in
the relative orientation between the reacting molecule and
its neighbors will affect the ability of these molecules to
participate in the tautomerization process.
Reaction mechanism
Tautomerization processes in derivatives of DNBP are asso-
ciated with a three-center proton transfer reaction pro®le
and can take a direct path, NH!CH, or an indirect path
through OH intermediate states, NH!OH!CH. Previous
semi-empirical and DFT calculations suggest that reactions
along both paths involve the o-nitro group either as an active
intermediate, OH, or as a chaperon that escorts the moving
proton through a hydrogen bond, thus lowering the barrier
along the direct path.16 While the OH tautomer was not yet
observed in the two phases of 2(2,4-dinitrobenzyl)-3-methyl
pyridine, it was identi®ed as a metastable state in many
analogous systems.12,13 Therefore, both the direct and
indirect pathways should be considered in the theoretical
treatment.
Model A: a single constrained molecule
In order to determine the relative importance of these
different site effects, we have studied the NH!CH tauto-
merization processes in the two different phases of 2(2,4-
dinitrobenzyl)-3-methyl pyridine, 6. This system provides a
favorable test case for a computational study of site effects
for the following reasons: (a) the structure of the thermo-
dynamically stable tautomer and its environment is known
experimentally in both phases; (b) systematic errors
associated with the choice of speci®c computational
models should not be expressed in the difference between
the reaction paths. These errors are minimized since the two
different phases differ only slightly in terms of intra- and
intermolecular parameters (the same molecule in a slightly
different conformation). Nevertheless, the large number of
As a ®rst model, a single geometrically constrained
molecule is considered. At this level, the major conforma-
tional difference between the two phases of 2(2,4-dinitro-
benzyl)-3-methyl pyridine, 6, is expressed by the pyridine±
phenyl interplanar angle, being 56.18 in the low-temperature
phase (phase A) and 68.38 in the high-temperature phase
(phase B).14 This difference between the two phases was
represented by ®xing two carbon atoms on each ring
(atoms C2, C5, C11 and C13 in Fig. 3) to their Cartesian
crystallographic coordinates. All other molecular para-
meters were optimized using semi-empirical MOPAC
(PM3-SCF) electronic structure calculations. The resulting
optimized geometry in each phase constitutes the

S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
6757
nates vector. The mass-weighted normal mode force
con2stants are the eigenvalues3of2f (see Eq. (2)).
3
1
1
p
p
6
7
6
7
m1
m1
6
7
6
7
6
7
6
7
6
7
6
7
]
]
6
7
6
7
6
7
6
7
6
7
6
7
1
1
6
7
6
7
f ˆ 6
p
7´F´6
p
7
7
6
7
6
mi
mi
6
7
6
7
6
6
7
7
6
6
7
7
]
]
6
7
6
7
6
4
7
5
6
4
7
5
1
1
p
p
m3N
m3N
ꢀ2†
In order to impose the lattice constraints on the normal
modes in consistency with the constrained electronic struc-
ture calculations, we associate each constrained atom with
an arti®cial large mass, i.e. we let mi ! 1 (iˆ1,2,¼,n), so
that the elements of the corresponding ith row and ith
column of f approach zero, Eq. (3).
Figure 4. Calculated reaction pro®les (circles and squares for phases A and
B respectively) for the direct and indirect NH!CH reactions within a
model of a single constrained molecule (the full line is for illustration,
see text for constrained atoms).
2
3
0
6
6
6
6
7
7
7
7
.
.
.
compact model for the thermally stable CH tautomer.
The crystallographic structure of the NH phototautomer
and the transition-state, TS, are experimentally unknown.
However, according to our basic model assumptions, the
interplanar ring in the NH phototautomer is kept as in the
thermally stable CH phototautomer during the tautomeri-
zation process.18 Therefore, the structure of the NH photo-
tautomer was determined within the same geometrical
constraints as above. Once the constrained structures of
the reactant NH and the product CH tautomers were
realized, the transition states for the direct NH!CH and
the indirect NH!OH!CH tautomerization reactions were
determined using a saddle point search algorithm19
subjected to the same geometrical constraints. Unlike in
the case of unconstrained molecule in the gas phase, the
TS geometry is not an extreme point on the full 3N-6 dimen-
sional molecular potential energy surface. Assuming that n
atoms were ®xed to their crystallographic locations (where
n.1), the TS is a saddle-point on a 3 (N±n) dimensional
subsurface of the remaining active degrees of freedom. In
order to characterize the transition state frequencies, a
constrained normal mode analysis was carried out at the
saddle-point geometry. Denoting the Cartesian coordinates
of N atoms as Xˆ(x1,x2,¼,x3N), the nuclear Hamiltonian at
the saddle point is approximated (harmonically) as Eq. (1)
6
7
6
7
f ! 6 0
¼
0
¼
0 7
7
ꢀ3†
m !1 6
i
6
6
6
4
7
.
.
.
7
7
5
0
Diagonalization of this arti®cial mass-weighted Hessian
matrix yields only (3N23n) non-zero force constants
(eigenvalues), associated with the normal modes of the
active (3N23n) nuclear degrees of freedom.
Fig. 4 presents the energy pro®le calculated for a single
isolated constrained molecule along the different reaction
paths. The model of a single constrained molecule fails to
reproduce the relative stability of the different phases as was
observed experimentally. One barrier was found along the
NH!CH direct path. Along the indirect path, two barriers
were allocated, corresponding to the two consecutive
processes, NH!OH and OH!CH. All calculated values
for the different paths are depicted in Table 3. These calcu-
lations, based on the model of a single constrained
molecule, show no signi®cant difference between the two
phases in terms of the energetics along the indirect reaction
path and a somewhat lower barrier in phase A along the
direct path. Similar results were obtained when the
constraints were placed on atoms (C1, C4, C8 and C11 in
Fig. 3), Table 3. In this case, the molecules are allowed
some motion along the ring axes. These results do not
agree with the experimentally measured difference in the
t
t
1
_
_
Hnuc
ˆ
2 X MX 1 12 X FX
ꢀ1†
where M is a diagonal matrix whose non-zero elements are
the nuclei masses, Mi,jˆmidi,j, F the Hessian matrix in
Cartesian coordinates and Xt denotes the transposed coordi-
Table 3. Calculated electronic energies (corrected for zero point energy) (kcal mol21) along the NH!CH reaction path for a single constrained molecule
Phase A C2,C5,C11,C13
Phase B C2,C5,C11,C13
Phase A C1,C4,C8,C11
Phase B C1,C4,C8,C11
CH
CHOH
OH
NH±OH
NH
NH±CH
164.62
202.35
194.55
212.43
178.04
241.95
164.50
202.38
194.01
211.79
176.91
246.34
162.06
205.32
196.61
203.41
177.93
217.25
163.03
204.17
197.60
205.56
179.45
217.18

6758
S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
mations originating from the different phases exhibit
different behavior. Although the same calculation cannot
be easily performed on the indirect path due to problems
originating from imposing constrains on the o-nitro group it
is expected that libration (the dynamics of the nitro group)
plays an even more important role along the indirect path.
Detailed investigation of the relative orientation of the
reacting molecule with respect to its ®rst shell neighbors
in the two different phases show a signi®cant difference in
the distance between the o-nitro group of the reacting
molecule and atoms of neighboring molecules, Fig. 6.
Additionally, there is a signi®cant difference between the
crystals of the two phases in terms of the distance between
different Lewis bases and protons of neighboring molecules
and the groups participating in the process (active proton,
nitrogen atom of the pyridine ring, o-nitro group) within the
reacting molecule. It is therefore desirable to include the
effects of the environment within a more realistic model.
Figure 5. Calculated activation energy for a single constrained molecule in
the two phases as a function of the (constrained) interplanar angle between
the o-nitro and the phenyl ring (the full line is for illustration, see text for
constrained atoms).
Model B: Compact models for the crystalline
environment
reaction activation energy between the two phases
(EaB2EaAˆ28.45 kcal mol21).
A major effort in our approach is to determine the number of
neighbors, which are required for a reliable representation
of the reaction site with a minimal number of constrained
atoms in the reacting molecule. The following selection
process is proposed, and tested for the 2(2,4-dinitro-
benzyl)-3-methyl pyridine, 6, system. The constraints,
based on the crystallographic structure of the CH tautomer,
were set as follows: All skeleton atoms of selected neigh-
boring molecules were ®xed, assuming only negligible
perturbation to their structure due to the tautomerization
process. Hydrogen atoms (of which the crystallographic
coordinates are not accurate20) and nitro groups, which
exhibit signi®cant libration in the crystal, were not
constrained. In the reacting molecule, selected atoms were
®xed to their crystallographic coordinates in order to further
restrict the motion. All other coordinates were optimized
computationally, using mopac PM3-SCF. The structures
of the NH and the different OH tautomers were determined
as above within the same constraints. The calculated atomic
coordinates of the reacting molecule were compared to the
crystallographic structure, and a measure for the difference
The role of the o-nitro group
Another possible difference in the crystalline structure of
2(2,4-dinitrobenzyl)-3-methyl pyridine, 6, is expressed in
the libration of the o-nitro group of the reacting molecule
within the crystal lattice. Differences in crystal packing may
limit the motion of the o-nitro group and thus affect the
ability of this group to participate in the process. We have
therefore investigated the in¯uence of ®xing the o-nitro-
phenyl interplanar angle on the calculated reaction barrier
along the direct path. The angle was set and frozen by ®xing
the nitrogen atom (N2) and an oxygen atom (O1) to their
positions. All other parameters in the calculations were
identical to the ones reported for the ®rst model of an
isolated constrained molecule (C2, C5, C11 and C13 in
Fig. 3). Fig. 5 depicts the calculated activation enthalpy as
a function of the o-nitro-pheny interplanar angle. As can be
seen from Fig. 5, the ability of the static o-nitro group to
assist in the proton transfer along the direct path is angle-
dependent. Additionally, the different molecular confor-
Figure 6. Supramolecular arrangement of 6 in phases A (left) and B (right) viewed along the c axis.

S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
6759
Figure 7. A plot of the distance, D, as a function of the number of neighboring molecules in the cases of four (1Ð phase A, £Ð phase B) and one (BÐ
phase A, XÐ phase B) constrained atoms. See Table 4 for the speci®c identity of each molecule and text for constraint atoms.
between the model calculation and the experimental
structure was de®ned as the distance D, Eq. (4), where
N is the number of heavy (non H) atoms in the reacting
molecule and X is the vector of Cartesian atomic
coordinates.
tion path. Therefore, calculations that take into account
higher number of neighbors and less intramolecular
constraints are favorable. Another measure of the reliability
of the computational model is the comparison of the differ-
ences in enthalpy between the two phases. Fig. 8 depicts the
calculated lattice enthalpy (per molecule) in the different
models as a function of the number of molecules. The lattice
energy calculated for phase A is lower than the one calcu-
lated for phase B, regardless of the particular model. This is
in consistency with the experimental data.14 Interestingly,
the enthalpies of formation calculated for a single isolated
molecule adopting the conformation at the two phases do
not differ signi®cantly. This degeneration is lifted, however,
upon the introduction of a molecular environment.
v
u
3N
X
u
t
1
2
D ˆ
ꢀXical 2 Xiexp
†
ꢀ4†
N
iˆ1
Fig. 7 depicts the distance, D, as a function of the number of
neighboring molecules for different constraints imposed on
the reacting molecule, Table 4. When four atoms are
constrained in the reacting molecule so that the inter-ring
angle is ®xed (Model B4, C1, C4, C8, C11 in Fig. 3) the
molecular geometry is essentially ®xed by the constraints.
Consequently, the structure of the reacting molecule, as
expressed by the distance, D, is insensitive to the number
and identity of the neighboring molecules. When only a
single atom in the reacting molecule is constrained
(Model B1, C7 in Fig. 3), the distance, D, becomes depen-
dent on the number and the identity of the neighboring
molecules. Nevertheless, ®ve to seven neighboring mole-
cules are suf®cient in order to converge the in¯uence of
the molecular environment on the geometry of the reacting
molecule. This holds for the thermodynamically stable CH
tautomer as well as for the NH and OH phototautomers.
Minimizing the number of constrained atoms in the reacting
molecule is crucial for a reliable representation of the reac-
These thermodynamic studies demonstrate that it is possible
to represent realistically the local in¯uence of the lattice on
the reacting molecule, by a relatively small number of
neighbors. A detailed calculation of the reaction path and
the activation energy within such a compact model is
currently in progress.
Conclusions
Surroundings effects on intra-molecular PT processes in
crystals of 2(2,4-dinitrobenzyl) pyridines were studied and
characterized in terms of energetics and mechanism. A
combined experimental±theoretical approach based on
Table 4. The distances, D, in the two models, as a function of the number of molecules in the calculation.
Ê
D (A)
Molecule added to the model
Symmetry
Model B4 Phase A
Model B4 Phase B
Model B1 Phase A
Model B1 Phase B
1
2
3
4
5
6
7
8
x, y, z
x, y, 11z
x, y, 12z
x, (1/2)2y, (1/2)1z
2x, (1/2)1y, (1/2)2z
2x, 2y, 2z
0.07
0.04
0.04
0.05
0.05
0.04
0.03
0.03
0.05
0.04
0.04
0.04
0.04
0.03
0.03
0.03
0.07
0.40
0.40
0.15
0.15
0.12
0.11
0.11
0.38
0.40
0.96
0.46
0.45
0.10
0.08
0.07
12x, 2y, 12z
2x, 2y, 12z

6760
S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
pyridine12a were prepared according to previously published
procedures.
Apparatus
Time dependent absorption spectra were measured on a
Cary 1E (Varian) spectrophotometer. Time dependent
optical density curves were recorded using a PC-controlled,
home-made, spectrometer having
a
Nd:YAG laser
(lˆ355 nm) or a Mercury lamp equipped with an appro-
priate ®lter (UG11, Schott) as the exciting light beam. The
detection system consisted a liquid nitrogen cooled CCD
(Princeton Instruments) connected to a 150i spectrograph
(Acton Research) or a photomultiplier system. A liquid
nitrogen cooled optical cryostat (Oxford, Instrument, DN
1704) equipped with a temperature controller (Lake Shore
330, Cryotronics) was used to regulate the temperature of
the samples. All experiments were performed in high dilu-
tion, photoexciting only a very small (p0.1%) part of the
molecules in the crystal. Semi-empirical calculations were
carried out using a modi®ed mopac93 package.15 The code
was modi®ed in order to enable a constrained transition-
state search and constrained normal mode analysis.
Figure 8. Calculated lattice enthalpy (per molecule) as a function of the
number of molecules: (a) four constrained atoms (C1, C4, C8 and C11); (b)
one constrained atom (C7).
constrained compact models for the reaction site was intro-
duced and applied to the study of proton transfer in 2-(2,4-
dinitrobenzyl)-3-methyl pyridine. It was found that
differences in the molecular packing in two crystalline
phases affect signi®cantly the calculated energy pro®le
along the different reaction paths, as suggested by the
thermodynamic and kinetic measurements. The insight
gained by the different models implies that the intra-
molecular o-nitro group activates the direct NH!CH PT
reaction and that interactions between this group and neigh-
boring molecules in the reaction site affect dramatically the
PT reaction pro®le.
2-Benzyl-4-methyl pyridine. Benzyl bromide (2.68 g,
0.014 mol) was added dropwise to a suspension of activated
zinc dust (3.8 g, 0.058 mol) in dry THF under argon
atmosphere. As soon as the ¯ask reaches room temperature,
the solution was ®ltered under inert atmosphere and added
to a mixture of 2-bromo-4-methyl pyridine (2 g, 0.011 mol)
and [ph3P]4Pd (0.1 g, 0.086 mmol) in 25 ml dry THF under
argon. The mixture was stirred overnight then evaporated
and ®ltered using a short alumina column. The product was
Presently, the proposed theoretical approach relies on
experimental crystallographic data and it is limited to
ordered single crystals whose stable structure can be deter-
mined experimentally. It is also assumed that the PT reac-
tion is in high dilution, so that the crystal structure does not
change during the reaction. The main advantage of the
present approach is the ability to treat speci®c molecular
interactions in the reaction site and to characterize their
effects on reaction energetics and mechanism. However,
the model is currently limited to short range local inter-
actions and neglects long-ranged (global) effects that are
likely to be of important in some cases. Even so, when
only the ®rst solvation shell is considered, the number of
atoms is large (typically .102) and the present calculations
were limited to the semi-empirical Hartree±Fock level. We
anticipate that optimized choices of the constraints would
enable us to obtain smaller realistic models, which will
enable calculations at ab initio levels.
1
isolated as a colorless viscous oil, 2.1 g, 99% yield. H
NMR(CDCl3): dppm; 2.25(s, 3H); 4.09(s, 2H); 6.9(s, 2H);
7.25(m, 5H); 8.4(d, 1).
2-Benzyl-5-methyl pyridine. Benzyl bromide (2.17 g,
0.011 mol) was added dropwise to a suspension of activated
Zn dust (3.8 g, 0.058 mol) in dry THF under argon atmos-
phere. As soon as the ¯ask reaches room temperature, the
solution was ®ltered under inert atmosphere and added to a
mixture of 2-bromo-5-methyl pyridine (2 g, 0.011 mol) and
[ph3P]4Pd (0.1 g, 0.086 mmol) in 25 ml dry THF under
argon. The mixture was stirred overnight then evaporated
and ®ltered using a short alumina column. The product was
1
isolated as a colorless viscous oil, 1.7 g, 80% yield. H
NMR(CDCl3): dppm 2.26(s, 3H); 4.09(s, 2H); 6.95(d, 1H);
7.2(m,6H); 8.3(s, 1H).
1-Phenyl-1(2-pyridine) ethane. Butyl lithium 2.5 M solu-
tion in hexane (5.5 ml) were added dropwise to 2-benzyl-
pyridine (1.9 g, 11.24 mmol) in dry THF under argon
atmosphere at 2308C. Methyl iodide (1 ml, 16 mmol) was
added after 20 min and the solution was allowed to reach
room temperature. After stirring the solution for three hours
the THF was evaporated and the product was chromato-
graph (alumina, ether/hexane 30:70) to yield 1.97 g (96%)
of the product 1H NMR(CDCl3): dppmˆ1.66(d, 3H); 4.26(q,
1H); 7.1(m, 2H); 7.2(m, 5H); 7.53(t, 1H); 8.5(d, 1H).
Experimental
Materials
All reagents were used as received unless noted. 2-benzyl
pyridine derivatives were prepared by [ph3P]4Pd catalyzed
heterocoupling between benzylzincbromide and the appro-
priate 2-bromopyridine derivative. 2-benzyl-3-methyl pyri-
dine,12a 2-benzyl-6-methyl pyridine,12a 2(2,4-dinitrobenzyl)
-3-methyl pyridine12a and 2(2,4-dinitrobenzyl)-6-methyl
2(2,4-Dinitrobenzyl)-4-methyl pyridine (2). 25 ml of cold
sulfuric acid were added dropwise to 2-benzyl-4-methyl

S. Khatib et al. / Tetrahedron 56 (2000) 6753±6761
6761
pyridine, (1 g, 5.46 mmol) at 2108C, and stirred for several
References
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basic using ammonia solution and extracted with three
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This research was supported by the US±Israel Binational
Science Foundation (BSF), the Israel Science Foundation
(ISF), the Israeli Ministry of Science and the foundation
for promotion of research at the Technion.