*Author for correspondence e-mail: ramchemi@intnet.mu
1
Lydia Rhyman
BSc(Hons) Chemistry
University of Mauritius
2
1) Introduction
2) Computational Methods
3) Results and Discussion
4) Conclusion
5) Future Work
3
What is 1,3-dipolar cycloaddition?
1,3-Dipolar cycloaddition (1,3-DC), as laid out by Huisgen and coworkers in
the early 1950s, is the union of a 1,3-dipole with a multiple bond system.
Since the systematic classification of 1,3-DC, these reactions have been
extensively studied.
1,3-Dipole: a three atoms π-electron system with four delocalised π-electrons.
b
b
a
c
d
e
a
c
d
e
Dipolarophile: usually olefins, acetylenes or other multiple bonds.
R. Huisgen, Angew. Chem., Int. Ed. Engl. 2 (1963) 565.
R.R. Kumar, S. Perumal, S.C. Manju, P. Bhatt, P. Yogeeswari and D. Sriram, Bioorg. Med. Chem. Lett. 19 (2009) 3461.
G. Wagner, T.N. Danks and V. Vullo, Tetrahedron 63 (2007) 5251.
4
Importance of 1,3-dipolar cycloaddition
1-Substituted-pyridinium-3-olates have been extensively investigated as they
behave as 1,3-dipoles and undergo 1,3-DC reactions with a variety of
dipolarophiles.
One of the reasons for the interest in these cycloaddition reactions is that the
cycloadducts have a common structural unit, the 8-azabicyclo[3.2.1]octane
skeleton, which is a key building block in naturally occurring tropane
alkaloids.
The tropone derivatives are attractive synthetic target as they possess
potent biological activity such as atropine, scopolamine and cocaine.
The feasibility of these cycloaddition processes has been interpreted based
on the valence bond and frontier molecular orbital (FMO) treatment.
N. Dennis, A.R. Katritzky and Y. Takeuchi, Angew. Chem., Int. Ed. Engl. 15 (1976) 1.
B. Dräger, J. Chromatogr. A 978 (2002) 1.
S.M. Verma, B.K. Razdan and D. Sasmal, Bioorg. Med. Chem. Lett. 19 (2009) 3108.
5
Interplay between experiment and theoretical computation
In order to have a better understanding of the mechanistic pathway, a
detailed characterisation of the different steps involved in the reaction
sequence is required.
This is difficult by experimentation alone and its interpretation relies heavily
on quantum mechanical computation as the latter provides a direct tool for
providing physical insight into the nature of transition state.
Reaction mechanism with high accuracy can be predicted due to the
explosive growth of computational power and many excellent methods of
computations.
The reaction mechanisms of pyridinium-3-olates have received scant
attention and no theoretical study has yet been reported. Therefore, these
mechanistic details have been investigated and analysed theoretically to
understand the intimate details of the 1,3-DC.
J.J. Klici and R.A. Friesner, J. Phys. Chem. A 103 (1999) 1276.
6
The aim of this work is to provide a theoretical insight of the 1,3-DC of 1substituted-pyridinium-3-olates with methyl acrylate as shown below:
R
N
O
TS1-H
TS1-Me
O
H
N
P1-H
P1-Me
R
2a
2b
R=H
R=Me
CO2Me
R
N
O
MeO2C
1
TS2-H
TS2-Me
CO2Me
H
P2-H
P2-Me
Molecular geometries were optimised using DFT method with BHLYP, B3LYP
and BLYP as the functionals and the basis set employed was 6-311++G(d,p).
All computations were carried out with Gaussian 03 suite of software.
Frisch, M. J. et al., Gaussian 03, Revision B04, Gaussian Inc., Wallingford, CT, (2004).
7
•
Location of transition states
Transition states were ascertained by frequency computations and
characterised by only one imaginary vibrational mode.
•
Reactivity indexes
Global indexes were used to evaluate regioselectivity of the 1,3-DC using
the following equations:
Chemical potential, , is associated to charge transfer.
Chemical hardness, , determines the stability of the system.
Global electrophilicity index, ω, was also calculated based on  and .
L. R. Domingo, Tetrahedron 58 (2002) 3765.
T. A. Koopmans, Physics 1 (1933) 104.
R. G. Parr, L. von Szentpaly and S. Liu, J. Am. Chem. Soc. 121 (1999) 922.
8
•
Reaction rate constant
The rate constant was determined at 298.15 K using the conventional
transition state theory with the Wigner tunneling coefficient. According to
the standard Eyring TST, the rate constant, k, for a second-order reaction
is calculated as:
The Wigner coefficient is given by:
•
Solvent effects
Solvent effects were also taken into account by single point
computations by the polarizable continuum model using the integral
equation
formalism
variant,
developed
by
Tomasi’s
group.
Tetrahydrofuran and ethanol were used as solvents.
E. P. Wigner, Z. Phys. Rev. B 19 (1932) 203.
M. T. Cancès, B. J. Mennucci and J. Tomasi, J. Chem. Phys. 107 (1997) 3032.
B. Mennucci and J. Tomasi, J. Chem. Phys. 106 (1997) 5151.
9
Geometrical Parameters
The computed structural parameters of the reactants are shown below:
The conformation properties of methyl acrylate are first investigated and the
stable conformation is found to be the cis conformer. This is in good
agreement with the structure obtained by electron diffraction. This
preference is supported by the B3LYP/6-311++G(d,p) computation which
shows that the cis conformation is 2.76 kJ/mol lower in energy compared to
the trans conformation.
A. Brown and T. Gillbro, J. Polym. Sci., Part A: Polym. Chem. 9 (1971) 1509.
T. Egawa, S. Maekawa, H. Fujiwara, H. Takeuchi and S. Konaka, J. Mol. Struct. 352/353 (1995) 193.
10
Geometrical Parameters
An analysis of the structural parameters of methyl acrylate (1) shows that the
results are in perfect concordance with the experimental data as there is a
close relation between the predicted parameters and those obtained
experimentally.
Additionally, computations give cyclic structures for both the 1H-pyridinium 3olate (2a) and 1-methylpyridinium-3-olate (2b). All the DFT functionals are
correlated in their predictions with those reported for the related molecule
namely, 1-methyl-3-hydroxypyridinium chloride.
The geometrical changes are marginal as all the three functionals are
correlated in their predictions but B3LYP performs better when compared
with the experimental results while BHLYP and BLYP underestimate the
geometrical values.
M. Szafran, A. Komasa, A. Katrusiak, Z. Dega-Szafran and P. Barczyński, J. Mol. Struct. 844 (2007) 102.
11
Geometrical Parameters
During the cycloaddition process, various observations are made at the
transition state structures:
•
The planarity of the pyridinium ring is lost due to
changes occurring at the –C-NR-C moiety.
•
The C-1-C-5 bond is longer than the C-2-C-3 bond
and thus, resulting in asynchronous transition
state.
•
The synchronicity difference of TS1-Me and TS2Me is larger than TS1-H and TS2-H which
corresponds to the electron-donating ability of the
methyl group on the nitrogen.
•
The Wiberg bond order analysis is also in
conformity with the synchronicity differences
calculated.
H. Wang, Y. Wang, K. Han and X. Peng, J. Org, Chem. 70 (2005) 4910.
K. B. Wiberg, Tetrahedron 24 (1968) 1083.
12
Geometrical Parameters
Additionally, the imaginary frequencies of the transition states show that the
values for the exo TSs, TS2-H and TS2-Me, are slightly lower than for the endo
ones, TS1-H and TS1-Me. Hence, these results indicate that earlier TSs are
found since they have lower force constants for the two forming bonds.
It is of interest to note that the decrease in the imaginary frequency is parallel
to the increase of the asynchronicity of these reactions. Analysis of the atomic
movement associated with the unique imaginary frequency shows that it is
mainly the motion of C-2–C-3 bond formation.
TS1-H and TS1-Me are more polar then TS2-H and TS2-Me and the former have
larger dipole moments than their corresponding cycloadduct namely P1-H
and P1-Me. However, dipole moments of TS2-H and TS2-Me with P2-H and P2Me are comparable while the TSs are slightly more polar than their respective
cycloadducts. The same variational tendency is observed with the different
functionals used and thus suggesting that the results obtained are reliable.
13
Energetic
The table below shows the computed thermodynamics parameters of the
1,3-DC at 298.15 K and 1 atm.
B3LYP/6-311++G(d,p)
E
(au)
∆E
(kJ/mol)
∆H
(kJ/mol)
∆G
(kJ/mol)
∆S
(J/molK)
1
-306.468797
-
-
-
-
2a
-323.485661
-
-
-
-
2b
-362.777706
-
-
-
-
TS1-H
-629.924101
79.7
77.6
133.6
-187.8
TS2-H
-629.932180
58.5
56.0
113.6
-193.0
TS1-Me
-669.217199
76.9
74.6
132.9
-195.6
TS2-Me
-669.221427
65.8
63.2
122.7
-199.5
P1-H
-629.966470
-31.6
-35.7
23.9
-199.9
P2-H
-629.966993
-32.9
-37.0
22.3
-198.7
P1-Me
-669.255088
-22.5
-27.0
35.6
-209.9
P2-Me
-669.255682
-24.1
-28.6
33.9
-209.7
14
Energetic
Analysis of the activation energies for the TSs relative to the reactants reveals
that the exo approach is favoured over the endo approach; TS2-H and TS2Me are more stable than TS1-H and TS1-Me by 22.5 and 12.2 kJ/mol for BHLYP,
21.2 and 11.1 kJ/mol for B3LYP and 18.7 and 11.2 kJ/mol for BLYP,
respectively.
Hence, it can be concluded that substitution of hydrogen atom by the
methyl group on the nitrogen of 1-methylpyridinium-3-olate does not change
the course of the reaction pathway. The energy barrier is not sensitive to the
electron functions employed in the DFT computations as the change in the
activation energies is marginal.
Interestingly, the activation energies are close to that obtained
experimentally by Guiheneuf et al. for the cycloaddition of 2b to 1,
79.1 kJ/mol .
G. Guiheneuf, C. Laurence and A.R. Katritzky, J. Chem. Soc., Perkin Trans. 2 (1976) 1829.
15
Energetic
The computed activation enthalpies for the 1,3-DC range from 67.7 (BHLYP) to
80.0 (BHLYP) kJ/mol which is in close agreement with the experimental value,
77.4 kJ/mol. It is interesting to note that the activation enthalpies for the exo
approaches in all cases are lower compared to the endo ones.
It is also observed that all the cycloaddition are exothermic processes and the
exo cycloadducts are slightly more stable than the endo ones. These results
suggest that the pathway leading to the exo cycloadduct is preferentially
followed both in terms of kinetic and thermodynamic viewpoints.
According to experimental studies, a mixture of the two major isomers is
obtained and therefore, the theoretical computations support this
observation as there is a close energy difference between these two endo
and exo cycloadducts.
G. Guiheneuf, C. Laurence and A.R. Katritzky, J. Chem. Soc., Perkin Trans. 2 (1976) 1829.
N. Dennis, A.R. Katritzky and Y. Takeuchi, Angew. Chem., Int. Ed. Engl. 15 (1976) 1.
16
Energetic
A schematic representation of the energy profiles along the endo and exo
attacks of the dipolarophile 1 to the dipoles 2a and 2b is presented below:
85.0
65.0
45.0
25.0
5.0
-15.0
-35.0
TS1H
85.0
TS1Me
TS2H
65.0
TS2Me
45.0
25.0
5.0
-15.0
-35.0
In general, it can be seen from the energy profiles that the Bell-EvansPolanyi-Leffler-Hammond rule holds as an increase in the exothermicity of
the reaction is accompanied by a lower activation energy.
J. E. Leffler, Science 117 (1953) 340.
G. S. Hammond, J. Am. Chem. Soc. 77 (1955) 334.
R. P. Bell, Proc. R. Soc. London, A 154 (1936) 414.
M. G. Evans and M. Polanyi, Trans. Faraday Soc. 32 (1936) 1333.
17
Frontier Molecular Orbital Analysis
The figure below shows a better picture of the FMO analysis computed at
B3LYP/6-311++G(d,p).
The (HOMOdipole – LUMOdipolarophile) interaction will mainly control
the reactivity due to the small energy difference between them.
18
Frontier Molecular Orbital Analysis
The HOMO of 2a is slightly lower than that of 2b
due to the presence of the substituent. This fact
causes
the
energy
gap
of
(HOMO2b–
LUMOdipolarophile) to have a smaller energy
separation and consequently, lowering the
activation energies. This agrees with Sustmann’s
type I reaction.
It is worth pointing out that the presence of –
CO2Me group exerts an electron-withdrawing
effect which tends to reduce the LUMO energy
compared to ethene. As a result, there is an
efficient decrease of the energy gap. This may be
the reason to account for the successful 1,3-DC
reactions with olefinic dipolarophiles bearing
strong electron-withdrawing groups only.
R. Sustmann, W. Sicking, Chem. Ber. 120 (1987) 1653.
R. Sustmann, W. Sicking, Chem. Ber. 120 (1987) 1471.
N. Dennis, A.R. Katritzky and Y. Takeuchi, Angew. Chem., Int. Ed. Engl. 15 (1976) 1.
HOMO of 2b
LUMO of 2b
19
Reactivity Indexes
In recent years, reactivity indexes have become useful means to study the
reactivity of cycloaddition reactions.
B3LYP/6-311++G(d,p)
1
2a
2b
HOMO(au)
-0.290
-0.210
-0.205
LUMO(au)
-0.063
-0.072
-0.068
μ(au)
-0.176
-0.141
-0.137
η(au)
0.227
0.139
0.137
ω(eV)
1.86
1.95
1.86
∆Nmax(au)
0.775
1.018
0.998
The table above shows that μ(2a) is greater than μ(1), thereby indicating that
charge transfer will take place from dipole to dipolarophile. This is in line with
the small energy gap observed during FMO analysis.
The electrophilicity value of 1 is classified as a strong electrophile according to
the electrophilicity scale. However, 2a presents an electrophilicity value larger
than 1 while 2b has a lower value. Thus, even though 2a is classified as a
strong electrophile, it has a high chemical potential which is the index that
determines the direction of the electronic flux along the cycloaddition.
L. R. Domingo, M. J. Aurell, P. Pérez and R. Contreras, Tetrahedron 58 (2002) 4417.
P. Pérez, L. R. Domingo, M. J. Aurell and R. Contreras, Tetrahedron 59 (2003) 3117.
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Reaction Rate Constant
Reaction Pathway
1 + 2a → P1-H
1 + 2a → P2-H
1 + 2b → P1-Me
1 + 2b → P2-Me
Rate constant (cm3/mol/s)
4.83 × 10-8
2.95 × 10-4
6.87 × 10-8
6.83 × 10-6
6.56 × 10-7
3.17 × 10-3
8.73 × 10-7
5.26 × 10-5
7.86 × 10-7
6.28 × 10-4
9.83 × 10-7
3.55 × 10-5
It turns out from these results that TS2-H and TS2-Me have higher rate
constants compared to TS1-H and TS1-Me and this may be due to their lower
activation energies. Moreover, the rate constant of TS2-H is higher than that
of TS2-Me as formation of TS2-H has lower activation energy and thus is
formed faster. However, changing the substituent from hydrogen to methyl
group results in comparable rate constants of TS1-H and TS1-Me as their
formation have similar energy barriers.
21
Solvent Effects
As these 1,3-DC reactions have polar character, solvent effect has also been
taken into account. All the species are stabilised in the solvents with the
reactants being more stable than the TSs. As a result, the activation energy for
all the cycloaddition processes increases considerably.
However, due to the large dielectric constant for ethanol (ε = 24.85), the
activation energies for the 1,3-DC is lower than that in THF (ε = 7.43). Solvation
computations do not influence the 1,3-DC as there are no relevant
differences in the reaction mechanism features when compared to the gas
phase and the exo transition states remain the least energetically favourable
in the two solvents used.
22
The main conclusions are given below:
1. The geometrical parameters of the TSs analysis show that the 1,3-DC is an
asynchronous reaction by calculating the synchronicity differences. This
has been further confirmed by using the Wiberg bond indices.
2. For both reaction pathways, the exo cycloadducts are kinetically and
thermodynamically favoured over the endo ones. In addition, substitution
of hydrogen by methyl on the 1,3-dipole does not affect the activation
energies.
3. The FMO analysis shows that the regioselectivity of the 1,3-DC is
controlled by (HOMOdipole – LUMOdipolarophile) interactions.
4. Rate constants for transition state formations correlate well with the
activation energies.
5. Solvent effects do not influence the 1,3-DC as there are no significant
differences in the reaction pathway from kinetic and thermodynamic
point of views when compared to the gas phase. Hence, the exo
transition states remain the least energetically favourable in the two
solvents used.
23
In order to extend our study, the cycloaddition reaction of 1substituted-pyrazinium-3-olate
will
be
studied
both
experimentally and theoretically with methyl acrylate and
methyl methacrylate.
Me
N
R
N
O
R
O
R
R
N
Me
MeO2C
N
R
CO2Me
R
R = H, Me
24
 Doctorial Consortium Organiser
 Tertiary Education Commission
 University of Mauritius
 Universiti of Sains Malaysia
25