*Author for correspondence e-mail: ramchemi@intnet.mu1

Lydia RhymanBSc(Hons) Chemistry University of Mauritius

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3

1)1) IntroductionIntroduction

2)2)Computational MethodsComputational Methods

3)3)Results and Discussion Results and Discussion

4)4)Conclusion Conclusion

5)5)Future Work Future Work

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What is 1,3-dipolar cycloaddition?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.

ab

c

d e

ab

c

d e

1,3-Dipole: a three atoms π-electron system with four delocalised π-electrons.

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.

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Importance of 1,3-dipolar cycloadditionImportance 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.

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Interplay between experiment and theoretical Interplay between experiment and theoretical computationcomputation

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.

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The aim of this work is to provide a theoretical insight of the 1,3-DC of 1-substituted-pyridinium-3-olates with methyl acrylate as shown below:

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).

N

R

O

MeO2C

1

2a R=H2b R=Me

N

CO2Me

R

O

H

N

H

R

O

CO2MeP1-Me

P2-Me

TS1-Me

TS2-Me

TS1-H

P1-H

TS2-H

P2-H

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• Location of transition statesTransition states were ascertained by frequency computations and characterised by only one imaginary vibrational mode.

• Reactivity indexesGlobal 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.

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• Reaction rate constantThe 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.

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Geometrical Parameters

The computed structural parameters of the reactants are shown below:

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.

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.

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Geometrical Parameters

M. Szafran, A. Komasa, A. Katrusiak, Z. Dega-Szafran and P. Barczyński, J. Mol. Struct. 844 (2007) 102.

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 3-olate (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.

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Geometrical ParametersDuring the cycloaddition process, various observations are made

at the transition state structures:

H. Wang, Y. Wang, K. Han and X. Peng, J. Org, Chem. 70 (2005) 4910.K. B. Wiberg, Tetrahedron 24 (1968) 1083.

• 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 TS2-Me 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.

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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 P2-Me 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.

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Energetic

B3LYP/6-311++G(d,p)E

(au)∆E

(kJ/mol)∆H

(kJ/mol)∆G

(kJ/mol)∆S

(J/molK)

1 -306.46879

7

- - - -

2a -323.48566

1

- - - -

2b -362.77770

6

- - - -

TS1-H -629.92410

1

79.7

77.6 133.6 -187.8

TS2-H -629.93218

0

58.5

56.0 113.6 -193.0

TS1-Me

-669.21719

9

76.9

74.6 132.9 -195.6

TS2-Me

-669.22142

7

65.8

63.2 122.7 -199.5

P1-H -629.96647

0

-31.6

-35.7 23.9 -199.9

P2-H -629.96699

3

-32.9

-37.0 22.3 -198.7

P1-Me -669.25508

8

-22.5

-27.0 35.6 -209.9

P2-Me -669.25568

2

-24.1

-28.6 33.9 -209.7

The table below shows the computed thermodynamics parameters of the 1,3-DC at 298.15 K and 1 atm.

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Energetic

G. Guiheneuf, C. Laurence and A.R. Katritzky, J. Chem. Soc., Perkin Trans. 2 (1976) 1829.

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 TS2-Me 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 .

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Energetic

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.

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.

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Energetic

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.

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:

In general, it can be seen from the energy profiles that the Bell-Evans-Polanyi-Leffler-Hammond rule holds as an increase in the exothermicity of the reaction is accompanied by a lower activation energy.

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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.

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Frontier Molecular Orbital Analysis

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

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.

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Reactivity Indexes

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.

In recent years, reactivity indexes have become useful means to study the reactivity of cycloaddition reactions.

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.

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Reaction Rate Constant

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.

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Solvent EffectsAs 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.

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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.

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In order to extend our study, the cycloaddition reaction of 1-substituted-pyrazinium-3-olate will be studied both experimentally and theoretically with methyl acrylate and methyl methacrylate.

NMe

N OR

R

R

MeO2C N

N

Me

O

R

RCO2Me

R = H, Me

R

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Doctorial Consortium OrganiserDoctorial Consortium Organiser

Tertiary Education CommissionTertiary Education Commission

University of Mauritius University of Mauritius

Universiti of Sains Malaysia Universiti of Sains Malaysia