INTRODUCTION:

The theoretical chemistry is used to propose mechanism of reaction by considering various possible reaction path^1-2. If the mechanism is established with help of experimental data and theoretical calculation then we can predict the reactive side of the reactant by applying theoretical calculation. The reactive side of the reactant is determined by theoretical chemistry in different way and also it depends upon nature of mechanism involved in the reaction^3-8 for example isomer of diels – alder reaction^,is predicted by calculating local softness of terminal carbon of diene and dinenophile and stereochemistry of product of Suzuki coupling can be determined by calculating interaction between the atoms in transition state. In this work we studied the role of predicted bond length of carbon – halogen and electron population on halogen atom of aryl halide in the reactivity determination towards Suzuki coupling. The reactivity of aryl halide in the Suzuki coupling is I > Cl > Br. If aryl halide containing different halogen atom then the reaction will proceed in above order of reactivity but if aryl halide containing more than one same halogen atom as poly substitute then the prediction of reactive portion of molecule comes in question.

In this situation the calculated bond length and charge density on halogen atom gives detail about reactive portion of aryl halide.

RESULT AND DISCUSSION:

Scott T. Handy et al⁹ in 2007 has carried the Suzuki reaction with 2,3-dibromo pyridine, 2,5 dibromo pyridine and reported the reactive portion of molecule and the reaction carried are shown below.

Reaction 1

Reaction : 2

Ortho and meta bromine atom of 2,5-dibromopyridine and 2,3-dibromopyridine are reacting with aryl boronic acid but reactivity order differs. The two isomers A and B are possible for both the reactions 1 and 2. If meta bromo atom of 2,5-dibromopyridine and 2,3-dibromopyridine is reacting first with aryl boronic acid (ArB(OH)₂), we would have got the isomer B but only isomer A is obtained in both the experiment. The experimental results show very clearly that the ortho bromine is more active towards suzuki coupling than meta bromine atom in the ortho and meta dibromo substituted pyridine. The above experimental result is explained by the theoretical calculation. If we look at the mechanism of reaction, it is clear that the aryl halide is reacting with Pd complex in oxidative addition step. From the knowledge of mechanism, we can correlate two theoretical parameter of aryl halide with its reactivity. The bond order difference between halogen and carbon bond (difference in bond order between ortho bromo with its connected carbon and meta bromo with its connected carbon) and the electron density on the halogen are correlated with reactivity order of aryl halide. The numbering for atom of 2,3-dibromopyridine and 2,5-dibromopyridine are shown in the below optimized geometry structure and theoretically estimated energy of HOMO, LUMO, energy of molecule, dipole moment, Mulliken and ZDO (Zero differential Overlap) charge density on atoms of 2, 5 – dibromo pyridine and 2, 3-dibromopyridine are shown in the below tables 1,2 and 3. The mechanism of reaction is shown below.

2,5- dibromopyridine

(optimized Geometry)

2,3-dibromopyridine

(optimized geometry)

Table :1 Charge density on atoms of 2,5 dibromopyridine and 2,3 dibromopyridine

Atom No	Atom Type	2,5-dibromo pyridine		2,3-dibromo pyridine
Atom No	Atom Type	ZDO Charge	Mulliken Charge	ZDO Charge	Mulliken Charge
1	C	-0.0383	-0.1267	-0.0270	-0.1138
2	C	-0.1764	-0.2274	-0.1708	-0.2172
3	C	-0.0337	-0.1096	-0.0892	-0.1078
4	N	-0.0224	-0.0370	-0.0135	-0.0274
5	C	-0.0897	-0.1131	-0.0587	-0.1390
6	C	-0.1131	-0.2094	-0.1406	-0.2394
7	H	0.1285	0.2266	0.1259	0.2229
8	H	0.1395	0.2397	0.1242	0.2193
9	H	0.1347	0.2348	0.1190	0.2136
10	Br	0.0331	0.0581	0.0693	0.0991
11	Br	0.0377	0.0638	0.0614	0.0898

Comparative study of 2,5- dibromopyridine

Graph: 1 Mulliken Charge

Graph: 2 ZDO Charge

Graph: 3 Bond order

Comparative study of 2,3-dibromopyridine

Graph: 4 Bond order

Graph: 5 mulliken Charge

Graph: 6 ZDO Charge

Table:2) 2,3-dibromopyridine descriptor.

Details	Value
Energy of molecule	-54.34
Dipole Moment	2.042
HOMO	-0.3734
HOMO	-0.0238
C2 - Br 11(Bond order)	0.9721
C5 - Br 10(Bond order)	0.9475

Table:3) 2,5-dibromopyridine descriptor

Details	Value
Energy of molecule	-54.53
Dipole Moment	2.4138
HOMO	-0.3727
HOMO	-0.0214
C3- Br 11(Bond order)	0.9501
C2- Br 10(Bond order	0.9741

Energies are in au unit, Bond order in bhor unit and Dipole Moment is in dyen for both table.

From the mechanism it is very clear that the reaction proceeds in three step a) oxidative addition of aryl halide with Pd(0) complex, step b) transmetallation with activated boronic acid, the boronic acid is activated by base, step c) reductive elimination of product from Pd(II) complex and finally the catalyst is recovered. Table 2 shows the mulliken and ZDO charge density on each atom of 2,5 dibromopyridine and the graph 1 and 2 shows the comparison of mulliken and ZDO charge density on ortho and meta (Br10, Br11) bromine atom of 2,5-dibromopyridine and it makes clear that ortho bromine (Br10, mulliken: 0.0581, ZDO: 0.0331) is having lower positive value, both type ZDO as well as mulliken charge, than meta bromine(Br11, mulliken: 0.0638, ZDO: 0.0377). The lower positive value of chare can be taken as higher electron density on halogen atom. The graph 3 shows the comparison of bond order of ortho-bromo – carbon and meta-bromo- carbon (C2 – Br11, 0.9721 and C5 – Br10, 0.9475) of 2,5-diromopyridine and it makes clear that ortho-bromo – carbon bond(C5 –Br10) is weaker bond than meta-bromo –carbon (C2 – Br11) bond order. And also table 2 shows the mulliken and ZDO charge density on each atom of 2,3-dibromopyridine and the graph 4 and 5 shows the comparison of charge density on ortho(Br11 mulliken: 0.0898, ZDO: 0.0614) and meta (Br10 mulliken: 0.0991, ZDO: 0.0693) bromine atom of 2,3-dibromopyridine and it makes clear that ortho bromine (Br10) is having lesser positive value, both type charge ZDO as well as mulliken charge, than meta bromine. The lesser positive value atom can be taken as higher electron density atom. The graph 6 shows the comparison of bond order of ortho-bromo - carbon (C3 – Br11, 0.9501)and ortho-bromo - carbon bond of 2,3-dibromopyridine (C2 – Br10, 0.9475) and it makes clear that ortho-bromo – carbon bond (C2 –Br10) of 2,5-dibromopyridine is weaker bond than meta bromo –carbon (C3 – Br11). So from the above discussion we can conclude that the halogen atom of aryl halide holding higher electron density (lower positive value) is more reactive than the halogen holding lesser electron density (higher positive value) towards Suzuki coupling because of this reason in the reaction 1 and 2 the isomer A is obtained. The mulliken as well as ZDO charge density value are showing the same trend so any one of charge density whether mulliken or ZDO charge density value can be used for prediction of isomer of Suzuki coupling reaction. If we compare the bond order with reactivity aryl halide with boronoic acid, it makes clear that carbon – halogen having lower bond order is more reactive than carbon – halogen having higher bond order towards Suzuki coupling. So above discussion emphasis that the charge density on halogen atom and the bond order of carbon – halogen of aryl halide parameters can be used to predict the isomer of Suzuki coupling.

EXPERIMENTAL SECTION:

The molecules geometry was optimized in semi-empirical^10-13method with PM3 hamiltonian in RHF method with the convergence limit of 10 ×10 ^–
10 kcal / mol. The arguslab^14-17 software has been used for calculation.

CONCLUSIONS:

- The halogen atom having more electron density is reacting first with boronic acid when compared charge density with reactivity order.

- The halogen bonded with lower bond order reacts first with boronic acid when compared bond order with reactivity order.

- The charge density, mulliken as well as ZDO charge, and bond order parameters can be used to predict the isomer of product of suzuki coupling reaction in the case where aryl halide containing more than one bromo atom as poly substitute.

REFERENCES:

1. Donard S Dwyer. Electronic properties of amino acid side chains: quantum mechanics calculation of substituent effects, BMC Chemical Biology. 2005; 5: 1-10.

2. Asit K. Chandra and Minh Tho Nguyen. Use of Local Softness for the Interpretation of Reaction Mechanisms. Int J Mol Sci. 2002; 3: 310-323.

3. Kolandavel P et al, Study of atomic and condensed atomic indices for reactive sites of Molecules. J Chem Sci. 2005; Vol. 117, No.5: 591–598.

4. Abhijit Chatterjee. Application of localized reactivity index in combination with periodic DFT calculation to rationalize the swelling mechanism of clay type inorganic Material. J. Chem Sci. 2005; Vol. 117, No. 5: 533–539.

5. Giorgio Molteni and Alessandro Ponti. Regioselectivity of aryl azide cycloaddition to methyl propiolate in aqueous media: experimental evidence versus local DFT HSAB principle, ARKIVOC. 2006; (xvi): 49-56.

6. Fernando R Ramos-Morales. Theoretical Study of Reactivity Based on the Hard-Soft/Acid-base (HSAB) in Isatoic Anhydride and Some Derivatives. J Mex Chem Soc. 2008; 52(4): 241-248.

7. Marcos C. Rezende. A Theoretical HSAB Study of the Acidity of Carbon Acids CH3Z. J Braz Chem Soc. 2001; Vol. 12, No. 1: 73-80.

8. L.R. Domingo L R. Perezb P and Contreras R. A DFT Analysis of the Strain-Induced Regioselective[2+2]Cycloaddition of Benzyne Possessing Fused Four-Membered Ring. Letters in Organic Chemistry. 2005; 2: 68-73.

9. Scott T. Handy, Thomas Wilson, and Aaron Muth. Disubstituted Pyridines: The Double-Coupling Approach. J Org Chem. 2007; 72: 8496-8500

10. Cardoso1 S P. Predictive QSPR analysis of corrosion inhibition for super 13% steel in hydrochloric acid. Brazilian Journal of Chemical Engineering. 2007; Vol.24, No. 04: 547 - 559.

11. Lemi Turker. AM1 Treatment of Some Phenoxyacetic Acid Herbicides. Turk J Biol. 2000; 24: 291–298.

12. Gerhard Raabe. The Use of Quantum-Chemical Semiempirical Methods to Calculate the Lattice Energies of Organic Molecular Crystals. Part II: The Lattice Energies of - and -Oxalic Acid (COOH)₂. Z. Naturforsch. 2002; 57a: 961–966.

13. Juan S Gomez-Jeria. Luis Lagos-Arancibia and Eduardo Sobarzo-Sanchez. Theoretical study of the opioid receptor selectivity of some 7-arylidenenal. J Chil Chem Soc. 2003; 48: 1-9.

14. Shalini Mehta et al. Microwave-assisted synthesis: anticonvulsant activity and quantum mechanical modelling of N-(4-bromo-3-methylphenyl) semicarbazones. J Zhejiang Univ Sci B. 2007; 8(1): 45-55.

15. Erick L Bastosa and Wilhelm Baaderb J. Theoretical studies on thermal stability of alkyl-substituted 1,2-dioxetanes, ARKIVOC. 2007; (viii): 257-272.

16. Jainendra Kumar, Vimal Kumar Roy and Preeti Vihwal. Analysis of interaction of atropine with phospholipase A2, On-line Journal of Modern Biology, 2008;Vol. 1; 1-15

17. Afshan Naz et al. Conformational analysis (geometry optimization) of nucleosidic antitumor antibiotic showdimycin by argus lab 4 software, Pak J Pharm Sci. 2009; Vol.22, No.1:78-82.

Received on 12.10.2010 Modified on 28.10.2010

Asian J. Research Chem. 4(3): March 2011; Page 377-380