Computational insight on the chalcone formation mechanism by the ...

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Received: 29 November 2016

Revised: 18 January 2017

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Accepted: 2 February 2017

DOI: 10.1002/qua.25365

FULL PAPER

Computational insight on the chalcone formation mechanism by the Claisen–Schmidt reaction Venelin Enchev1

Aleksandar Y. Mehandzhiyski2

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1 Theoretical Chemistry Lab, Institute of Organic Chemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria 2

Department of Chemical Engineering, Norwegian University of Science and Technology, SemSaelandsvei 4, Trondheim, NO-7491, Norway Correspondence Venelin Enchev, Bulgarian Academy of Sciences, Institute of Organic Chemistry, Acad. G. Bontchev Str. Bl. 9, Sofia 1113, Bulgaria. Email: [email protected]

Abstract New insight of the formation mechanism of chalcones is presented in the current study. Ab initio calculations were applied in studying the mechanistic pathways for the base-catalyzed Claisen– Schmidt condensation for obtaining chalcones (1,3-diphenyl-2-propen-1-ons). The energies of the stationary points along the reaction coordinate were obtained at two levels of theory—MP2/631 1 G(d,p) and SCS-MP2/6-31 1 G(d,p). The role of water in the reaction mechanisms is examined. The theoretical results show that the process is catalyzed by an ancillary water molecule. The reaction mechanism, proposed in this study, consists of two reactions—an activation of the acetophenone by a removal of proton is followed by the attack of the formed acetophenone anion to the aromatic aldehyde, which through few steps leads to the formation of the final product—chalcone. The first reaction proceeds very fast in one step while the second reaction goes through four steps and three intermediate complexes before the formation of the final product.

KEYWORDS

ab initio, chalcone, Claisen–Schmidt reaction, reaction mechanism

1 | INTRODUCTION

shown great performance concerning the yields and the stereoselectivity of the final product, obtaining mainly the trans configuration of the

The chalcones are organic compounds belonging to the family of flavo-

chalcone, which has been considered biologically active. Two mechanisms have been proposed to explain the reaction of ace-

noids. There is great interest to chalcones because of their photochemical

[1]

[2]

reactivity,

behavior,

[4]

biological activity.

physicochemical

[3]

properties,

and

tophenones with benzaldehydes in the presence of a basic catalyst.[17–20] To explain the reaction of acetophenone with benzaldehyde in

The high extinction coefficients of some chalcones

alkaline solution of ethanol–water, Nayak and Rout[17,18] proposed the

in UV-visible region make them useful as photoprotectors.[5] Although the chalcones (1,3-diphenyl-2-propen-1-ons) are widely [6]

reaction mechanism in which ethylate ion attacks the methyl group of

and can be isolated by extractive meth-

acetophenone and abstracts a proton. After that the acetophenonate

ods,[7] they are most frequently obtained by synthesis. In spite of the

ion (I) attacks the carbon atom of the aldehyde group in benzaldehyde

development of new synthetic methods,[8–12] the Claisen–Schmidt

forming intermediate anion (II) which then interacts with water mole-

distributed natural products

[13–16]

reaction

remains one of the most widely used for obtaining chal-

cones. The base-catalyzed Claisen–Schmidt condensation, presented

cule and forms a neutral intermediate (III). A last step is dehydration of the neutral intermediate III to Chalcone (Scheme 1). Later Gasull et al.[20] have shown that the values of the standard

on Scheme 1, generally involves formation of the anion of acetophenone, followed by its attack on the carbonyl group of benzaldehyde. [14–16]

Recent studies

have shown that chalcone pyrazoline deriva-

tives[14] and chalconyl esters,[15] possessing valuable pharmacological properties, can be synthesized from chalcones. In both of these stud[14,15]

ies

energy of reaction (DGr) for the reactions:   EtOH 1 OH2 5 EtO2 1 H2 O DGr 5 227:1 kcal mol21 and

the precursor (chalcone) has been obtained by the Claisen– [16]

Schmidt reaction. Sazegar et al.

A 1OH2 1A2 1H2 O

have developed a new protonated



DGr 5246:8 kcal mol21

 (2)

aluminate mesoporous silica nanomaterial to catalyze the Claisen–

where A is acetophenone and A2 is acetophenonate ion, clearly reveal

Schmidt reaction for the synthesis of chalcones. The new catalyst has

that the formation of the acetophenone anion A- (Equation 2) is

Int J Quantum Chem. 2017;117:e25365. https://doi.org/10.1002/qua.25365

http://q-chem.org

C 2017 Wiley Periodicals, Inc. V

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SCHEME 1

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MEHANDZHIYSKI

Base-catalyzed Claisen-Schmidt reaction for obtaining chalcones

preferring in comparison to the ethylate ion (Equation 1). They have

energy minima or transition states. For the optimized TS one single imagi-

been also proposed mechanism which explains the global rate of the

nary frequency was found in the diagonalized mass-weighted Hessian

third-order reaction and the equilibrium constants of 4-substituted-

matrix and the corresponding vibrational mode was confirmed to deter-

chalcogene formation. The proposed mechanism consists of five steps:

mine the reaction coordinate. All transition structures were checked by

2

(i) rapid nucleophilic attack of the catalyst (OH ) on the carbon atom

intrinsic reaction coordinate (IRC) calculations. Starting from the transition

of the methyl group of acetophenone; (ii) attacks of the acetopheno-

state, the reaction path was generated as the steepest descent path in

nate ion on the carbon atom of the aldehyde group (slow step of the

mass-scaled coordinates using the Gonzalez–Schlegel algorithm,[23]

reaction); (iii) a configurational equilibrium cis-s-cis$trans-s-trans

employing a step size of 0.05 Bohr (1 Bohr corresponds to 0.53 Å). On

between intermediate compounds is achieved; (iv) electrophilic attack

both branches of the reaction coordinate 40 steps were performed.

of a molecule of water on the oxygen atom bound to Cb of the inter-

We also used the spin-component-scaled MP2 (SCS-MP2)

mediate anion, forming a neutral intermediate, with catalyst regenera-

model[24] for single-point energy calculations. This model represents an

tion; and (v) intramolecular dehydration of the neutral intermediate to

improved version of standard MP2 in which the correlation energy is

give the 4-substituted-chalcone trans-s-trans.

partitioned into parallel- and antiparallel-spin components that are sep-

In experimental conditions, the reaction takes usually place in ethanol–water medium. It is, therefore, important to analyze the specific influences of water on the process as a medium but also its possible interaction with the reactants and its role on the mechanistic pathway.

arately scaled. It provides significantly improved energetics compared to standard MP2 reaching QCISD(T) accuracy. The Gibbs free energy, G, for all structures was obtained as sum: G 5 Et 1 Ecorr, where Et is the total (electronic 1 nuclear) energy and

In the present work, we apply ab initio computations at MP2/6-

Ecorr—thermal correction (RT 1 TS). The values of Gibbs free energies

31 1 G(d,p) and SCS-MP2/6-31 1 G(d,p) levels of theory to study the

(DG) and activation barriers (DG#) were calculated at temperature

mechanistic pathways for the base-catalyzed Claisen–Schmidt condensation for obtaining chalcones. The catalytic role of an explicit ancillary

298.15 K. The rate constants at 298.15 K were obtained using the Eyr# ing equation, k5ðkB T=hÞ:e2DG =RT , where kB and h are the Boltzmann

water molecule on the process was examined.

and Planck constants, respectively. The GAMESS program package[25] was used to perform the ab ini-

2 | AB INITIO QUANTUM-CHEMICAL CALCULATIONS

tio, calculations.

3 | RESULTS AND DISCUSSION The geometries and normal mode vibrational frequencies of the reactants, intermediates, products, and the transition states (TS) were computed at

As was noted in the Introduction the convenient method for the syn-

€ ller–Plesset (MP2) level using 6-31 1 G(d,p) basis set.[21,22] The the Mo

thesis of chalcones is the Claisen–Schmidt condensation of equimolar

basis sets include diffuse functions for proper description of the anionic

quantities of acetophenone with aromatic aldehyde in the presence of

stable structures and transition states. Vibration frequency calculations

a relatively strong base such as the OH2 ion (aqueous alcoholic alkali).

were performed numerically to obtain vibrational zero point and thermal

In the Claisen–Schmidt reaction, the concentration of alkali used, usu-

energies and to validate that the found structures corresponded to the

ally ranges between 10 and 60%.

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In water media, the hydroxide ion and water molecule should not be considered as separate reactants. An acceptable model system

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transition state structures and the intermediates along the stepwise pathway of addition-elimination process are presented in Figure 2.

reflecting the interaction between these two reactants is the respective

The first step, (i), of the reaction is the addition of the acetophe-

hydrogen-bonded complex. In presence of water it is correct to con-

none anion to the benzaldehyde molecule and formation of intermedi-

sider this complex as the real reactant species, rather than the individ-

ate I1 (Figure 3). In complex 3, the molecules of the acetophenone

ual components. This complex satisfies the high demand for solvation

anion and of benzaldehyde are arranged parallel to each other. The

of the hydroxide ion.

water molecules are bonded by hydrogen bonds to each of the car-

The OH2 base was modeled as OH2 (H2O). For consistency, a sin-

bonyl oxygen atoms. Thus, they form an interesting complex—the two

gle nonreagent water molecule was also added to all of the complexes,

water molecules stabilizing and retain the complex of acetophenone

intermediates, transition states, and products. Thus, there were two

anion and of benzaldehyde molecules of an appropriate distance and

water molecules involved in the intermediates and products, one of

with an appropriate orientation relative to one another for the prepara-

which was derived from the reagents, in particular from the hydroxide

tion of a suitable transition structure and the formation of the CAC

ion and the abstracted proton.

bond. In TS2 lateral attack of the carbanion to the aromatic aldehyde is

The critical structures in this study—reactants, products, intermedi-

observed as the distance C8AC17 in complex 3 is 3.73 Å. The water

ates, and transition states—along the reaction pathways in the pres-

molecules form hydrogen bonds with atom O9—the distances are

ence of an ancillary water molecule were optimized at MP2/6-31 1 G

1.967 Å and 1.870 Å. The main vectors of the imaginary vibrational fre-

(d,p) level of theory. The MP2 computed energies of the stationary

quency (104.9i cm21) for TS2 are shown in Figure 3 and correspond

points and transition states and their single-point SCS-MP2 calculated

mainly to a bond formation between the nucleophile CH2 group of

energies are summarized in Table 1.

benzophenone anion and the carbon atom of the carbonyl group of

The base-catalyzed Claisen–Schmidt condensation consists of two

benzaldehyde molecule and deformation vibrations of the water mole-

reactions. During the first reaction (Figure 1), the base OH2 and the

cules, facilitating the attraction of the two molecules. The hybridisation

acetophenone generates acetophenonate anion A2. During the second

of the electrophilic carbonyl carbon atom converts from sp2 to sp3

reaction, the obtained acetophenonate anion attacks the carbonyl

during the process. The C@O double bond becomes longer (1.286 Å in

group of benzaldehyde–chalcone is formed and hydroxide ion is regen-

TS2) and new CAC bond begins to created (2.376 Å in TS2). At the

erated (Figure 2). The second reaction includes four steps: (i) the aceto-

end, in anion intermediate I1, the CAC bond has a length of 1.552 Å.

2

phenonate ion A attacks the carbon atoms of the aldehyde group of

Water molecules are arranged in a specific cluster in Intermediate 1 as

benzaldehyde forming CAC bond—Intermediate 1; (ii) proton transfer

the distance between them is 2.17 Å. One of the water molecules is

from water molecule to the oxygen atom bound to Cb of Intermediate

too close to the oxygen atom O29—the distance is 1.54 Å (Figure 3).

1, formation of Intermediate 2 and regeneration of hydroxide ion; (iii)

The calculated energy barrier of the first step i) is 10.31 kcal mol21 and

double bond formation in Intermediate 3; (iv) intramolecular dehydra-

the rate constant—1.72 3 102 s21.

tion of Intermediate 3 to give chalcone.

The next step, (ii), of the reaction (see Figure 4) is ketol formation (Intermediate 2). It is reaction of proton transfer from water molecule

3.1 | Acetophenone anion formation

to the oxygen atom O29 in Intermediate 1. In the transition state TS3, the migrated proton is situated 1.19 Å from the water molecule and

The first reaction begins with nucleophilic attack of the catalyst OH2

1.23 Å from the accepting oxygen atom O29. The imaginary frequency

(H2O) on the carbon atom of the methyl group of acetophenone. The

characterized this proton transfer is 251.3i cm21. The dihedral angle

transition state TS1 for the reaction of acetophenone anion formation

C3AC7AC8AC17 is also changed—while in Intermediate 1 its value is

involves simultaneous cleavage of the CAH bond, proton transfer from

252.48, in TS3 it becomes 246.98 and reaches 63.68 in Intermediate 2.

carbon to the oxygen atom and creation of OAH bond. The transition

The rotation around the C7AC8 bond is facilitated by the fact that in

structure involved in this concerted pathway and the main vector of

the TS3 the bond is by 0.007 Å longer than in Intermediate 1 (1.515 Å

the imaginary vibrational frequency (1126.7i cm21; see Table 1) of TS1

in TS3 and 1.508 Å in Intermediate 1). As a result Intermediate 2 is

are shown in Figure 1.

obtained and the catalyst, hydroxide ion is regenerated. This step is

The reaction is exothermic—the product, Complex 2, is 7.73 kcal 21

mol

lower in energy than the reagents, Complex 1. The energy bar-

rier of the acetophenone anion formation reaction is 4.69 kcal mol21. The reaction is very fast—the rate constant is 2.27 3 106 s21.

very fast. The energy barrier is calculated to be only 0.38 kcal mol21, indicating that the ketol formation occurs extremely fast the rate constant is 3.27 3 109 s21. In the step (iii), after the ketol formation (Figure 5), the hydroxyl anion detached proton from the methylene group of Intermediate 2.

3.2 | Chalcone formation—addition-elimination process

This is the first step of the formation of the double bond. That is also the step at which the stereoselectivity of the reaction arises and leads to the formation of the trans-s-trans configuration of the final prod-

The reaction of chalcone formation is stepwise pathway—an addition-

uct.[23] In the transition state TS4, the leaving proton is situated at a

elimination process accompanied by proton transfer processes. The

distance of 1.37 Å from the C8 atom of the methylene group and 1.25

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MP2/6-31 1 G(d,p) and SCS-MP2/6-31 1 G(d,p) calculated total energies (ET) and Gibbs free energies (G298), in a.u, of the structures shown on Figures 1 and 2

T A B LE 1

ET

Species

G298

DG298

MP2 Reaction 1 Complex 1

2535.663520

2535.532576

0.000000 (0.00)

TS 1

2535.652593

2535.525102

0.007474 (4.69)

Complex 2

2535.677515

2535.544902

20.012326 (27.73)

Reaction 2 Complex 3

2880.266159

2880.031031

0.000000 (0.00)

TS 2

2880.250824

2880.014595

0.016436 (10.31)

Intermediate 1

2880.267703

2880.030185

0.000846 (0.53)

TS 3

2880.264946

2880.029574

0.001456 (0.91)

Intermediate 2

2880.270793

2880.031994

20.000963 (20.60)

TS 4

2880.245707

2880.011661

0.019369 (12.15)

Intermediate 3

2880.263136

2880.025567

0.005463 (3.43)

TS 5

2880.242806

2880.007252

0.023778 (14.92)

Complex 4

2880.257833

2880.025504

0.005527 (3.47)

SCS-MP2 Reaction 1 Complex 1

2535.615761

2535.484816

0.000000 (0.00)

TS 1

2535.601990

2535.474498

0.010318 (6.47)

Complex 2

2535.628684

2535.496070

20.011254 (27.06)

Reaction 2 Complex 3

2880.178655

2879.943527

0.000000 (0.00)

TS 2

2880.163193

2879.926963

0.016534 (10.39)

Intermediate 1

2880.181445

2879.943926

20.000399 (20.25)

TS 3

2880.177990

2879.942618

0.000909 (0.57)

Intermediate 2

2880.183715

2879.944916

20.001389 (20.87)

TS 4

2880.155883

2879.921837

0.021690 (13.61)

Intermediate 3

2880.174913

2879.937343

0.006184 (3.88)

TS 5

2880.154079

2879.918525

0.025002 (15.69)

Complex 4

2880.171885

2879.939556

0.003971 (2.49)

The relative Gibbs free energies (DG298), in brackets, are in kcal mol21.

Å of the hydroxyl anion. The main vector of the imaginary vibrational 21

frequency (1141.2i cm

) for TS4 (Figure 5) corresponds to proton

Intermediate 2. The calculated activation energy is 12.75 kcal mol21 and the respective rate constant is 2.8 s21

transfer from the methylene group of Intermediate 2 to the hydroxyl

The structure of Intermediate 3 is similar to the final product.

anion. The rotation around the C7AC8 bond continues in TS4. The

There is already a trans-s-trans configuration of chalcone. The torsion

value of the dihedral angle C3AC7AC8AC17 in TS4 is 41.38, that is,

angles O9AC7AC8AC17 and H16AC8AC17AH30 are 164.98 and

reduced in comparison of that one in Intermediate 2 (63.68) and

179.68, respectively, which shows trans configuration with respect to

reached to 215.28 in Intermediate 3. The C7AC8 bond becomes

the C8AC17 bond.

shorten—from 1.502 Å in Intermediate 2 and 1.443 Å in TS4 to 1.379

In the last step (iv) of the Reaction 2 (Figure 6), the final product

Å in Intermediate 3. This reaction step is endothermic because

chalcone is obtained and the catalyst to the reaction, the hydroxyl

the formed Intermediate 3 is 4.03 kcal mol21 higher in energy than

anion, is regenerated. In the transition state TS5 the C7AC8 bond is

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Reaction profile of reaction 1 calculated at MP2/6-31 1 G(d,p) level of theory. The Gibbs free energy differences (DG298) are given in kcal mol21. The DG298 values obtained at SCS-MP2/6-31 1 G(d,p) level are given in brackets. The distances are in Å. The arrow in the transition state structure TS1 indicate the normal coordinate with an imaginary frequency 1126.7 cm21

FIGURE 1

lengthen to 1.436 Å while the C8AC17 bond becomes double, short-

chalcone is in trans-s-trans configuration. The C7AC8 and C8AC17

ened to 1.387 Å. The water molecules form with the leaving hydroxyl

bonds have length 1.436 Å and 1.387 Å, respectively. The calculated

anion hydrogen bonds distances of 1.662 Å and 1.861 Å. The imagi-

activation energy in the last step of the reaction is 11.49 kcal mol21

21

nary frequency 2225.4i cm

characterizes the cleavage of the

C17AO29 bond.’he hydroxyl anion in Complex 4 is located at a dis-

and the rate constant is 2.34 3 101 s21. Complex 4 has the same energy as Intermediate 3 (Figure 6).

tance of 2.03 Å from atom C17 of chalcone and water molecules are

The last two steps (iii) and (iv) have been considered as a single

coordinated around it at distances 1.59 Å and 1.58 Å (Figure 6). The

dehydration step,[26] where the migration of the proton form the

Reaction profile of reaction 2 calculated at MP2/6-31 1 G(d,p) level of theory. The Gibbs free energy differences (DG298) are given in kcal mol21

FIGURE 2

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Reaction profile of step (i) of reaction 2 calculated at MP2/6-31 1 G(d,p) level. The Gibbs free energy differences (DG298) are given in kcal mol21 and distances in Å. The DG298 values obtained at SCS-MP2/6-31 1 G(d,p) level are given in brackets. The arrow in the transition state structure TS2 indicate the normal coordinate with an imaginary frequency 104.9 cm21

FIGURE 3

Reaction profile of step (ii) of reaction 2 calculated at MP2/6-31 1 G(d,p) level. The Gibbs free energy differences (DG298) are given in kcal mol21 and distances in Å. The DG298 values obtained at SCS-MP2/6-31 1 G(d,p) level are given in brackets. The arrow in the transition state structure TS3 indicate the normal coordinate with an imaginary frequency 251.3 cm21

FIGURE 4

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Reaction profile of step (iii) of reaction 2 calculated at MP2/6-31 1 G(d,p) level. The Gibbs free energy differences (DG298) are given in kcal mol21 and distances in Å. The DG298 values obtained at SCS-MP2/6-31 1 G(d,p) level are given in brackets. The arrow in the transition state structure TS4 indicate the normal coordinate with an imaginary frequency 1141.2 cm21

FIGURE 5

methylene group and the detachment of the hydroxyl group happens

formed between the ketol and the final chalcone product. The high

simultaneously, which needs high activation energy. However, we have

activation energy for the dehydration step[26] is clearly seen from Fig-

shown that an intermediate stable structure (Intermediate 3) can be

ures 5 and 6. Moreover, it is also apparent that first the detachment of

Reaction profile of step (iv) of reaction 2 calculated at MP2/6-31 1 G(d,p) level. The Gibbs free energy differences (DG298) are given in kcal mol21 and distances in Å. The DG298 values obtained at SCS-MP2/6-31 1 G(d,p) level are given in brackets. The arrow in the transition state structure TS5 indicate the normal coordinate with an imaginary frequency 225.4 cm21

FIGURE 6

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the proton from the methylene group proceeds before the dehydration and in this way by separating this step into two, can explain the high activation energy mentioned elsewhere.[26] Single-point SCS-MP2/6-31 1 G(d,p) calculations based on the MP2/6-31 1 G(d,p) optimized structures show the same or higher energy reaction barriers (see Figures 1 and 3–6). For Reaction 1 the SCS-MP2 calculated energy barrier is 1.76 kcal mol21 higher than the MP2 one (Figure 1) and for step (ii) of Reaction 2 the energy barrier 21

increase from 0.38 kcal mol

(calculated at MP2 level) to 0.82 kcal

mol21 (calculated at SCS-MP2 level), that is, 2 times (Figure 3). The activation barriers for steps (i), (iii), and (iv) of Reaction 2 calculated at both levels of theory are practically the same. There are qualitative changes when we compare the energy differ-

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[3] a) F. Gao, K. F. Johnson, J. B. Schlenoff, J. Chem. Soc. Perkin Trans. 1996, 2, 269; b) S. E. Blanco, F. H. Ferretti, Talanta 1998, 45, 1103. [4] a) J. R. Dimmock, D. W. Elias, M. A. Beazely, N. M. Kandepu, Curr. Med. Chem. 1999, 6, 1125; b) K. Yamaguchi, Y. Sakurai, H. Kurumi, Japanese Patent 1972, 72, 016.C.A. 78 (1973) 97330d; c) Z. Nowakowska, B. Kedzia, G. Schroeder, Eur. J. Med. Chem. 2008, 43, 707; d) D. Batovska, I. Todorova, Curr. Clin. Pharmacol. 2010, 5, 1; e) D. Batovska, S. Parushev, Int. J. Curr. Chem. 2010, 1, 217. [5] N. A. Shaath, in Sunscreens: Development, Evaluation and Regulatory Aspects, 2nd ed. (Eds: N. J. Lowe, N. A. Shaath, M. A. Pathak), Marcel Dekker, Ink, New York 1997, p. 25 [6] D. N. Dhar, in The Chemistry of Chalcones and Related Compounds, Wiley, New York 1981, pp. 201–212. [7] H. Ghouila, N. Meksi, W. Haddar, M. F. Mhenni, H. B. Jannet, Ind. Crops Prod. 2012, 35, 31.

ence between the reactants and products in steps (i)–(iv) of Reaction 2

[8] M. J. Climent, A. Corma, S. Iborra, J. Primo, J. Catal. 1995, 151, 60.

as calculated at MP2 and SCS-MP2 levels of theory. Computations

[9] G. R. Subbanwad, Y. B. Vibhute, J. Indian Chem. Soc. 1992, 69, 337.

show that at both levels step (ii) is exothermic and step (iii) is endother-

[10] Y. Patonay, D. Molnar, Z. Muranyi, Bull. Soc. Chim. Fr. 1995, 132, 233.

mic. However, according to the calculations at MP2 level, step (i) is endothermic and for step (iv) reactants and products has the equal

[11] J. T. Li, W. Z. Yang, S. X. Wang, S. H. Li, T. S. Li, Ultrasonics Sonochemistry 2002, 9, 237.

energies while calculations at SCS-MP2 level show that both steps are

[12] N. M. Rateb, H. F. Zohdi, Synth. Commun. 2009, 39, 2789.

exothermic (Figures 3 and 6).

[13] H. Wagner, L. Farkas, in The Flavonoids, Part I (Eds: J. B. Harborne, T. J. Mabry, H. Mabry), Academic Press, New York 1975, p. 131.

4 | CONCLUSIONS

[14] F. B. Miguel, J. A. Dantas, S. Amori, G. F. S. Andrade, L. A. S. Costa, M. R. C. Couri, Spectrochim. Acta A Mol. Biomol. Spectrosc. 2016, 152, 318.

The Claisen–Schmidt condensation for the formation of chalcones (1,3diphenyl-2-propen-1-ons) has been investigated through ab initio calcu-

[15] P. K. Patel, R. R. Shah, Mol. Cryst. Liq. Cryst. 2016, 641, 1.

reactions—an activation of the acetophenone by a removal of proton is

[16] M. R. Sazegar, S. Mahmoudian, A. Mahmoudi, S. Triwahyono, A. A. Jalil, R. R. Mukti, N. H. N. Kamarudin, M. K. Ghoreishi, RSC Adv. 2016, 6, 11023.

followed by the attack of the formed acetophenone anion to the aro-

[17] P. L. Nayak, M. K. Rout, J. Indian Chem. Soc. 1975, 52, 809.

lations. The reaction mechanism, proposed in this study, consists of two

matic aldehyde, which through few successive steps leads to the formation of the final product. While the first reaction proceeds in relatively easy way, the second reaction goes through multiple steps and three intermediate complexes before the formation of the final product. To take into account to some extend the role of the water in the

[18] P. L. Nayak, M. K. Rout, J. Indian Chem. Soc. 1970, 47, 807. [19] L. J. Yamin, E. I. Gasull, S. E. Blanco, F. H. Ferretti, J. Mol. Struct. 1998, 428, 167. [20] E. I. Gasull, J. J. Silber, S. E. Blanco, F. Tomas, F. H. Ferretti, J. Mol. Struct. (Theochem) 2000, 503, 31.

reaction, an extra water molecule has been added to the reaction com-

[21] P. C. Hariharan, J. A. Pople, Theor. Chim. Acta 1973, 28, 213.

plexes. Although, a single molecule cannot fully explain the role of the solvent, which is non-negligible in chemical reactions, the addition of

[22] M. M. Francl, W. J. Pietro, W. J. Hehre, J. S. Binkley, M. S. Gordon, D. J. Defrees, J. A. Pople, J. Chem. Phys. 1982, 77, 3654.

only one molecule was crucial in the stabilization of some reaction com-

[23] C. Gonzalez, H. B. Schlegel, J. Chem. Phys. 1989, 90, 2154.

plexes. Particularly, the transition state complex of the nucleophilic addi-

[24] S. Grimme, J. Chem. Phys. 2003, 118, 9095.

tion of the acetophenone anion to the aromatic aldehyde is stabilized by

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the presence of the second water molecule. The water molecules hold the two interacting centers in an appropriate distance for the addition to take place and also facilitate the attraction of the molecules by the water deformation vibrations. Without the presence of the second water molecule a transition state has not been located, which additionally highlights the importance of the solvent in the reaction mechanism.

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How to cite this article: Enchev V, Mehandzhiyski AY. Computational insight on the chalcone formation mechanism by the Claisen–Schmidt reaction. Int J Quantum Chem. 2017;117: e25365. https://doi.org/10.1002/qua.25365