Probing the mechanism of Morita–Baylis–Hillman reaction

in dichloromethane by density functional theory

Jianhua Xu

Department of Chemistry, Fuling Normal College, Chongqing 408003, China

Received 19 January 2006; received in revised form 26 April 2006; accepted 29 April 2006

Available online 11 May 2006

Abstract

The mechanism of Morita–Baylis–Hillman reaction was investigated at B3LYP/6-311CG(d) level combined with Tomasi’s IEF-PCM solvent

model. The computational results indicate that the catalytic cycle of Morita–Baylis–Hillman involves the following steps: 1,4-addition of PMe3,

aldolic addition, hydrogen transfer, and elimination of product. The hydrogen transfer step is predicted to be the rate-limiting step for the whole

process. And the predicted rate expression is in agreement with the previous kinetic studies. The computational results make clear that the Morita–

Baylis–Hillman process is equilibrated and it is in good agreement with the previous experimental results. The entropy plays a crucial role in the

1,4-addition and aldolic steps. The CN group in the whole process mainly serves as an electronic charge acceptor to delocalize the electronic

charge on carbon through the p–p interaction between C and the CN group.

q 2006 Elsevier B.V. All rights reserved.

Keywords: PMe3-catalyzed; Morita–Baylis–Hillman reaction; Mechanism; SCRF; DFT

1. Introduction

The Baylis–Hillman reaction is an atom economical

coupling of an activated alkene and an aldehyde in the presence

of a nucleophilic catalyst (Scheme 1). The reaction was first

reported by Morita and coworkers [1] in 1968 and by Baylis

and Hillman in 1972. [2] The nucleophilic catalyst employed

by Morita was tricyclohexylphosphine, while Baylis and

Hillman used tertiary amines such as DABCO. Activated

alkenes include acrylic esters, acrylonitrile, vinyl ketones,

phenyl vinyl sulfone, phenyl vinyl sulfonate ester, vinyl

phosphonate and acrolein. b-Substituted alkenes required

more forcing conditions due to the slow addition of the

phosphine catalyst. A variety of coupling partners such as

aliphatic, aromatic and a,b-unsaturated aldehydes have been

successfully employed [3–8].

Unfortunately, the applications of the Morita–Baylis–

Hillman reaction had been limited in complex syntheses by

low rates and conversions as well as high substrate-dependent

yields. The rate-determining step is typically the bimolecular

coupling of the zwitterionic intermediate and the aldehyde.[3]

The Morita–Baylis–Hillman reaction remained relatively

0166-1280/$ - see front matter q 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.theochem.2006.04.044

E-mail address: xujianhua64@163.com

undeveloped for many years, despite of its obvious synthetic

potential. In the 1980s research on the tertiary amine-

catalyzed variant escalated [4–6]. Although tertiary amines

are cheaper and less toxic than phosphines, the latter some-

times give higher yields in shorter reaction time. The

phosphine-catalyzed variant was explored only sporadically,

with an improvement in reaction efficiency reported by

Kawanisi using the cocatalysts tributylphosphine and triethyl-

aluminum in dichloromethane. [7]

Several mechanistic considerations and kinetic studies led

to the general acceptance of the Baylis–Hillman catalytic cycle

was summarized in Scheme 2. This mechanism was initially

proposed by Hill and Isaacs [9], and later refined by others [10–

12]. According to Scheme 2, the first reaction step I consists of

the 1,4-addition of the catalytic tertiary phosphine 1 to the

activated alkene 2, which generates the zwitterion intermediate

3. In step II, 3 adds to aldehyde 4 by an aldolic addition to yield

intermediate 5. Step III involves an intramolecular prototropic

shift within 5 to form intermediate 6, and in step IV forms the

final Baylis–Hillman adduct 7 through E2 or E1cb elimination

in the presence of a Lewis base. The last step IV regenerates

catalyst 1 to complete the catalytic cycle. The reaction rate

seems to be determined by step II because the dipole moment is

increased by further charge separation. Drewes et al. [13]

carried out the reaction of methyl acrylate with 2-hydroxyben-

zaldehyde in dichloromethane at 0 8C in the presence of

DABCO, isolated a type-6 intermediate (Scheme 2) as a

Journal of Molecular Structure: THEOCHEM 767 (2006) 61–66

www.elsevier.com/locate/theochem

C

X

R1

R1

R2

EWG

EWG

XHR2

Lewis base

catalysts

X = O,NTS,NCOR,NSO2PhR1 = HR2 = alkyl or arylEWG = COOR,CN,POEt2,CHO,COR,SO2Ph

Scheme 1.

J. Xu / Journal of Molecular Structure: THEOCHEM 767 (2006) 61–6662

coumarin salt, and characterized the salt by X-ray

crystallography.

Despite the considerable importance of the Baylis–Hillman

reaction for organic synthesis, there had been a remarkable lack

of theoretical studies published on the mechanism. Therefore,

density functional theory (DFT) calculations had been carried

out for PMe3-catalyzed Morita–Baylis–Hillman reaction at

B3LYP/6-311CG(d) level. These calculations aim to provide

specific help for the design and development of new selective

catalytic transformations proceeding through Baylis–Hillman

by amine and phosphine catalysts.

2. Models and computational detail

Our models are based on the PCy3-catalyzed Motira–

Baylis–Hillman reaction of acrylonitrile and ethanal in

CH2Cl2 [4]. The PCy3 is modeled by PMe3.

All computations were performed by the use of GAUSSIAN 03

package [14]. Geometries for all intermediates and transition

states were optimized by means of the density functional theory

(DFT) with Becke’s three-parameter functional (B3) [15] plus

Lee, Yang, and Parr (LYP) [16] correlation functional

combined with Tomasi’s IEF-PCM solvent [17–20] model

implemented in GAUSSIAN 03 with CH2Cl2 as solvent. The

6-311CG(d) [21–24] basis sets were utilized for all atoms.

The vibrational analysis and the natural bond orbital (NBO)

analysis [25,26] were performed at the same computational

level. The optimized transition states were characterized by a

sole imaginary frequency, whereas other optimized structures

had only real frequencies.

PMe3

1

CN2

Me3P+

-O CH3

CNMe3P

+

HO CH3

CNMe3P

+-

CN

H3C

OH

3

4

56

7 CH3CHO

Step I

Step II

Step III

Step IV

1

2

3

4

5

-CN

Scheme 2.

3. Results and discussions

As shown in Scheme 2, the complete catalytic cycle for the

title reaction was investigated. The total energy and free energy

profiles at 298.15 K and 1 atm are shown in Fig. 1. The

corresponding geometries and selected parameters are listed

in Figs. 2–5 and Table 1.

3.1. The process of the Morita–Baylis–Hillman reaction

As shown in Scheme 2, there exist four steps for the Morita–

Baylis–Hillman reaction. Because of the pro-chirality in

ethanal and intermediates 3, there are two chiral centers in

intermediate 5. Therefore, there have four enantiomers for 5,

RR, SR, SS and RS. The energies of SS and RS are equal to RR

and SR, respectively. For intermediate 6, there is only one

chiral center, and S configuration is connected to the RS and SS

isomers of the intermediate 5. Therefore, in the present paper,

only the pathways leading to S configuration were calculated

and the RS and SS were denoted R and S, respectively.

3.1.1. PMe3 addition to the activated alkenes

As displayed in Scheme 2, the first step of Morita–Baylis–

Hillman is trimethylphosphine 1 addition to the activated

alkene acrylonitrile 2 to form the zwitterionic phosphonium

intermediate 3. The transition state (TS1/3) of this step is

shown in Fig. 2.

Going from trimethylphosphine and acrylonitrile to inter-

mediate 3 via TS1/3, there involves formation of the P1–C2

bond and cleavage of p bond of the C2–C3. As shown in Fig. 1,

the C2–C3 bond varies from 1.336 A in 2 to 1.430 A in TS1/3

and finally 1.481 A in 3. These indicate that the C1–C2 bond

changes to single bond in intermediate 3 from the double bond

in acrylonitrile. The C1 becomes to sp3 hybridization while C2

remains sp2 hybridizated character. Interestingly, the three P–C

bonds in the PMe3 moiety of intermediate 3 and transition state

TS1/3 are shorter than that of the free PMe3 due to the positive

charges on phosphorus in 3 and TS1/3.

The C–N bonds of the acrylonitrile moiety in 3 and TS1/3

are longer than that of the free PMe3 because the p–pinteraction between 2p orbital of C3 and p bond of the CN

group. This p–p interaction also causes the electronic charge

on C3 to delocalizate to the CN group (the charges on the CN

group in 2, TS1/3 and 3 are K0.07, K0.16 and K0.33 a.u.,

respectively) and thus it stabilizes the zwitterionic phos-

phonium intermediate 3. At the same time, the variation of

the C3–CN bond in this process also demonstrates the p–pinteraction in 3 and TS1/3.

The formation of 3 causes the electronic charge transfer

from the PMe3 moiety to the acrylonitrile moiety. The

transferred charges are 0.58 and 0.96 a.u. for TS1/3 and 3

(Table 1), respectively. Therefore, the PMe3 can be considered

as a nucleophilic reagent. This also indicates that the formation

of zwitterionic phosphonium intermediate 3 results in a

markedly charge separation and the dipole moment of the

intermediate 3 is very large. The calculated dipole moments

of intermediate 3 (4.77 and 1.55 debye for 2 and 1 compared to

TS1/3+4

1+2+4

0.00(0.00)

3+4

TS3/5R

TS3/5S

5R

5S6

TS6/7

7+1

TS5/6S

TS5/6R

15.01(26.05)

14.05(25.33)

14.54(37.12)

15.91(38.77)

12.49(36.23)

14.01(37.86)

41.66(66.77)

38.50(63.20)

14.84(38.34)

17.85(40.87)

–1.21(10.18)

Er/GrKcal/mol

Fig. 1. The total energy and free energy profiles (298.15 K and 1 atm) of Marita–Baylis–Hillman reaction at B3LYP/6-311CG(d)/SCRF level. (The free energies are

in parentheses). Unit is in kilocalories/mol.

P

C

C

C

CC

C

N

1.8851.816

1.481

1.380

1.179P

CC

C

1

1.862

C C

C

N

1.336 1.429

1.157

2

3

NC

CC

P

C

C

C

1.846

2.1161.4301.394

1.172

TS1/3

Fig. 2. The optimized geometries and selected parameters of reactants,

intermediate and transition state involved in 1,4-addition step. Bond lengths

are in angstrom.

J. Xu / Journal of Molecular Structure: THEOCHEM 767 (2006) 61–66 63

12.10 and 14.56 debye for TS1/3 and 3) justify this point. The

natural charges on selected atoms (Table 1) indicate that the

nucleophilic site is C3.

The predicted energy barrier for the 1,4-addition step is

15.01 kcal/mol while the free energy of activation is

26.05 kcal/mol. Therefore the entropy plays a crucial role in

the process of the 1,4-addition to acrylonitrile of PMe3. The

formation of intermediate 3 is endothermic 14.05 kcal/mol.

The TS1/3 occurs late on the PES according to the parameters

shown in Fig. 2.

3.1.2. The aldolic addition reaction

Because of the pro-charilty of C3 in intermediate 3 and C4

in reactant ethanal 4, the addition of intermediate 3 to ethanal

will generate four pathways, RR, SR, RS and SS. The stationary

points on RR and SR potential energy surfaces (PES) are the

same as that of SS and RS PESs. So we only calculated the SS

and RS pathways and the related species were denoted as S and

R. The optimized structures and selected parameters are

depicted in Fig. 3.

The barrier heights for the two pathways are 0.49 and

1.86 kcal/mol, while the free energies of activation are 11.79

and 13.44 kcal /mol for S and R pathways. Therefore, this step is

easier than the first step. The two pathways are predicted to be

exothermic by 0.04 and 1.56 kcal/mol while the reaction free

energies are endothermic 10.90 and 12.53 kcal/mol, respect-

ively. So the entropy also plays an important role in this process.

The process of intermediate 3 addition to ethanal 4 involves

the formation of the C3–C4 bond and the cleavge of the p bond

of the C4–O5 double bond. It is also a nucleophilic addition.

Because of the large charge separation in intermediates 5R and

5S, the lengths of C3–C4 bonds are longer than that of normal

C–C bond. The P1–C2 bond becomes stronger from the

reactant intermediate 3 to TS3/5 and finally intermediate 5

(Figs. 1 and 2). This change results from the electronic charge

transfer from C2 and C3 to the O5. Interestingly, the P–C

methyl bonds in PMe3 moiety lengthen in the process of 3 to

TS3/5 and then shorten from TS3/5 to 5. In this process, the

hybridizations of C2 and C3 vary from sp2 to sp3.

The natural charges shown in Table 1 indicate that the

positive charge is gradually concentrated on P1 in this

process. The electronic charge on C3 transfer to O5 and this

point also predicts that this process is nucleophilic addition.

The electronic charges on the CH3CHO moiety are 0.34, 0.39,

0.75 and 0.75 a.u. for TS3/5R, TS3/5S, 5R and 5S, respect-

ively, and the positive charges of the PMe3 moiety are also

concentrated in the process of the nucleophilic addition. The

charges of the CN group increase because of the cleavage of

the p–p interaction between C3 and the CN group. The dipole

moments of 5R and 5S are 16.29 and 16.79 debye. The

variation of dipole moments in this process is smaller than

the above 1,4-addition step.

3.1.3. Hydrogen transfer

In the hydrogen transfer step, two transition states have been

located and they are both connected to the intermediate 6. The

optimized structures and selected parameters involved in this

step are depicted in Fig. 4.

The transition states TS5/6R and TS5/6S are connected with

5R and 5S, respectively. The energy barriers of the two

pathways are 29.17 and 24.49 kcal/mol while the activation

1.5081.212

O

CC

4

C CO C

CN

C

P

TS3/5R

1.522

1.257

2.1471.505

1.829

1.820

CC

O

CC

N

C

PC

1.526 1.261

2.114

1.4112.576

1.5101.827

1.820

TS3/5S

C

CO

CN

C C

P

C

5R

1.811

1.816

1.534

1.6671.449

1.160

1.3281.544

5S

P

C

CC

C

NO

C

C

1.814

1.814

1.538

1.451

1.159

1.6721.326

1.547

Fig. 3. The optimized geometries and selected parameters of reactants, intermediates and transition states involved in aldolic addition step. Bond lengths are in

angstrom.

J. Xu / Journal of Molecular Structure: THEOCHEM 767 (2006) 61–6664

free energies are 30.84 and 25.34 kcal/mol, respectively. From

the energy barrier point, the path S is more favorable than path

R. This process is endothermic slightly.

The hydrogen transfer process involves the cleavage of the

C2–H bond and formation of the O5–H bond. On going from

5R and 5S to 6 through TS5/6R and TS5/6S, the C3–C4 bond

shortens gradually. In 5R and 5S, the C3–C4 bonds are close to

the normal C–C bond length. Natural charges shown in Table 1

indicate that hydrogen transfer can be considered as a proton

transfer process (the hydrogen atoms being transferred are

positively charged 0.40 a.u. in both two transitions states).

Fig. 4. The optimized geometries and selected parameters of intermediate and tran

In this hydrogen transfer process, the hybridization of C3

changes from sp3 to sp2 and hence causes the increase of the

electronic charge of the CN group. The positive charge of the

PMe3 moiety also decrease slightly. An analysis the atomic

motions corresponding to the imaginary frequency of TS5/6R

and TS5/6S, indicates that the displacement of the H atom is

the main contribution to the transition vectors.

3.1.4. Product elimination

The last step of the Morita–Baylis–Hillman reaction is

elimination of product 7 from 6 and regenerates the catalyst

sition states involved in hydrogen transfer step. Bond lengths are in angstrom.

P

C

C

CC

N C

O

C

C

O

C

C

N

C

C

1.843

2.155

1.4291.398

1.172 1.5051.533

1.462

TS6/7 7

1.337

1.437

1.157

1.519

1.431

1.530

Fig. 5. The optimized geometries and selected parameters of product and

transition state involved in the elimination step. Bond lengths are in angstrom.

J. Xu / Journal of Molecular Structure: THEOCHEM 767 (2006) 61–66 65

PMe3. The optimized geometries of the transition state of the

elimination step and product are shown in Fig. 5.

The variation of the relative parameters in the elimination is

similar to the reverse process of the 1,4-addition. The C3–C4

and C4–O5 bonds shorten gradually. In TS6/7, the charge on

the PMe3 moiety is 0.69 a.u. The C4–CN bond weakens while

the CbN bond strengthens due to the disappearance of the p–pinteraction between C3 and the CN group.

The energy barrier and activation free energy of this process

are 3.01 and 2.54 kcal/mol, therefore the elimination process is

kinetically very favorable. From the thermodynamic point

(Fig. 1), the elimination process is also very favorable.

3.2. The overview of whole catalytic cycle

From the above discussions, the catalytic cycle of Morita–

Baylis–Hillman involves four steps: initially, PMe3 1,4-

addition to the activated alkene forms the zwitterionic phos-

phonium intermediate 3 via TS1/3; then, the zwitterionic

phosphonium intermediate 3 attacks the ethanal to give rise

to 5R and 5S through TS3/5R and TS3/5S, respectively; the

next step is an intramolecular hydrogen transfer to generate 6

via TS5/6R and TS5/6S and finally the product 7 is formed by

elimination from 6 and the catalyst PMe3 is regenerated.

Table 1

The natural charges (au) on selected atoms and groups at B3LYP/6-311CG(d) lev

Species P1 C2 C3 C

1 0.73 – – –

2 – K0.25 K0.33 –

3 1.44 K0.63 K0.68 –

4 – – – 0

5R 1.52 K0.72 K0.40 0

5S 1.51 K0.73 K0.40 0

6 1.49 K0.65 K0.50 0

7 – K0.17 K0.25 0

TS2/3 1.23 K0.48 K0.60 –

TS3/5R 1.50 K0.70 K0.55 0

TS3/5S 1.50 K0.70 K0.53 0

TS5/6R 1.51 K0.67 K0.53 0

TS5/6S 1.52 K0.66 K0.52 0

TS6/7 1.21 K0.45 K0.42 0

The total barrier heights for the R and S pathways are 41.66

and 38.50 kcal/mol and hence the S pathway is favorable

slightly in this process. The potential energy profile and free

energy profile shown in Fig. 1 indicate that the Morita–Baylis–

Hillman process is equilibrated and it is in good agreement

with the previous experimental works [5]. The computational

results also indicted that the hydrogen transfer is the rate-

limiting step energetically while the 1,4-addition or hydrogen

transfer may be the rate-determining step under various

conditions from free energy point. If the hydrogen transfer is

the rate-limiting step, the rate can be written as the following

formula:

PMe3 CCH2CHCN%k1

kK1

3 (1)

3CCH3CHO%k2

kK2

5 (2)

5%k3

kK3

6 (3)

6%k4

kK4

7CPMe3 (4)

Rate Zðk1k2k3Þ

ðkK1kK2Þ

� �½PMe3�½CH2CHCN�½CH3CHO� (5)

This rate expression is in agreement with the previous

kinetic studies [5] on the similar reaction.

4. Conclusion

From the above discussions, the following conclusions are

obtained:

(1) The catalytic cycle of Morita–Baylis–Hillman involves

four steps: initially, PMe3 1,4-addition to the activated

alkene forms the zwitterionic intermediate, then the

zwitterionic phosphonium adduct attacks the ethanal.

The next step is an intramolecular hydrogen transfer and

el in CH2Cl2 solvent

4 O5 CN PMe3

– – 0.0

– K0.07 K

– K0.33 0.96

.45 K0.56 – –

.20 K0.94 K0.11 1.10

.19 K0.94 K0.10 1.10

.11 K0.79 K0.29 1.03

.11 K0.75 K0.06 –

– K0.16 0.58

.34 K0.77 K0.21 1.06

.32 K0.78 K0.22 1.07

.14 K0.91 K0.17 1.09

.11 K0.91 K0.15 1.09

.12 K0.77 K0.22 0.69

J. Xu / Journal of Molecular Structure: THEOCHEM 767 (2006) 61–6666

finally the product eliminates from product complex and

the catalyst PMe3 is regenerated.

(2) The hydrogen transfer step is predicted to be the rate-

limiting step for the whole reaction. At the same time, the

predicted rate expression is in agreement with the previous

kinetic studies.

(3) The computational results make clear that the Morita–

Baylis–Hillman process is equilibrated and it is in good

agreement with the previous experimental works. The

entropy plays a crucial role in the 1,4-addition and

aldolic steps.

(4) The CN group in the whole process mainly serves as an

electronic charge acceptor to delocalize the electronic

charge on carbon through the p–p interaction between C

and CN group.

To the best of our knowledge, this work is the first

comprehensive computational study of the Baylis–Hillman

reaction. However, this work left unanswered the questions

related to the role of protonic solvent and product. These

questions are a subject of ongoing work and will be reported

elsewhere.

Acknowledgements

This work is supported by the project of science and

technology of Chongqing education council, People’s Republic

of China (No. KJ051302). I are grateful to the reviewers for

their pertinent comments and good suggestions concerning my

original manuscript.

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