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Chinese Chemical Letters 19 (2008) 375–378

www.elsevier.com/locate/cclet

DFT study on mechanism of the classical Biginelli reaction

Jin Guang Ma, Ji Ming Zhang, Hai Hui Jiang, Wan Yong Ma, Jian Hua Zhou *
School of Chemical Engineering, Shandong Institute of Light Industry, Jinan 250353, China
Received 27 August 2007

Abstract
The condensation of benzaldehyde, urea, and ethyl acetoacetate according to the procedure described by Biginelli was
investigated at the B3LYP/6-31G(d), B3LYP/6-31+G(d,p), and B3LYP/6-311+G(3df,2p)//B3LYP/6-31+G(d,p) levels to explore
the reaction mechanism. According to the mechanism proposed by Kappe, structures of five intermediates were optimized and four
transition states were found. The calculation results proved that the mechanism proposed by Kappe is right.
# 2007 Jian Hua Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Biginelli reaction; Dihydropyrimidines; Transition state; DFT study

In recent times, dihydropyrimidinone derivatives have attracted considerable attention owing to their high activity
as antihypertensive, antiviral, antitumor and anti-inflammatory agents, and as calcium channel blockers [1–4].
The original procedure for the preparation of this type of compounds was reported by Biginelli [5], involving one-pot
condensation of benzaldehyde (R1), urea (R2) and ethyl acetoacetate (R3) under strongly acidic conditions
(Scheme 1).
Due to the importance and current interests [6] in dihydropyrimidines, the mechanism of the classical three-
component Biginelli condensation was researched by many chemists [7–9]. In 1997, Kappe [10] reinvestigated the
mechanism using 1H and 13C NMR spectroscopy and proved that the first step reaction is the acid-catalyzed formation
of a N-acyliminium ion intermediate from the aldehyde and urea component. Interception of the iminium ion by ethyl
acetoacetate, possibly through its enol tautomer, produces an open-chain ureide which subsequently cyclizes to
dihydropyrimidine. But Kappe’s research could not isolate the highly reactive N-acyliminium.
At present, quantum chemistry methods are more and more used for elucidating mechanisms [11] of chemical
reaction. In this letter, the mechanism of the classical Biginelli reaction was investigated through density functional
theory method. The calculation results proved that the mechanism proposed by Kappe is right.

1. Calculation method

Geometry optimizations were carried out at the B3LYP/6-31G(d) level along with analytic vibrational frequency
calculations in order to characterize the obtained structures as minima or as transition states on the potential energy

* Corresponding author.
E-mail address: zhoujianhua4@163.com (J.H. Zhou).

1001-8417/$ – see front matter # 2007 Jian Hua Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2007.11.030
376 J.G. Ma et al. / Chinese Chemical Letters 19 (2008) 375–378

Scheme 1. The classical Biginelli reaction.

surface (PES). The intrinsic reaction coordinate (IRC) calculations were performed at the same level for connecting
the transition states to reactants and products. Moreover, the PES information of the reaction was also calculated at the
B3LYP/6-31+G(d,p) level. To obtain more reliable energies, single-point calculations were performed at B3LYP/6-
311+G(3df,2p)//B3LYP/6-31+G(d,p) level. All computations were performed using the Gaussian’03 program
package in Virtual Laboratory of Computational Chemistry, Computer Network Information Center, the Chinese
Academy of Sciences. Based on the results of DTF computed, the equilibrium constant was calculated by statistical
thermodynamics theory [12].

2. Results and discussion

The labels of various species and the mechanism of classical Biginelli condensation are shown in Scheme 2. The
relative energies of various species computed at B3LYP/6-31G(d) level and B3LYP/6-311+G(3df,2p)//6-31+G(d,p)
level are in Table 1. It can be seen that the computed results of the two methods are extremely close. The IRC curves of
TSs of the reaction computed at B3lyp/6-31G(d) level are shown in Fig. 1. The PES calculated at the B3LYP/6-
311+G(3df,2p)//6-31+G(d,p) level is shown in Fig. 2. The total process is an exothermic reaction with the reaction heat
of 24.64 kJ/mol.

Scheme 2. Mechanism of the classical Biginelli condensation.

 J.G. Ma et al. / Chinese Chemical Letters 19 (2008) 375–378 377

Table 1
Relative energies (kJ/mol) of various species for the classical Biginelli reaction
Species DE1 (6-31+G(d,p)) DE2 (6-311+G(3df,2p))
+
R1 + R2 + R3 + H3O 0.00 0.00
TS1 + R3 + H3O+ 172.18 181.96
IM1 + R3 + H3O+ 12.30 6.16
IM2 + R3 + 2H2O 199.68 209.70
TS2 + 2H2O 182.87 184.95
IM3 + 2H2O 190.25 190.35
IM4 + H2O + H3O+ 32.59 23.84
TS3 + H2O + H3O+ 139.92 156.85
IM5 + H2O + H3O+ 19.22 5.61
TS4 + H2O + H3O+ 176.54 190.68
P + 2H2O + H3O+ 27.71 24.64

The reaction proceeds is divided into six steps. Structures of five intermediates were optimized and four transition
states were found. The imaginary frequencies of the four transition states are 1630.99i, 260.24i, 1545.63i and
1727.10i, respectively. Vibrational frequency analyses and IRC calculations show that the transition states are
assuredly connecting the reactants and products. The first step in this condensation is the reaction of R1 with R2 to
produce IM1 via the transition state TS1. A four-member ring is formed in TS1. Next, IM1 is expected to undergo
rapid dehydration in the presence of acid to a carbenium ion which may be formulated as a highly reactive N-
acyliminium species, i.e. IM2. Then, in the present of enol-ethyl acetoacetate R3, iminium ion IM2 reacts with it to
furnish IM3 via the transition state TS2. This step can be regarded as an addition of a p-nucleophile to the electron
deficient N-acyliminium. On the view of PES, the second and the third steps are fast steps compared with the first step.
Therefore, the experiment [10] did not allowed to observe any intermediates, e.g. IM1 or IM2, in this process. The
fourth step, IM3 turns to IM4 with a hydrion removal. Furthermore, IM4 cyclized to IM5 via the transition state TS3.

Fig. 1. The IRC curves of TSs of the reaction computed at B3LYP/6-31G(d) level.
378 J.G. Ma et al. / Chinese Chemical Letters 19 (2008) 375–378

Fig. 2. Potential energy surface (PES) of the reaction computed at B3LYP/6-311+G(3df,2p)//6-31+G(d,p) level.

Finally, IM5 dehydrated to the Biginelli compound P via the transition state TS4. A four-member ring is formed in TS3
and TS4, respectively. The reaction could occur easily because all of the forward barriers are less than 200 kJ/mol.
Thus, the mechanism proposed by Kappe is to be proved right. The calculated equilibrium constant is 70.80, so the
conversion ratio of the reaction would be high.

Acknowledgments

This work was supported by the Natural Science Foundation of Shandong Province, China (Nos. Y2006B42 and
Y2006B24).

References

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