The legend of 4-aminocoumarin: use of the Delepinereaction for synthesis of 4-iminocoumarin

Ahmed A. Al-Amiery • Abdul Amir H. Kadhum •

Y. K. Al-Majedy • Hiba H. Ibraheem •

Ali A. Al-Temimi • Redah I. Al-Bayati •

Abu Bakar Mohamad

Received: 11 June 2012 / Accepted: 18 June 2012 / Published online: 4 July 2012

� Springer Science+Business Media B.V. 2012

Abstract Use of the Delepine reaction for synthesis of 4-aminocoumarin from

4-chlorocoumarin was not successful. The product was 4-iminocoumarin instead of

4-aminocoumarin. The 4-iminocoumarin was characterized by elemental analysis

and spectral studies (FT-IR, 1H NMR, 13C NMR). Density functional theory cal-

culations for 4-iminocoumarin were performed using molecular structure with

optimized geometry. Molecular orbital calculations provided a detailed description

of the orbitals, including spatial characteristics, nodal patterns, and the contributions

of individual atoms.

Keywords 4-Aminocoumarin � 4-Chlorocoumarin � Delepine �4-Hydroxycoumarin � 4-Iminocoumarin

Introduction

An overview of efforts directed toward the synthesis of new chemical compounds

and natural products with expected biological activity is of interest to researchers

nowadays because drug resistance has become a growing problem in the treatment

of infectious diseases caused by bacteria and fungi [1–6]. Coumarin and its

derivatives are among the most active classes of compounds with a wide range of

biological activity [7, 8], including anticoagulant, estrogenic, dermal photosensi-

tizing, antimicrobial, vasodilator, molluscicidal, antihelmintic, sedative and

A. A. Al-Amiery (&) � A. A. H. Kadhum � A. B. Mohamad

Department of Chemical and Processing Engineering, Faculty of Engineering and Built

Environment, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia

e-mail: dr.ahmed1975@gmail.com

A. A. Al-Amiery � Y. K. Al-Majedy � H. H. Ibraheem � A. A. Al-Temimi � R. I. Al-Bayati

Biotechnology Division, Applied Science Department, University of Technology,

Baghdad 10066, Iraq

123

Res Chem Intermed (2013) 39:1385–1391

DOI 10.1007/s11164-012-0694-7

hypnotic, analgesic, and hypothermic action [9–16]. In addition, coumarins have

been shown to inhibit N-methyl-N-nitrosourea, aflatoxin B1, and 7,12-dimethyl-

benz(a)anthracene-induced mammary carcinogenesis in rats [17, 18]. More recently,

coumarin derivatives had been evaluated for their ability to inhibit human

immunodeficiency virus [19, 20]. Only five papers have been published on the

synthesis of 4-aminocoumarin and in each of these the melting point of

4-aminocoumarin has been different [21–25]. In 2010 Stamboliyska et al. [26]

prepared 4-aminocoumarin by melting 4-hydroxycoumarin with ammonium acetate,

in accordance with the method reported by Manolov and Danchev [22]; again the

melting point was different. In this study we tried to synthesize 4-aminocoumarin

from 4-chlorocoumarin by use of the Delepine reaction, but the product was proved

by IR, NMR spectroscopy, and elemental analysis to be 4-iminocoumarin.

Results and discussion

The reaction sequence outlined in Scheme 1 was used for synthesis of 4-imino-

coumarin. We started from 4-hydroxycoumarin (1) which is commercially available

or, alternatively, readily accessible [26]. Addition of phosphorous oxychloride to

4-hydroxycoumarin yielded 4-chlorocoumarin which is easily converted to 4-imi-

nocoumarin via the Delepine reaction.

The Delepine reaction is the organic synthesis of primary amines by reaction of a

benzyl or alkyl halide with hexamethylenetetramine (HMTA) followed by acid

hydrolysis of the quaternary ammonium salt [27, 28]. The mechanism postulated for

synthesis of 4-iminocoumarin is depicted in Scheme 2.

In the IR spectrum of 4-iminocoumarin the lactone carbonyl stretching frequency

was observed at 1,718 cm-1, imino (C=N) stretching appeared at 1,646.1 cm-1, and

C–C aromatic was at 1,604.9 cm-1. The frequency of N–H stretching was

3,390 cm-1, that of aromatic C–H was at 3,077.8 cm-1, and that of aliphatic C–H at

2,927.2 cm-1. It is very clear from the IR spectrum that our product contains an

imino group, carbonyl, and aliphatic C–H, and no NH2 group. In the 1H NMR

spectrum of 4-iminocoumarin, a 2H singlet from the CH2 protons was observed at

3.85 ppm and a multiplet from the aromatic ring protons at 7.37–8.05 ppm. The

absence of peaks of C=C (doublet at 4.5 ppm and triplet at 5.5 ppm) for the lactone

ring is good evidence of the formation of an imine and not an amine. This 13C NMR

spectral analysis of iminocoumarin, combined with information from 1H NMR

spectroscopy, can be used as a guide for future synthetic work.

O O

NH2

N

N N

NO O

Cl

O O

NH

O O

OH

POCl3

Scheme 1 Reaction forsynthesis of 4-iminocoumarin

1386 A. A. Al-Amiery et al.

123

Computational studies

Atomic charges and stability

Theoretical studies of iminocoumarin revealed the atomic charges were affected by

the presence of the ring substituent. The optimized geometry is shown in Fig. 1, and

the atomic charges calculated for the compound are listed in Table 1. It is apparent

from Table 1 that the highest atomic charge is at O(3) (-0.5649); the next highest is

at N(12) (-0.3909). These results clearly indicate that these two atoms are the most

reactive sites in reactions and bonding with metals. The calculated bond and twist

angles and the 3D geometrical structure indicated the molecule is not planar.

Density functional theory (DFT)

DFT calculations were performed for iminocoumarin. The optimized molecular

structure of the most stable form is shown in Fig. 1. The calculated energies and

relative energies are listed in Table 2. Molecular orbital calculations provide a

detailed description of the orbitals, including spatial characteristics, nodal patterns,

and individual atom contributions. The contour plots of the frontier orbitals for the

ground state of 4-iminocoumarin are shown in Fig. 2, including the highest

occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital

(LUMO). It is interesting to see that these orbitals are substantially distributed over

the conjugation plane. It can be seen from Fig. 2 that the HOMO orbitals are located

on the substituent of the molecule whereas the LUMO orbitals resemble those of the

unsubstituted molecule; substitution thus has an effect on electron-donor activity but

only a small effect on electron-acceptor activity. The energy levels of the HOMO

and LUMO of 4-iminocoumarin are listed in Table 3. The energy gap between

HOMO and LUMO is approximately 8.1 eV. This low value for the HOMO–LUMO

energy gap explains the charge-transfer interaction which occurs within the

molecule. The dipole was also calculated and is given in Table 2.

O O

NH2

O O

NH

N

N N

N

O O

Cl

N

N N

N

O O

Cl

HCl/ H2O

Scheme 2 Mechanism postulated for synthesis of 4-iminocoumarin

The legend of 4-aminocoumarin 1387

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Experimental

The chemicals used for the synthesis were supplied by Sigma–Aldrich. The purity of

the compounds was checked by thin layer chromatography on silica gel G plates

with benzene–ethyl acetate–methanol (40:30:30 v/v) and toluene–acetone (75:25

v/v) as mobile phases. The spots were located under UV light (254 and 365 nm). IR

spectra were obtained on a Thermo Scientific Nicolet 6700 FT-IR spectrometer

Fig. 1 3D geometrical structure of 4-iminocoumarin

Table 1 Atomic charges of 4-iminocoumarin

Atom Charge Atom Charge Atom Charge Atom Charge

O(1) -0.140303 C(6) -0.0646747 C(11) 0.27405 H(16) 0.0254396

C(2) 0.632609 C(7) -0.0238036 N(12) -0.390919 H(17) 0.0249266

O(3) -0.564933 C(8) -0.0878448 H(13) 0.0383662 H(18) 0.0283406

C(4) -0.155057 C(9) -0.0175618 H(14) 0.071976 H(19) 0.110465

C(5) 0.325985 C(10) -0.110702 H(15) 0.0236411

Table 2 Total energy and

dipole moment (Debye) for

iminocoumarin

Total energy Dipole moment

12.7813 kcal/mol 6.6713

1388 A. A. Al-Amiery et al.

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(without use of KBr or CsI). 1H NMR spectra were obtained on a Jeol jnm-ECP400

FT-NMR system. Elemental microanalysis was performed with a model 5500-Carlo

Erba C.H.N elemental analyzer. A Gallenkamp M.F.B.600.010 F melting point

apparatus was used to measure the melting points of all the prepared compounds.

Synthesis of 4-chlorocoumarin

4-Hydroxycoumarin (3 g, 0.0185 mol) and 7 mL POCl3 were heated under reflux

for 2 h. After cooling the mixture was poured on to crushed ice with vigorous

stirring. The solid obtained was isolated by filtration and washed with cold water.

Yield (60 %) MP. 90 �C (lit. 89–91 �C) [29].

IR spectrum, m, cm-1: 3043 (C–H aromatic), 1700.1 (C=O), 1634.2 (C=C),

1609.1 (C=C aromatic), (C–O), 764(C–Cl).

HOMO LUMO

HOMO-1 LUMO+1

Fig. 2 HOMO and LUMO orbitals for 4-iminocoumarin

Table 3 HOMO and LUMO

orbital energies (eV)HOMO LUMO HOMO-1 LUMO?1

-11.070 -2.895 -12.104 -0.549

The legend of 4-aminocoumarin 1389

123

1H NMR spectrum (400 MHz, CDCl3), d, ppm (J, Hz): 6.62 (1H, s, C=C–H

alkene); 7.88–7.30 (4H, m, C–H aromatic).

Elemental analysis Found, %: C 59.85; H 2.79. C9H5ClO2. Calculated, %: C

60.23; H 2.31.

Synthesis of 4-iminocoumarin (Delepine reaction)

A mixture of 4-chlorocoumarin (0.0298 mol) and HMTA (4.61 g, 0.0328 mol) in

chloroform (CHCl3) (50 mL) was stirred at room temperature for 24 h then

concentrated under vacuum to give the crude Delepine adduct. Ethanol (25 mL,

95 %) and 12 M hydrochloric acid (HCl) (7.5 mL) were added to this solid. After

stirring at room temperature for 6 h, the heterogeneous reaction mixture was cooled

in an ice bath and filtered to remove ammonium chloride (NH4CI). The filter cake

was washed with EtOH (200 mL, 95 %). The combined filtrate was extracted with

CH2Cl2 (2 9 200 mL) and concentrated to give the 4-iminocoumarin. UV–visible

spectroscopy in ethanol, 290 and 310 nm, melting point 255 �C; lit. for 4-amino-

coumarin; 226–228 �C [26], 161.5–162 �C [21], 199 �C [25], 232–234 �C [21],

241–243 �C [23].

IR spectrum, m, cm-1: 3390 (N–H), 3077.8 (C–H aromatic), 2927.2 (C–H

aliphatic), 1718 (C=O), 1646.1 (C=N), 1604.9 (C–C aromatic).1H NMR spectrum (400 MHz, CDCl3), d, ppm (J, Hz): 3.85 (2H, s, J = 7.389,

CH2); 7.37–8.05 (4H, m, C–H aromatic).13C NMR spectrum (125 MHz, CDCl3), d, ppm: 20 (C4); 103 (C5); 118 (C7); 124

(C8); 127 (C9); 152 (C6); 162 (C11); 164 (C2).

Elemental analysis Found, %: C 66.70; H 4.38; N 8.69. C9H7NO2. Calculated, %:

C 65.99; H 4.01; N 8.50.

Conclusions

In this study a new method was used for synthesis of 4-iminocoumarin. The product

was characterized by use of a variety of spectroscopic methods and elemental

analysis. A mechanism for synthesis of the target compound has been postulated.

Acknowledgments The authors gratefully acknowledge Universiti Kebangsaan Malaysia for support of

this project.

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