Kinetics and mechanism of certain benzoylation reactions under Vilsmeier-Haack conditions using benzamide and oxychloride in acetonitrile medium

Article abstract of DOI:10.1002/kin.20740

Vilsmeier-Haack (VH) benzoylation reactions with benzaldehydes and acetophenones in acetonitrile medium obeyed second-order reaction kinetics. Under kinetic conditions, the reactions afforded benzoyl derivatives irrespective of the nature of oxychloride (

Full text of DOI:10.1002/kin.20740

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Kinetics and Mechanism of
Certain Benzoylation
Reactions under
Vilsmeier–Haack Conditions
Using Benzamide and
Oxychloride in Acetonitrile
Medium
K. C. RAJANNA, M. VENKATESWARLU, M. SATISH KUMAR, U. UMESH KUMAR,
G. VENKATESHWARLU, P. K. SAIPRAKASH
Department of Chemistry, Osmania University, Hyderabad 500 007, India
Received 20 August 2011; revised 6 December 2011, 28 February 2012; accepted 2 March 2012
DOI 10.1002/kin.20740
Published online 18 December 2012 in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: Vilsmeier–Haack (VH) benzoylation reactions with benzaldehydes and acetophe-
nones in acetonitrile medium obeyed second-order reaction kinetics. Under kinetic conditions,
the reactions afforded benzoyl derivatives irrespective of the nature of oxychloride (POCl3 or
SOCl2) used for the preparation of VH reagent along with benzamide. The present finding
is advantageous to understand the nature of reactive species as well as the mechanism of
benzoylation. ꢀ 2012 Wiley Periodicals, Inc. Int J Chem Kinet 45: 69–80, 2013
C
(VHR) is basically a halomethylene iminium salt, pre-
pared from equimolar oxychloride (POCl3) and N-Nꢁ-
dimethyl formamide (DMF) under chilled conditions
(at −5◦C temperature) in 1927 by Vilsmeier and Haack
[1]. Later on, it was also shown that a similar type of
VH adducts could be obtained from N-Nꢁ-dimethyl ac-
etamide or analogous N-Nꢁ-dialkyl amides along with
oxychloride. This reagent has attracted the attention
of chemists since its discovery due to simplicity in
its preparation and utility to synthesize a variety of or-
ganic carbonyl compounds that are being used as inter-
mediates and/or starting materials in several synthetic
INTRODUCTION
The Vilsmeier–Haack (VH) reaction is one of the
mildest methods for the introduction of a formyl or
acetyl group to various aromatic and heteroaromatic
compounds [1–3]. The Vilsmeier and Haack reagent
Corresponding to: K. C. Rajanna, e-mail: kcrajannaou@
rediffmail.com, kcrajannaou@yahoo.com.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
c
ꢀ
2012 Wiley Periodicals, Inc.

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RAJANNA ET AL.
protocols [4–14]. For instance, formylated anilines are
used for the synthesis of di- and polyamines of the
diphenyl methane derivatives [10]; formyl phenols are
used as prodrugs for the drug formyl phenyl aspirins
[11], whereas formyl quinolines are known to exhibit
antibacterial [12] and antifungal activity [13]. Over
the past two decades, our group is also actively work-
ing on exploiting the use of a variety of ecofriendly
materials such as surfactants and nonconventional en-
ergy sources for triggering VH reactions [14]. Earlier
publications from our laboratory reported kinetics and
mechanism for the formylation of coumarin derivatives
and orthohydroxy acetophenones (OHAP) under VH
conditions [9]. The present investigation is one such
exercise, which is aimed to explore the mechanism of
benzoylation reactions with aromatic aldehydes and
ketones under VH conditions by studying the kinetics
of certain organic compounds, such as benzaldehydes
and acetophenones.
Kinetic Method
The method that is followed for the kinetics of the VH
reaction is by and large similar to that reported in our
earlier paper [9]. Athermostat (Toshniwal, India) was
adjusted to desired reaction temperature. Two differ-
ent flasks, one containing known amount of VHR and
the other with the substrate solution, were clamped in
the thermostatic bath for about half an hour. A reac-
tion was initiated by adding requisite amount of sub-
strate solution to the reaction vessel containing VHR
and other contents of the reaction mixture. The en-
tire reaction mixture was stirred until the end of the
reaction. Aliquots of the reaction mixture were with-
drawn into a conical flask, containing about 50 mL of
hot distilled water, at regular time intervals. The un-
reacted VH adduct underwent hydrolysis and gave a
mixture of hydrochloric and sulfuric acids in the case
of [benzamide/SOCl2] and a mixture of hydrochloric
and phosphoric acids in the case of [benzamide/POCl3]
reagent. The acid content was estimated against stan-
dard NaOH solution to bromocresol green end point.
EXPERIMENTAL
The chemicals used in the present study, viz. aromatic
aldehydes, acetophenones, and oxychloride (POCl3,
SOCl2), were procured from either Aldrich or Merck.
The solvents acetonitrile (ACN), dichloromethane
(DCM), tetrahydrofuran (THF), benzene, and
dichloroethane (DCE) were either HPLC grade or pu-
rified according to standard literature reports.
Product Analysis under Kinetic Conditions
After completion of the kinetic study, remaining part
of the reaction mixture was refluxed further until the
reaction was over (as ascertained by TLC). The so-
lution was then transferred into a beaker containing
excess of water with vigorous stirring and kept aside
for about 2 h. The resultant solution was neutralized
by sodium hydrogen carbonate. The organic phase
was extracted with DCE, dried with MgSO4, and the
solvent evaporated. The reaction times and percent-
age yields of the products are compiled in Table I.
The products were characterized by IR, 1H NMR,
mass spectra, and physical data with authentic sam-
ples and found to be satisfactory. Spectroscopic data
(1H NMR, and mass spectra) for certain representative
General Procedure for Preparation of VHR
The VH adduct is prepared afresh before use from
equimolar oxychloride (POCl3 or SOCl2) and benza-
mide using standard literature procedures [9,14]. To a
chilled (at –5◦C) benzamide solution prepared in DCE
or ACN, calculated amount of POCl3was slowly added
dropwise and stored under cold conditions.
Table I VH Benzoylation Reactions of Carbonyl Compounds with (Benzamide + SOCl2) and (Benzamide + POCl3)
(Benzamide + SOCl2) (Benzamide + POCl3)
RT (h) Yield (%) RT (h) Yield (%)
Entry
Substrate
1
2
3
4
5
6
7
8
9
10
Benzaldehyde
Salicylaldehyde
4-OH benzaldehyde
4-OMe benzaldehyde
4-Cl benzaldehyde
Cinamaldehyde
12
12
11
13
13
13
12
12
12
11
65
70
80
67
63
62
74
80
71
69
11
12
11
12
11
13
12
11
11
11
69
70
83
67
75
73
77
76
75
70
Acetophenone
2- OH acetophenone
4-OH acetophenone
3-OH acetophenone
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KINETICS AND MECHANISM OF CERTAIN BENZOYLATION REACTIONS
71
Table II Spectroscopic Data for VH benzoylation of Aromatic Carbonyl Compounds
Spectral data
1H NMR
Entry
1
Substrate
Product
m/z
Benzaldehyde
3-Benzoyl benzaldehyde
210 δ 7.35 (m, 4H, Ar); δ 7.65 (d, 2H, Ar); δ 8.0 (d, 2H, Ar)
δ 8.37 (s, 1H, Ar); δ 10.05 (s, 1H, Ar-CHO)
258 δ 7.35–7.92 (m, 8H, Ar); δ 10.1 (s, 1H CHO); δ 10.7 (s,
1H, Ar-OH)
258 δ 7.3 (m, 4H, Ar); δ 7.6 (d, 1H, Ar); δ 8.0 (d, 2H, Ar) δ
8.3 (s, 1H, Ar); δ 9.95 (s, 1H, Ar-CHO); δ 10.95 (s,
2H, Ar-OH)
2
3
Salicylaldehyde
3-Benzoyl salicylaldehyde
4-OH benzaldehyde
3-Benzoyl 4-OH
benzaldehyde
4
4-OMe benzaldehyde 3-Benzoyl 4-OMe
benzaldehyde
240 δ 3.7 (s ,3H, OCH3); δ 7.4 (m, 4H, Ar); δ 7.75 (d, 1H,
Ar) δ 7.9 (d, 2H, Ar); δ 7.75 (d, 1H, Ar); δ 7.9 (d,
2H, Ar) δ 8.2 (d, 1H, Ar); δ 10.05 (s, 1H, Ar-CHO)
244 δ 7.4 (m 4H, Ar); δ 7.7 (d 1H, Ar); δ 8.3 (d 2H, Ar) δ
8.45 (s 1H, Ar); δ 10.0 (s 1H, Ar-CHO)
235 δ 6.75 (d,1H, CH); δ 7.4 (m, 1H, Ar); δ 7.45 (d, 1H,
Ar) δ 7.5–7.8 (m, 7H, Ar); δ 8.05 (d, 1H, CH); δ
9.9 (s, 1H, Ar)
5
6
4-Cl benzaldehyde
Cinamaldehyde
3-Benzoyl 4-Cl
benzaldehyde
3-Benzoyl cinamaldehyde
7
8
9
Acetophenone
3-Benzoyl acetophenone
3-Benzoyl chromone
224 δ 2.8 (s, 3H, CH3); δ 7.8 (m, 5H, Ar); δ 7.6 (m, 1H,
Ar), δ 7.95 (d, 2H, Ar); δ 8.45 (s 1H, Ar)
250 δ 6.34 (s, 1H, Ar); δ 7.4 (m, 6H, Ar); δ 7.65 (d, 2H, Ar),
δ 7. 9 (d, 1H, Ar)
240 δ 2.9 (s, 3H, CH3); δ 7.3 (m, 3H, Ar); δ 7.6 (d, 2H, Ar),
δ 8.45 (m, 2H, Ar); δ 8.8 (s, 1H, Ar);δ 10.9 (s, 1H,
Ar-OH)
2-OH acetophenone
4-OH acetophenone
3-Benzoyl 4-OH
acetophenone
10
3-OH acetophenone
3-Benzoyl 3-OH
acetophenone
240 δ 2.8 (s, 3H, CH3); δ 7.45 (s, 1H, Ar); δ 7.6–7.8 (m,
5H, Ar), δ 7.95 (s, 2H, Ar); δ 10.05 (s, 1H, Ar)
compounds are given in Table II. Aromatic compounds
such as aldehydes and ketones generally underwent
benzoylation even under kinetic conditions with VHR
and afforded good yields of products. It is of inter-
est to note that only OHAP underwent cyclization fol-
lowed by benzoylation and afforded benzoyl chromone
derivatives. Meta and para hydroxy benzophenones (3-
OHAP, and 4-OHAP) did not undergo cyclization but
afforded benzoyl derivatives. The difference in the re-
activity of OHAP from 3-OHAP and 4-OHAP could
be attributed to the fact that the –OH group is far
from the carbonyl (main) functional group, which is
favorable to form a stable ring through cyclization.
A general VH benzoylation reaction is presented in
Scheme 1.
RESULTS AND DISCUSSION
Salient Features of the Kinetic Study
Under pseudo–first-order conditions, viz., [VHR] <<
[substrate], plots of ln Vt vs. time have been found to be
linear with negative slope indicating first order with re-
spect to [VHR] (Fig. 1A). From the slopes of the plots
kꢁ was calculated. However, under equimolar condi-
tions ([VHR] = [substrate]), the plots of 1/Vt vs. time
have been found to be linear with positive slopes and an
intercept on the ordinate depictingover all second-order
reaction (Fig. 1B). Activation parameters for these re-
actions are computed from Eyring’s plots (Fig. 1C) and
presented in Tables III and IV. (The rate constant data
for the first-order kinetics are presented in Tables S.1
and S.2, and the data for the evaluation of second-order
rate constants at various temperatures are compiled in
Tables S.3–S.10 as Supporting Information.)
Y
O
II
Y
VHR = benzamide / oxychloride
ACN/DCE
Ph
X
X
Formation and Reactive Species
of VH Adduct
Scheme 1
VH benzoylation of benzaldehydes and
benzamide/SOCl2 or
acetophenones, where VHR
=
Reaction kinetics could be used as one of the
most efficient tools to propose the mechanism of a
benzamide/POCl3; Y = CHO, COCH3; X = electron-
donating or -withdrawing groups.
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RAJANNA ET AL.
Figure 1 Kinetics and Eyring plots for VH benzoylation of benzaldehyde using (benzamide + SOCl2). (A) [VHR] =
0.010 mol dm−3; [Benzaldehyde] = 0.100 mol dm–3; solvent = MeCN; temperature = 300 K; (B) [VHR] = 0.100 mol
dm–3;[benzaldehyde] = 0.100 mol dm–3; solvent = MeCN; temperature = 300 K; (C) the temperature effect.
chemical reaction. However, it is essential to gain an in-
sight into the nature of reactive species that are present
in the reaction mixture during the course of study to
propose the mechanism. On the basis of elemental anal-
ysis [1a], Vilsmeier and Haack indicated that 1 mol of
oxychloride [POCl3] reacts with one of the amides to
form an intermediate adduct, which is responsible for
formylation. Since then different opinions prevailed for
the formulations of the reactive VH adduct species [4–
9]. Infrared spectroscopic studies of Arnold and Holy
International Journal of Chemical Kinetics DOI 10.1002/kin.20740