Synthesis of dipyrromethanes in aqueous media using boric acid

Article abstract of DOI:10.24820/ark.5550190.p009.847

Boric acid acts as an efficient and green catalyst for the condensation reaction of pyrrole and aldehydes in aqueous medium to produce parallel library of dipyrromethanes including new compound analogue, meso-acetyldipyrromethane in moderate to good yield. The use of boric acid as catalyst and selective reactivity of aldehydes over ketones in its presence, and water as reaction medium are important attributes in the present protocol.

Full text of DOI:10.24820/ark.5550190.p009.847

General Papers
ARKIVOC 2016 (vi) 144-151
Synthesis of dipyrromethanes in aqueous media using boric acid
Anchal Singhal,a Snigdha Singhb and Shive M. S. Chauhan*a
a Department of Chemistry, University of Delhi, Delhi 110 007, India
b Department of Chemistry, Hans Raj College, University of Delhi, Delhi 110 007, India
E-mail: smschauhanchemistry@gmail.com
DOI: https://doi.org/10.24820/ark.5550190.p009.847
Abstract
Boric acid acts as an efficient and green catalyst for the condensation reaction of pyrrole and
aldehydes in aqueous medium to produce parallel library of dipyrromethanes including new
compound analogue, meso-acetyldipyrromethane in moderate to good yield. The use of boric acid
as catalyst and selective reactivity of aldehydes over ketones in its presence, and water as reaction
medium are important attributes in the present protocol.
Keywords: Pyrrole, aldehydes, boric acid, dipyrromethanes, meso-acetyldipyrromethane
Introduction
Dipyrromethanes are the important precursors for synthesis of various natural and functional
porphyrins, porphyrinoid macrocycles, linear porphyrin arrays and expanded porphyrins.1-4
Recently, its applications have been extended for synthesis of gold nanoparticles.5 The
condensation of aldehydes with excess of pyrrole in the presence of acid such as trifluoroacetic
acid,6 BF3etherate,7,8 ptoluenesulfonic acid,9 acetic acid,10,11 indium chloride,12 or metal
triflates13 in organic solvents or in the absence of solvent has been reported as general methods for
synthesis of mesosubstituted dipyrromethanes along with oligomeric byproducts.14,15 The major
disadvantages of these methods include the requirement of large amounts of pyrrole, corrosive
acidic catalyst and the use of chlorinated solvents. Hence, a mild route to synthesis of
dipyrromethanes is desirable due to its vast applications in organic syntheses.
Organic reactions in aqueous media comprise an important area of current research interests
including green chemistry.16-18 Our research group has developed a few green methods for
synthesis of dipyrromethanes and related compounds19-22 in addition to other groups.23-25 Boric
acid has been used as catalyst for synthesis of bis(indolyl)methanes,26 benzoxanthenes,27
dehydration of glucose,28 protection and deprotection of alcohols and ethers,29 Nacylation,30
bromination,31 aza Michael reactions,32 Biginelli reactions33 and other condensation reactions.34-36
Herein, we have described the use of boric acid as an innocuous and highly efficient catalyst for
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the condensation reaction of pyrrole and aldehydes in aqueous medium to afford the corresponding
dipyrromethanes. This investigation presents the simplest protocol for this type of reactions and
anticipates as interesting for wide range of organic chemists.
Results and Discussion
In this report, we describe an efficient method for synthesis of dipyrromethanes using boric acid
in aqueous medium at 30°C (~room temperature) as depicted in Scheme 1. The reaction of 37%
formaldehyde with 2.5 equiv. of pyrrole in aqueous solution of boric acid at 30°C for 6 h gave
dipyrromethane (3a) in 65% yield. The reaction of benzaldehyde with pyrrole under similar
reaction conditions for 8 h gave meso-phenyldipyrromethane (3b) in 59% yield. No product was
formed in the absence of boric acid. Further, the reaction of pyrrole with different aldehydes in
presence of boric acid in aqueous media was performed under similar reaction conditions to
produce a parallel library of dipyrromethanes.
Scheme 1. Key reaction for synthesis of dipyrromethanes.
The reaction of ketones with pyrrole catalyzed by boric acid in aqueous solution at 30°C did
not provide any product. This was further confirmed when the reaction of methylglyoxal with
pyrrole gave only mesoacetyl dipyrromethane (3k) under similar conditions for 12h. (This
compound is introduced for the first time and has never been reported in the literature to the best
of our knowledge). This confirmed that aldehyde was reacted selectively with pyrrole in aqueous
solution of boric acid. This could be attributed to low reactivity of ketones as compared to
aldehydes and mild nature of boric acid. The reaction time and yield of different dipyrromethanes
are summarized in Table 1.
Its easy availability, cost effectiveness and environmental compatibility in addition to weak
−
acidity and ability to produce H+ from its reaction with water, B(OH)3 + H2O → B(OH)4 + H+
were some of the most important reasons for selecting boric acid as catalyst. Further, because of
easy handling and operation, its weak acidity lead to the desired product selectively in high efficacy
without any side products.
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Table 1 Dipyrromethane derivatives 3a−k produced according to Scheme 1
Product
3a
R
H
Time (h)
Yield (%)
6
65
59
65
63
65
63
68
67
69
68
70
3b
3c
Ph
8
4-ClC6H4
4-FC6H4
4-BrC6H4
4-O2NC6H4
4-CH3C6H4
2,4,6-(CH3)3C6H2
4-CH3OC6H4
4-pyridyl
CH3CO
12
12
12
12
10
10
10
12
12
3d
3e
3f
3g
3h
3i
J
3k
The condensation reaction of pyrrole with aldehydes is believed to occur at the interface of
organic and aqueous layers. The release of dipyrromethane from the aqueous layer through
interphase to organic layer was responsible for completion of the reaction and protection of the
dipyrromethane from further reactions. The prolonging of the reaction time and changing the
reaction conditions lead to the formation of some undesirable products such as tripyrromethane
and other higher oligomers as observed by TLC. The reaction of pyrrole with aldehydes in aqueous
boric acid solution gave the pure dipyrromethanes in high yields (Table 1).
The plausible mechanism of the reaction could be explained as that reaction proceeded with
protonation of carbonyl oxygen of aldehyde molecule in presence of aqueous solution of boric acid
followed by nucleophilic attack at the α-position of pyrrole. Deprotonation at this step stabilized
the intermediate. Further protonation and subsequent reaction with a second molecule of pyrrole
with the loss of water molecule followed by deprotonation gives dipyrromethane (Scheme 2).
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Scheme 2. Plausible mechanism for the synthesis of dipyrromethane.
Conclusions
Boric acid is advocated as mild and eco-friendly catalyst for the synthesis of a parallel library of
dipyrromethanes including new compound analogue, meso-acetyldipyrromethane in aqueous
medium. Boric acid, being mild in nature, offered desired dipyrromethanes selectively without any
polymerization of the products or other side reactions. The advantages of the present method
include avoiding the use of large excess of pyrrole and corrosive acidic catalyst.
Experimental Section
General Information. All chemicals used were of analytical grade. Pyrrole, aldehydes and
solvents were freshly distilled prior to use. Identities of all known products were confirmed by
comparison with their physical and spectral data. The dipyrromethanes were easily visualized upon
exposure of thin layer chromatography plates to iodine vapor. 1H NMR spectra were recorded on
a Bruker Avance Spectrospin 300 MHz spectrophotometer. The chemical shifts in parts per million
(ppm) for proton (1H) NMR spectra were internally referenced relative to tetramethylsilane (TMS,
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0.00 ppm). The mass spectra (ESI-MS) were recorded on Micromass LCT KC-455 instrument
using electron spray positive ion mode.
General reaction procedure for the synthesis of dipyrromethanes
Aldehyde (20 mmol, 1 equiv.) was added to aqueous solution of boric acid (248 mg in 10 ml of
water) followed by dropwise addition of pyrrole (3.35 g, 50 mmol). The reaction mixture was
stirred on a magnetic stirrer in an open atmosphere at 30°C and the progress of the reaction was
monitored by TLC. After completion of the reaction (when aldehyde was consumed, as checked
by TLC), the organic layer was separated and aqueous layer was extracted with dichloromethane,
the combined organic layers were dried over anhydrous Na2SO4 and purified by column
chromatography over silica gel (60-120 mesh) using petroleum ether-chloroform (ratio varied with
product) to give corresponding dipyrromethanes respectively. The spectral data of the compounds
are reported below:
Dipyrromethane (3a). Greyish solid, mp 73 °C (lit.11 mp 75 °C, lit. yield11 41%). 1H NMR (300
MHz, CDCl3): 3.92 (s, 2H), 6.02 (s, 2H), 6.14 (d, J 2.4 Hz, 2H), 6.64 (s, 2H), 7.83 (s, 2H, NH).
MS m/z (%): 146 [M]+ (100) calc. for C9H10N2.
meso-Phenyldipyrromethane (3b). White crystals, mp 100 °C (lit.11 mp 100-101 °C, lit. yield11
53%). 1H NMR (300 MHz, CDCl3): 5.48 (s, 1H), 5.92 (s, 2H), 6.16 (q, 2H), 6.70 (d, 2H), 7.21-
7.32 (m, 5H), 7.92 (brs, 2H). MS m/z (%): 222 (M+, 97), (M+_ C6H5, 100) calc. for C15H14N2.
meso-Chlorophenyldipyrromethane (3c). Pale yellow solid, mp 110 °C (lit.13 mp 112-113 °C,
lit. yield13 44%). 1H NMR (300 MHz, CDCl3): 5.44 (s, 1H), 5.88 (m, 2H), 6.24 (m, 2H), 6.70 (m,
2H), 7.24-7.29 (m, 2H), 7.93 (brs, 2H, NH). MS m/z (%): 256 (M+, 43), 258 (M+2)+, 14), 145 (M+_
C6H4Cl, 100) calc. for C15H13ClN2.
meso-Fluorophenyldipyrromethane (3d). White crystals, mp 81 °C (lit.11 mp 81 °C, lit. yield11
28%). 1H NMR (300 MHz, CDCl3): 5.49 (s, 1H), 5.93 (m, 2H), 6.20 (dd, J 2.8 Hz, 2H), 6.74 (m,
2H), 7.04 (m, 2H), 7.94 (m, 2H), 8.18 (brs, 2H, NH). MS m/z (%): 240 (M+, 100), 145 (M+_ C6H4F,
45) calculated for C15H13FN2.
meso-Bromophenyldipyrromethane (3e). White solid, mp 122 °C (lit.13 mp 122-123 °C, lit.
yield13 20%). 1H NMR (300 MHz, CDCl3): 5.43 (s, 1H), 5.86 (s, 2H), 6.15 (dd, J 4.5 Hz, 2H), 6.68
(d, J 8.2 Hz, 2H), 7.10-7.24 (m, 4H), 7.92 (brs, 2H, NH). MS m/z (%): 301 (M+, 100), 303 [(M+2)+,
98], 112 (M+_ C6H4Br, 80) calculated for C15H13BrN2.
meso-Nitrophenyldipyrromethane (3f). Yellow solid, mp 159 °C (lit.11 mp 159-160 °C, lit.
yield11 56%). 1H NMR (300 MHz, CDCl3): 5.58 (s, 1H), 5.87 (s, 2H), 6.17 (dd, J 4.4 Hz, 2H), 6.75
(d, J 4.8 Hz, 2H), 7.37-8.02 (m, 4H), 8.17 (brs, 2H, NH). MS m/z (%): 267 (M+, 100), 145 (M+_
C6H4NO2, 80) calculated for C15H13N3O2.
1
meso-Tolyldipyrromethane (3g). Buff solid, mp 112 °C (lit.11 mp 114 °C, lit. yield11 33%), H
NMR (300 MHz, CDCl3): 2.35 (s, 3H, CH3), 5.44 (s, 1H), 5.92 (s, 2H), 6.15 (dd, J 4.2 Hz, 2H),
6.83 (d, J 4.8 Hz, 2H), 7.05-7.16 (m, 4H), 7.91 (brs, 2H, NH). MS m/z (%): 236 (M+, 15), 221
(M+_ CH3, 3) calculated for C16H16N2.
meso-Mesityldipyrromethane (3h). Pale yellow solid. mp 170 °C (lit,11 mp 170-171 °C, lit.
yield11 27%), 1H NMR (300 MHz, CDCl3): 2.04 (s, 6H, CH3), 2.27 (s, 3H, CH3), 5.92 (s, 1H), 6.03
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(dd, J 2.6 Hz, 2H), 6.17 (m, 2H), 6.65 (m, 2H), 6.86 (s, 2H), 7.95 (brs, 2H, NH). MS m/z (%): 264
(M+, 15) calculated for C18H20N2.
meso-(4-Methoxyphenyl)dipyrromethane (3i). Brownish white crystals, mp 99 °C (lit11 mp
1
99 °C, lit. yield11 68%). H NMR (300 MHz, CDCl3): 3.78 (s, 3H, OCH3), 5.41 (s, 1H), 5.90 (s,
2H), 6.13 (dd, J 2.9 Hz, 2H), 6.82 (d, J 8.6 Hz, 2H), 7.10 (dd, J 8.6 Hz, 4H), 7.89 (brs, 2H, NH).
MS m/z (%): 252 (M+, 94), 145 (M+_ C7H7O, 100) calculated for C16H16N2O.
meso-(4-Pyridyl)dipyrromethane (3j). Light brown solid, mp 140 °C (lit.14 mp 140 °C, lit. yield14
58%). 1H NMR (300 MHz, CDCl3): 5.44 (s, 1H), 5.89 (s, 2H), 6.60 (dd, J 4.6 Hz, 2H), 7.09 (d, J
8.2 Hz, 2H), 8.41 (m, 2H), 10.62 (s, 2H, NH). MS m/z (%): 223 (M+, 100) calculated for C14H13N3.
meso-Acetyldipyrromethane (3k). Viscous brown liquid. 1H NMR (300 MHz, CDCl3): 2.26 (s,
3H, CH3), 5.14 (s, 1H), 6.15 (d, J 2.4 Hz, 2H), 6.16 (d, J 2.4 Hz, 2H), 6.7 (d, J 0.3 Hz, 2H), 8.46
(brs, 2H, NH). HRMS m/z (%): 189.1020 (M + H+, 100) calculated for C11H13N2O 189.1028. The
spectral data of compound 3k are reproduced in the Supplementary Data File.
Acknowledgements
The authors gratefully acknowledge financial assistance from the Council of Scientific and
Industrial Research, New Delhi, India. We also thank University Science Instrumentation center
(USIC), University of Delhi, India for spectral analysis of compounds.
Supplementary Data
1
13
The H and C NMR spectra, and the HRMS trace in the region of M+, of compound 3k, are
contained in the Supplementary File.
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