Syntheses of new imidazole ligand series and evaluation of 1-, 2- and 4,5-imidazole substituent electronic and steric effects on N-donor strengths

Article abstract of DOI:10.1016/j.molstruc.2010.09.015

A series of new imidazole based heterocycles (5-(4,5-diphenyl-1H-imidazol- 2-yl)furan-2-yl)methyl acetate (Him-dp), (5-(1H-phenanthro[9,10-d]imidazol-2-yl) furan-2-yl)methyl acetate (HIm-pt), (5-(1H-imidazo[4,5-f][1,10]phenanthrolin-2- yl)furan-2-yl)methy

Full text of DOI:10.1016/j.molstruc.2010.09.015

Journal of Molecular Structure 984 (2010) 117–124
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Syntheses of new imidazole ligand series and evaluation of 1-, 2- and
4,5-imidazole substituent electronic and steric effects on N-donor strengths
d,
c
b
Abiodun O. Eseola a, , Wen-Hua Sun
, Wen Li , Joseph A.O. Woods
⇑
⇑⇑
a Department of Chemical Sciences, Redeemer’s University, Redemption City, Ogun State, Nigeria
b Department of Chemistry, University of Ibadan, Ibadan, Nigeria
c Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, The Chinese Academy of Sciences, Beijing 100190, China
d Key Laboratory of Engineering Plastics and Beijing National Laboratory for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new imidazole based heterocycles (5-(4,5-diphenyl-1H-imidazol-2-yl)furan-2-yl)methyl
acetate (Him-dp), (5-(1H-phenanthro[9,10-d]imidazol-2-yl)furan-2-yl)methyl acetate (HIm-pt),
(5-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)furan-2-yl)methyl acetate (HIm-phen), 2-(2-nitro-
phenyl)-4,5-diphenyl-1H-imidazole (HIm-n), 1-methyl-2-(2-nitrophenyl)-4,5-diphenyl-1H-imidazole
(MeIm-n), N-(2-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)phenyl)benzamide (EtIm-ba) and 2,4-di-tert-
butyl-6-(8-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)-1,4-dihydroquinolin-2-yl)phenol (EtIm-q) were
synthesized and studied for the dependence of their azole donor characteristics on substituent factors
by means of experimentally determined ionization constant data (derived as pKas), spectroscopic analy-
ses and calculated properties of their DFT optimized molecular geometries performed at the B3LYP/6-
311 + Gꢀ level. Results showed that the lowest donor strength recorded for HIm-pt (pKa = 2.67 0.07)
Received 23 July 2010
Received in revised form 14 September
2010
Accepted 14 September 2010
Available online 18 September 2010
Keywords:
Protonation–deprotonation
Substituent effects
Spectroscopy
could be traced to the extensive electronic conjugation of the azole
uents. On the other hand, the strongest imidazole donor strength in the series was obtained from EtIm-q
(pKa = 4.61 0.04) for which the substituents possessed negligible -overlap with the azole ring. The
p-electrons with 4,5- and 2-substit-
DFT calculations
p
experimental results and theoretical calculations lead to conclusions that effective conjugation between
the imidazole ring and substituent aromatic groups is accountable for significant withdrawal of charge
densities on the imidazole N-donor atom and vice versa. Furthermore, observed donor strengths in the
series suggest that electronic inductive effects of the substituents provided lesser impact on donor
strength modification of imidazole base and that alkylation of 1-imidazole position did not yield the
anticipated push of electron density in favour of the N-donor atom. It is anticipated that the results
should promote the understanding of azole-containing bio-macromolecular species and reactions as well
as tuning and application of azole functions in molecular science.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
other heterocycles containing sp2 N-donor bases [9–11]. The imid-
azole fragment in a molecule significantly controls the intermolec-
The incorporation of five-membered azole ring fragments into
organic materials have continued to arouse considerable attention
in various areas of molecular sciences such as organic lighting, or-
ganic field effect transistor, fluorescence sensing and emission
switching/signaling research fields [1–8]. Presence of such five-
membered rings has been reported to impart desirable properties
or enhance previously known characteristics. Furthermore, the
electronic characteristic of the azole rings, which also depend on
the nature of substituents on it, are distinguishable from those of
ular/intramolecular events involving the molecule. Examples of
these interactions, which are of great chemical and biochemical
interests, are hydrogen bonding, activity of metalloenzymes, ex-
cited state intramolecular proton–electron transfer (ESIPT), ligand
donor strength, self-assembly in coordination polymers and supra-
molecular architectures, etc. [9,12].
Imidazole derived molecules have found widespread applica-
tions as coordination ligand donors and as base catalysts
[9,12,13]. The role of imidazole rings in base catalysis of various
reactions depend largely on the electronic donor nature of the
nitrogen base, which is substantially different from those of six-
membered pyridyl fragments [14–16]. Base fragments such as his-
tidine, adenine and guanine represent some of the forms in which
imidazole base occurs in important bio-macromolecules [17].
Small and properly characterized synthetic analogues are routinely
⇑
Corresponding author. Address: P.M.B 3005, Redemption City, Mowe, Ogun
State, Nigeira. Tel.: +234 (0) 7062192104.
⇑⇑
Corresponding author. Tel.: +86 10 62557955; fax: +86 10 62618239.
E-mail addresses: bioduneseola@run.edu.ng (A.O. Eseola), whsun@iccas.ac.cn
(W.-H. Sun).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.09.015

118
A.O. Eseola et al. / Journal of Molecular Structure 984 (2010) 117–124
employed as research models for probing biological reaction
mechanisms involving bio-macromolecules especially since struc-
ture–property characterization of macromolecular species still
poses some challenge [18,19]. Furthermore, small azole-containing
molecules are currently attracting attention for their potential
activities as drugs and successful exploration of such active ingre-
dients depend on proper understanding/characterization of the
electronic properties of the concerned molecules [20–22].
rials were obtained commercially as reagent grades and used with-
out further purification. 1,10-Phenanthroline-5,6-dione was
synthesized according to a literature procedure [25]. The acid cat-
alyzed imidazole ring synthesis was accomplished through a mod-
ified literature method [12]. TLC slides were routinely applied to
monitor purity of all organic compound preparations. The synthe-
sized organic compounds were purified on silica gel column to ex-
clude impurities. Elemental analyses were performed on a Flash EA
1112 microanalyzer, CE Instruments. 1H and 13C NMR spectra were
recorded on a Bruker ARX-400 MHz instrument using deuterated
chloroform as solvent and TMS as internal standard. FTIR spectra
were recorded on Shimadzu 8740 spectrometer as KBr discs
(4000–400 cmꢂ1). Protonation–deprotonation equilibrium con-
stant determination experiments were accomplished spectroscop-
ically by UV–visible measurements done on Shimadzu 1600
Spectrophotometer using ꢁ10ꢂ5 M solutions of the compounds
in ethanol–water mixture which consists of 70% absolute EtOH
and 30% H2O. Calculated amount of potassium chloride was used
to maintain fairly constant ionic strength of 0.1 M. The adjust-
ment of pH of solutions was achieved through the addition of
potassium hydroxide or hydrochloric acid solutions and moni-
tored with the aid of Omega PHB-212 Microprocessor pH Meter
using buffers of pH 4.0 and 9.2 as calibrants. The variable pH elec-
tronic spectra were collected using fresh solutions of the com-
pounds and the time duration between acid or base treatments
and collection of spectra was routinely kept at the minimum.
Optimized geometries and calculated properties obtained by
DFT calculations at the B3LYP/6-311 + Gꢀ level were done on
Gaussian 98 package of programmes [26]. Input files were created
based on simulated dielectric constants for 70% ethanol–water
mixture.
In view of the important role of azole components in various as-
pects of organic molecular sciences, systematic study of their base
donor characteristics was considered necessary. Such knowledge
would be useful for rational tuning of already known qualities or
modeling of new compounds with projected characteristics. While
a large number of azole-containing compounds have been studied
and exploited, systematic examination of substituent influence on
electronic nature of azole rings is scarce. In a recent work, the
effect of substituents on azole basicity and phenol acidity was re-
ported for a series of eight 2-(1H-imidazol-2-yl)phenol chelators
that are prone to ESIPT phenomenon [23]. Subsequently, hemila-
bility of a series of thirteen bidentate 2-(1H-imidazol-2-yl)pyri-
dines was quantitatively established using spectroscopic
methods, single crystal X-ray diffraction analyses and density func-
tional theory (DFT) methods [24]. In both cases, the Frontier
orbitals were found to be concentrated on the imidazole or oxazole
rings except in the cases where phenanthroline moiety is fused to
the 4,5-carbons of the azole ring. From our reported single crystal
structures for which DFT optimized geometries gave good
agreement, the observed C–C bond length (ꢁ1.40 Å) as well as high
degree of co-planarity between the azole rings and the phenol/
pyridyl rings attached at position-2 of the azole ring suggest that
strong overlap of
p-systems of the two aromatic rings may have
significant influence on the chemistry of the azole base
[9,12,23,24]. Therefore, it was considered attractive to introduce
bulky groups that may introduce a tilt in co-planarity.
2.2. Preparation of imidazoles/oxazoles
Motivated by the interest to investigate new molecules having
varied substituent environments with steric and electronic
importance and by progress already made in the understanding
of the electronic nature of the azole rings, we herein report the
synthesis, characterization and spectroscopic investigation of the
dependence of imidazole N-donor strengths on steric/electronic
characteristics of substituents for 2-(furan-2-yl)-1H-imidazoles
(HIm-dp, HIm-pt and HIm-phen) and 2-phenyl-1H-imidazole
derivatives (HIm-n, MeIm-n, EtIm-ba and EtIm-q, Scheme 1).
In efforts to further probe the experimentally observed trends,
molecular properties were obtained through DFT calculations
at the B3LYP/6-311 + Gꢀ levels and the results are herein
discussed.
2.2.1. (5-(4,5-Diphenyl-1H-imidazol-2-yl)furan-2-yl)methyl acetate
(Him-dp)
1,2-Diphenyl-1,2-ethanedione (Benzil) (1.00 g, 4.76 mmol),
ammonium acetate (7.33 g, 95.10 mmol) and (5-formylfuran-
2-yl)methyl acetate (0.80 g, 4.76 mmol) were weighed into a
Schlenk flask, charged with nitrogen and refluxed for 2 h in glacial
acetic acid (15 mL). The resulting reaction solution was cooled,
diluted with 20 mL water and neutralized with concentrated
ammonia solution. The crude product was filtered and purified
on silica gel column with acetone/petroleum ether (1:4) to obtain
HIm-dp as a white micro-crystalline wool (0.75 g, 44.3%). Mp.
176–177 °C. Selected IR peaks (KBr, cmꢂ1):
m 3058s, 3030s,
2919s, 1742vs, 1601s, 1489s, 1232vs, 766vs, 698vs. 1H NMR
(400 MHz, TMS, CDCl3); d 9.50 (vbr, 1H, NH); 7.53 (m, 4H, 4,5-di-
phenyl); 7.33 (m, 6H, 4,5-diphenyl); 7.06 (s, br, 1H, furanyl); 6.55
(d, J = 4.6 Hz, 1H, furanyl); 5.11 (s, 2H, methine); 2.11 (s, 3H, acet-
yl). 13C NMR (100 MHz, CDCl3) (d, ppm): 170.64, 149.35, 145.99,
138.37, 128.59, 127.88, 127.60, 113.20, 108.51, 57.89, 20.87.
Found: C, 73.31; H, 5.13; N, 8.26%. Calc. for C22H18N2O3: C, 73.73;
H, 5.06; N, 7.82%.
2. Experimental
2.1. General considerations
Handling of oxidation-prone reactions was done under nitrogen
atmosphere using standard Schlenk techniques. All starting mate-
Scheme 1. Compounds studied for 1-, 2- and 4,5-substituent effects.

A.O. Eseola et al. / Journal of Molecular Structure 984 (2010) 117–124
119
2.2.2. (5-(1H-Phenanthro[9,10-d]imidazol-2-yl)furan-2-yl)methyl
acetate (HIm-pt)
(0.35 mL, 5.62 mmol) was added and the resulting mixture stirred
at room temperature for 24 h. The solvents were removed on ro-
tary evaporator and the product purified by column chromatogra-
phy on silica gel column using ethyl acetate/petroleum ether (1:2)
to obtain MeIm-n as yellow crystals (0.85 g, 81.2%). Analytical data
Phenanthrene-9,10-dione (0.50 g, 2.40 mmol), ammonium ace-
tate (3.66 g, 47.48 mmol) and (5-formylfuran-2-yl)methyl acetate
(0.40 g, 2.40 mmol) were reacted as for the preparation of HIm-
dp above. However, the reaction mixture in this case set to a solid
mass within few minutes thus necessitating the addition of more
glacial acetic acid (5 mL) to enable resumption of stirring by the
magnetic bar. After dilution and neutralization, ethanol (ꢁ10 mL)
was added to the aqueous mixture and stirred for a few minutes.
The crude product was filtered, washed with water and dried. This
was then recrystallized from ethanol, filtered, washed with little
amount of diethyl ether and dried at 60 °C to obtain HIm-pt as
light brown solid (0.48 g, 58.0%). Mp. 207–208 °C. Selected IR peaks
for MeIm-n: Mp. 173–174 °C. Selected IR peaks (KBr, cmꢂ1):
m
3088 m, 3059 m, 2946 m, 1618 m, 1599s, 1526vs, 1382vs, 743vs.
1H NMR (400 MHz, TMS, CDCl3); d 8.17 (d, J = 8.1 Hz, 1H); 7.75
(d, J = 4.2 Hz, 1H); 7.66 (m, 1H); 7.47 (m, 7H, 4,5-diphenyl); 7.20
(m, 2H); 7.14 (m, 1H); 3.27 (s, 3H, N-methyl). HIm-n (3.76 g,
11.01 mmol) and K2CO3 (3.04 g, 22.02 mmol) were refluxed for
30 min in acetonitrile/acetone mixture (40 mL each) and, on cool-
ing to 60 °C, C2H5I (1.32 mL, 16.52 mmol) was added and stirring
continued for 24 h. The solvents were removed by rotary evapora-
tor and the residue was treated with water from which the crude
product was extracted by dichloromethane. The dried extract
was filtered, concentrated and layered with petroleum ether to ob-
tain the intermediate 1-ethyl-2-(2-nitrophenyl)-4,5-diphenyl-1H-
imidazole (EtIm-n, Scheme 2) as large yellow crystal blocks
(3.44 g, 84.58%). 1H NMR (400 MHz, TMS, CDCl3); d 8.17 (d,
J = 8.2 Hz, 1H); 7.74 (m, 2H); 7.67 (dd, J = 1.9, 7.2 Hz, 1H); 7.48
(m, 7H, 4,5-diphenyl); 7.18 (dd, J = 7.2 Hz, 2H); 7.12 (dd,
J = 7.0 Hz, 1H); 3.74 (q, J = 7.2 Hz, 2H, N-ethyl); 0.96 (t, J = 7.2 Hz,
3H, N-ethyl). A portion of EtIm-n (2.30 g, 6.23 mmol), hydrazine
hydrate (2 mL) and 10% Pd–C catalyst (0.05 g, 5% equivalent) were
weighed into a reaction flask and refluxed in EtOH (20 mL, 1 h). The
solvent was removed under reduced pressure and the product
purified over silica gel column using ethyl acetate/petroleum ether
(1:3) as eluent to afford 2-(1-ethyl-4,5-diphenyl-1H-imidazol-
2-yl)benzeneamine (EtIm-am, Scheme 2) as white micro-crystals
(1.86 g, 88.2%). 1H NMR (400 MHz, TMS, CDCl3); d 7.49 (m, 5H,
4,5-diphenyl); 7.43 (m, 2H); 7.29 (d, J = 7.6 Hz, 1H); 7.20 (m, 3H);
7.13 (dd, J = 7.2 Hz, 1H); 6.82 (dd, J = 7.6 Hz, 2H); 4.75 (s, br, 2H,
amine); 3.90 (q, J = 7.2 Hz, 2H, N-ethyl); 1.00 (t, J = 7.1 Hz, 3H,
N-ethyl). Applying the Doebner synthesis [27] of quinoline–
carboxylic acids from benzamines, the solution of a portion of
EtIm-am (1.00 g, 2.95 mmol) in ethanol (10 mL) was added to a
refluxing solution of pyruvic acid (0.32 g, 4.42 mmol) and benzal-
dehyde (0.31 g, 2.95 mmol) in ethanol (100 mL). The reflux was
continued for 3 h and the mixture was allowed to cool. The result-
ing reaction mixture was concentrated and purified on silica gel
column using ethyl acetate/petroleum ether. The pure benzamide
product EtIm-ba was obtained as whitish crystals (<5%) and the
quinoline product could not be isolated. Mp. 139–140 °C. Selected
(KBr, cmꢂ1):
m 3522s, 3390s (imidazole N–H), 3077s (Ar–H), 2993s,
1723vs (C@O), 1603s, 1462s, 1264vs, 752vs, 721vs. 1H NMR
(400 MHz, TMS, CDCl3); d 11.35 (br, 1H, NH); 8.73 (d, J = 4.0,
7.2 Hz, 2H, phenanthrene); 8.50 (s, br, 2H,, phenanthrene); 7.63
(m, 4H, phenanthrene); 7.13 (d, J = 3.6 Hz, 1H, furanyl); 6.52 (d,
J = 3.6, 1H, furanyl); 5.06 (s, 2H, methine); 2.06 (s, 3H, acetyl). 13C
NMR (100 MHz, CDCl3) (d, ppm): 170.70, 150.10, 146.22, 141.30,
128.64, 127.18, 125.62, 123.72, 121.90, 113.44, 110.07, 57.82,
20.80. Found: C, 67.31; H, 5.22; N, 7.23%. Calc. for C22H16N2O3.2-
H2O: C, 67.34; H, 5.14; N, 7.14%.
2.2.3. (5-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)furan-2-yl)-
methyl acetate (HIm-phen)
1,10-Phenanthroline-5,6-dione (0.50 g, 2.38 mmol), ammonium
acetate (3.66 g, 47.48 mmol) and (5-formylfuran-2-yl)methyl ace-
tate (0.39 g, 2.32 mmol) in glacial acetic acid (10 mL) were reacted
in the same manner as for the preparation of HIm-dp above. The
resulting light brown precipitate was filtered, washed and dried
to obtain HIm-phen as light brown micro-crystalline solid
(0.79 g, 91.8%). Mp. 177–178 °C. Selected IR peaks (KBr, cmꢂ1):
m
3350vs, 3123vs, 3017s, 3966s, 2922s, 1754s (C@O), 1733vs
(C@O), 1607 m, 1431s, 1230vs, 744vs. 1H NMR (400 MHz, TMS,
CDCl3); d 8.95 (d, J = 3.1, 2H, phenanthrolineyl); 8.82 (J = 7.4 Hz,
2H, phenanthrolineyl); 7.52 (dd, J = 4.2, 7.6 Hz, 2H, phenanthroli-
neyl); 7.06 (d, J = 3.2 Hz, 1H, furanyl); 6.46 (d, J = 4.3, 1H, furanyl);
4.92 (s, 2H, methine); 1.99 (s, 3H, acetyl). 13C NMR (100 MHz,
CDCl3) (d, ppm): 170.75, 150.48, 148.02, 146.19, 144.24, 143.45,
130.63, 123.32, 122.02, 113.23, 110.84, 57.80, 20.80. Found: C,
62.24; H, 4.25; N, 14.48%. Calc. for C20H14N4O3.3/2H2O: C, 62.33;
H, 4.45; N, 14.54%.
IR peaks (KBr, cmꢂ1):
m 3249s, 3064s, 3017s, 2974s, 1675vs (amide
2.2.4. 2-(2-Nitrophenyl)-4,5-diphenyl-1H-imidazole (HIm-n), 1-
methyl-2-(2-nitrophenyl)-4,5-diphenyl-1H-imidazole (MeIm-n) and
N-(2-(1-ethyl-4,5-diphenyl-1H-imidazol-2-yl)phenyl)benzamide
(EtIm-ba)
C@O), 1617s, 1602s, 1589vs, 1476vs, 699vs. 1H NMR (400 MHz,
TMS, CDCl3); d 12.05 (s, 1H, amide NH); 8.80 (d, J = 8.4 Hz, 1H);
8.01 (d, J = 7.8 Hz, 2H); 7.51 (m, 7H, 4,5-diphenyl); 7.44 (m, 4H);
7.23 (m, 5H, 4,5-diphenyl); 4.04 (q, J = 7.1 Hz, 2H, ethyl); 1.08 (t,
J = 7.1 Hz, 3H, ethyl). 13C NMR (100 MHz, CDCl3) (d, ppm):
165.21, 144.19, 137.77, 137.15, 134.87, 133.90, 131.64, 131.10,
131.01, 129.93, 129.79, 129.24, 129.10, 128.53, 128.18, 128.01,
127.57, 126.63, 123.06, 121.85, 118.65, 40.15, 16.14. Found: C,
81.14; H, 5.50; N, 9.68%. Calc. for C30H25N3O: C, 81.24; H, 5.68;
N, 9.47%.
1,2-Diphenyl-1,2-ethanedione (benzil) (3.00 g, 14.27 mmol),
ammonium acetate (22.00 g, 285.42 mmol) and 2-nitrobenzalde-
hyde (2.16 g, 14.29 mmol) in glacial acetic acid (60 mL) were re-
acted in the same manner as for the preparation of HIm-dp
above under nitrogen atmosphere. After dilution with water
(400 mL) and neutralization with aqueous ammonia, the crude
product was filtered, washed with plenty water, dried and recrys-
tallized from acetone/petroleum ether to obtain HIm-n as yellow
micro-crystals (4.19 g, 86.1%). Analytical data for HIm-n: Mp.
2.2.5. 2,4-Di-tert-butyl-6-(8-(1-ethyl-4,5-diphenyl-1H-imidazol-2-
yl)quinolin-2-yl)phenol (EtIm-q)
234–235 °C. Selected IR peaks (KBr, cmꢂ1):
m
3068s, 1619 m,
Applying a similar Doebner protocol as for preparation of EtIm-
ba above, EtIm-am (1.00 g, 2.95 mmol), pyruvic acid (0.32 g,
4.42 mmol) and 3,5-di-tert-butyl-2-hydroxybenzaldehyde (0.72 g,
2.95 mmol) were reacted to obtain the decarboxylated product
EtIm-q as yellow crystalline blocks (0.10 g, 5.50%). Mp. 170–
1586 m, 1527vs, 1355s, 725vs. 1H NMR (400 MHz, TMS, CDCl3); d
10.22 (s, 1H, NH); 8.34 (d, J = 8.0, 1H); 7.90 (d, J = 8.2 Hz, 1H);
7.67 (dd, J = 7.4 Hz, 1H, furanyl); 7.63 (d, J = 7.3 Hz, 2H); 7.52 (dd,
J = 6.9 Hz, 1H); 7.47 (d, J = 7.0 Hz, 2H); 7.39 (m, 3H, 4,5-diphenyl);
7.30 (m, 3H, 4,5-diphenyl). Some portion of HIm-n (1.00 g,
2.93 mmol) and K2CO3 (0.81 g, 5.86 mmol) were refluxed in aceto-
nitrile/acetone solvent for 30 min and cooled. Subsequently, CH3I
171 °C. Selected IR peaks (KBr, cmꢂ1):
m 3067 m, 2966vs, 2907s,
2868s, 1615s, 1589s, 1441vs, 1172vs, 757vs. 1H NMR (400 MHz,
TMS, CDCl3); d 13.08 (s, 1H, phenolic OH); 8.68 (s, 1H, phenol ring

120
A.O. Eseola et al. / Journal of Molecular Structure 984 (2010) 117–124
Scheme 2. Synthetic route to EtIm-ba and EtIm-q products.
CH); 7.73 (d, J = 1.1 Hz, 1H); 7.43 (m, 10H, 4,5-diphenyl); 7.35 (d,
J = 7.9 Hz, 1H); 7.16 (m, 3H); 7.09 (s, 1H, phenol ring CH); 3.85
(q, J = 7.1 Hz, 2H, N-ethyl); 1.46 (s, 9H, t-Bu); 1.29 (s, 9H, t-Bu);
1.85 (t, J = 7.2 Hz, 3H, N-ethyl). Found: C, 82.40; H, 7.68; N,
7.50%. Calc. for C40H41N3O: C, 82.86; H, 7.13; N, 7.25%.
EtIm-ba when benzaldehyde was used. The low yields have been
attributed to steric demands caused by the 1-ethyl-4,5-diphenyl-
1H-imidazole moiety that is at ortho-position to the amine
function of EtIm-an (Scheme 2). Decarboxylation of target 4-carb-
oxyquinoline products as observed in the preparation of EtIm-q
and the formation of N-substituted amide by-products as for
EtIm-ba are known to accompany the Doebner quinoline synthesis
[28,29]. The compounds were properly characterized by 1H NMR,
13CNMR, FTIR and elemental analyses. The 1H NMR spectra of
EtIm-q is presented as Supplementary data S2.
3. Results and discussion
3.1. Syntheses and characterization
The molecules considered for this study were selected to
investigate the relative importance of substituents at 1-, 2- and
4,5-positions on the electronic characteristics of the imidazole ring.
Furthermore, in order to explore the dependence of imidazole do-
3.2. Electronic spectral determination of imidazole N-donor strengths
Table 1 contains the UV absorption and ionization constant data
derived as pKa for the investigated molecules. The imidazole ring
protonation–deprotonation equilibria were followed by electronic
absorption spectroscopy within the pH range of 0–14 as illustrated
in Scheme 3 for the (furan-2-yl)methyl acetate-analogues. Applica-
tion of electronic spectral method in quantifying concentrations of
equilibrium species in solution has been known to render reliable
results and modification of aqueous media composition has been
reported to yield notable influence on Lewis basicity/acidity of sol-
utes [30–33]. However, this submission aimed to make comparison
between imidazole base donor characteristics of the new series by
subjecting all to the same conditions in terms of solution media,
temperature and acidic/basic species present in solution.
Therefore, it is believed that the variations observed in the proton-
ation–deprotonation behaviour originates from inherent electronic
characteristics of the imidazole ring. Three protonation states cor-
responding to imidazolium cation (lower pH end), neutral imidaz-
ole (pH ꢁ 5–7) and deprotonated imidazole anion (higher pH end)
nor strengths on the overlap between the aromatic p-electrons of
the imidazole ring and those of the 2-aryl substituents, some of
the studied compounds (HIm-n, MeIm-n, EtIm-ba and EtIm-q)
were chosen to bear bulky 2-aryl-substituents with the intention
to promote loss of co-planarity between the imidazole ring and
the 2-aryl aromatic system.
Compounds HIm-dp, HIm-pt, HIm-phen and HIm-n were ob-
tained by condensation of corresponding
a-diketones and alde-
hydes in the presence of excess ammonium acetate and high
yields were obtained such that re-crystallization was enough to
isolate the pure compounds in some cases. However, attempts to
carry out a three-component condensation of pyruvic acid, appro-
priate aldehyde and the aniline intermediate EtIm-an according to
the Doebner quinoline synthetic procedure (Scheme 2) yielded
very small amounts of the decarboxylated quinoline product
EtIm-q when 3,5-di-tert-butyl-2-hydroxybenzaldehyde was em-
ployed as the reactant aldehyde and the benzamide by-product
Table 1
Experimental UV absorption and pKa data of studied imidazole molecules.
Compounds [conc. (mol dmꢂ3)]
kmax (nm) [
e
(dm3/mol cm)]a
Neutral
Ionization constantsb
Cation
Anion
pKa,N
:
S
pKa,NH
: S
HIm-dp [1.4230 ꢃ 10ꢂ5
]
]
316 [29,490]
363 [19,310]
309 [48,980]
260 [31,420]
255 [28,600]
253 [26,450]
368 [9420]
310 [29,770]
363 [14,430]
325 [30,960]
282 [21,490]
267 [20,020]
271 [23,330]
360 [9480]
318 [29,280]
380 [5880]
3.18 0.24
2.67 0.07
3.80 0.04
3.29 0.02
3.03 0.17
3.98 0.02
4.61 0.04
>13.50
12.26 0.11
HIm-pt [1.1505 ꢃ 10ꢂ5
HIm-phen [1.4233 ꢃ 10ꢂ5
]
309 [37,830]
11.10 0.28
HIm-n [7.9095 ꢃ 10ꢂ6
]
292 []c
>13.50c
MeIm-n [1.0130 ꢃ 10ꢂ5
]
]
–
–
–
–
–
–
EtIm-ba [1.2599 ꢃ 10ꢂ5
EtIm-q [9.0336 ꢃ 10ꢂ6
]
a
b
c
kmax = the longest wavelength absorption band maximum at the various protonation states.
S represents standard errors.
Molar absorptivity and pKa could not be calculated because not all species in solution exists in deprotonated anionic form at ꢁpH 14.

A.O. Eseola et al. / Journal of Molecular Structure 984 (2010) 117–124
121
Scheme 3. Protonation–deprotonation equilibria of the (furan-2-yl)methyl acetate derivatives.
A ꢂ Ao
were observed within pH 0–14 for the (furan-2-yl)methyl acetate-
analogues (HIm-dp, HIm-pt and HIm-phen). However, within the
same pH range, only the cationic and neutral protonation states
could be achieved for HIm-n, MeIm-n, EtIm-ba and EtIm-q.
Different protonation states possessed different absorption profiles
with clearly defined isosbetic points (Fig. 1a–d). Moreover, spectral
characteristics gave no suggestions of degradation of the esters at
higher pH values. A more comprehensive presentation of variable
pH spectral overlays in all pH environments as well as separately
in acidic or alkaline media is provided as Supplementary data S1.
Sigmoid relationship between pH and absorbance enabled applica-
tion of the Henderson–Hasselbalch theory according to the follow-
ing equation.
pKa ¼ pH þ log
:
Af ꢂ A
A0 and Af represent the absorbance values at a given wavelength
when the solute molecules are totally in either of the relevant pro-
tonated–deprotonated forms for a given equilibria. A represents
absorbance value of the protonation–deprotonation equilibrium
mixtures at the same wavelength. The pKa values were obtained
from non-linear least square fittings on plots of pH against absor-
bance values at selected wavelengths (Fig. 1a and b, inset). R2 values
were in the range 0.9783–0.9997.
Comparison of the spectral peak positions for the S0 ? S1 elec-
tronic transitions showed that the (furan-2-yl)methyl acetate
derivatives (HIm-dp, HIm-pt, HIm-phen) possessed lower energy
Fig. 1. Absorption profiles in 70% aqueous ethanol for some of the studied
molecules; (a) HIm-pt, (b) HIm-phen, (c) HIm-n and (d) EtIm-ba (inset: non-
linear least square fitting for pH vs. abs. and DFT optimized molecular structures).
Fig. 1 (continued)

122
A.O. Eseola et al. / Journal of Molecular Structure 984 (2010) 117–124
absorption bands than the rest except for the quinolineyl analogue
EtIm-q (Table 1). This implies that the 2-furanyl ring provided a
more effective electronic conjugation with imidazole ring than
does the 2-phenyl-substututed counterparts. The absorption band
was notably red-shifted for HIm-pt bearing the 4,5-phenanthre-
neyl group. It could be reasoned that, though the aromatic system
of 4,5-diphenyl, 4,5-phenanthreneyl and 4,5-phenanthrolinyl sub-
conjugative interaction between the imidazole and phenanthroline
aromatic -systems, produced more effects on donor nature of the
imidazole than does their electron-withdrawing effects.
p
The compounds HIm-dp, HIm-n, MeIm-n, EtIm-ba and EtIm-q
all possess the same 4,5-diphenyl substituent groups and differ in
substituents at the 1-position or 2-position of the imidazole ring.
Comparing the pKas of HIm-dp (3.18 0.24), HIm-n (3.29 0.02)
and MeIm-n (3.03 0.17), which are fairly similar, with the higher
values obtained for compounds EtIm-ba (3.98 0.02) and EtIm-q
(4.61 0.04) (Table 1), it could be concluded that introduction of
bulky ortho-substituent favoured higher donor strengths in the la-
ter compounds relative to the former set. Structurally, higher co-
planarity between imidazole and 2-aryl rings was expected for
HIm-dp, HIm-n and MeIm-n than for EtIm-ba and EtIm-q. Hence,
stituents all possessed some extent of
p-interactions with the
imidazole aromatic system, the 4,5-phenanthreneyl group yielded
more electron delocalization. The molar absorptivity for the
longest wavelength absorption band of EtIm-q (360 nm,
9480 dm3 molꢂ1 cmꢂ1) is notably lower than for the electronic
transition next to it (279 nm, 28,070 dm3 molꢂ1 cmꢂ1), which is
more like the longest wavelength absorption bands for the related
compounds HIm-n, MeIm-n and EtIm-ba. This suggests that the
molecule behaves as bi-chromophoric such that the electronic sys-
tem of the quinolineyl fragment and that of the imidazole moiety
tends to be independent of each other. Hence, the two fragments
probably undergo separate and competitive electronic excitation
processes with varying extent of oscillator strengths.
greater
set and the observed trend in donor characteristics is similar to the
phenomenon observed for 4,5-substituents. The more the -inter-
p-overlap is expected in the former set relative to the later
p
action, the more the electron density appears to be removed from
the imidazole ring and vice versa. This further supports the sug-
gested importance of the extent of conjugative
inductive effects of substituents.
p-interactions over
3.3. Effect of substituents on lewis basicity of investigated imidazoles
Furthermore, substitution of methyl group on 1-imidazole posi-
tion failed to produce better donor strength in MeIm-n over that of
HIm-n despite the expected +I contribution of the methyl group. In
fact, there was slight decrease in donor strength on methylation of
HIm-n. It is noteworthy that the difference in pKas of the 1-ethyl-
imidazole substituted compounds EtIm-ba and EtIm-q (0.63),
which is solely attributable to different extents of loss of co-planar-
ity between imidazole and 2-aryl rings, also deemphasizes the
electronic inductive effects at 1-imidazole position. In summary,
the amount electron density on the imidazole base appears to be
In previous experiments, attempts to prepare Zn(II) and Ni(II)
complexes from the series of azole-containing bidentate phenols
and pyridines failed to produce coordination products for some
of the ligands especially those bearing the phenanthrene and oxa-
zole fragments. This observation prompted further studies on
dependence of the azole donor strengths on varying substituent
environments and quantitative estimation of the hemilability for
azole-pyridines [9,12]. Experimental data showed that imidazole/
oxazole bases generally gave pKas between the 0.5–6.5 range based
on electron donating/withdrawing effects of common substituents
such as methyl, ethyl, hydroxyl, methoxyl, t-Bu, naphthaleneyl,
phenyl and pyridyl groups that are directly on the azole ring or
on phenyl group attached to the 2-position of the azole ring. It
was observed that combination of push–pull effect across the azole
ring from 2-azole position to the 4,5-azole axis lead to very low do-
nor characteristics and consequent inability to form stable transi-
tion metal complexes of these bidentate chelators [23,24].
The pKa value is directly proportional to Lewis basicity of the
imidazole ring. Concerning the (furan-2-yl)methyl acetate deriva-
tives in the present work (Table 1; HIm-dp, HIm-pt and
HIm-phen), it was anticipated that variations in imidazole donor
characteristics would only depend on the natures of 4,5-substitu-
ents and the phenanthrene-substituted compound (HIm-pt) gave
the lowest ionization constant of 2.67 0.07, which implies the
lowest donor characteristics. Therefore, it could be concluded that
the greater electron delocalization in the 4,5-azole substituent as
in HIm-pt, which was significantly perturbed by the phenanthroli-
neyl N-heteroatoms in the case of HIm-phen, is important for
reduction in Lewis basicity of azole bases. Effective overlap of imid-
largely influenced by the amount of
p–p interaction between the
imidazole ring and it substituents such that greater conjugation
limits the donor strength of the imidazole ring.
3.4. Spectral and computational analysis of investigated compounds
In efforts to further probe, the electronic characteristics of the
imidazole ring, it was considered necessary to examine the spectral
signals that pertain to the 5-membered ring especially for HIm-dp,
HIm-pt and HIm-phen, which differed at the 4,5-substitution.
Table 2 contains the vibrational spectral signals for C@C/C@N
bonds. The experimental results showed slightly higher vibrational
energies for the nitro-, amide and quinoline-substituted com-
pounds relative to the furan-substituted imidazole compounds.
This agrees with the greater electronic conjugation earlier sug-
gested by the longer S0 ? S1 absorption wavelengths for HIm-dp,
HIm-pt and HIm-phen. The 1H-imidazole chemical shift signal re-
corded for HIm-pt (11.35 ppm, Table 2) was found to be more
deshielded than for other observed 1H-imidazole signals indicating
that the imidazole ring charge density was most withdrawn from
the N-heteroatoms in the case of HIm-pt when compared with
other unsubstituted 1H-imidazoles.
azole p-system with fused 4,5-aromatic substituents having good
degree of electron delocalization appears to favour the shift of
imidazole ring electron density away from the donor N atom,
especially in the presence of the electron-withdrawing furanyl
group at the 2-azole position. In other words, the degree of
All molecular structures were optimized in search of their sta-
tionary points and their calculated properties such as dipole mo-
ment, dihedral angles and atomic charge densities for selected
atoms are presented in Table 2. The Frontier molecular orbital view
of the optimized geometries are shown in Fig. 2 for the highest
occupied molecular orbital (HOMO), HOMO – 1 and lowest unoc-
cupied molecular orbital (LUMO) states. Among the furanyl deriv-
atives on one hand and the nitro, amide and quinolineyl molecules
on the other hand, increasing dipole moments generally correlated
with increasing experimental donor strengths, which suggests that
the molecular dipole is across the heteroatoms of the imidazole
ring. In efforts to examine, the theoretical orientation of electronic
dipole, the charge density on imidazole N-atoms and the difference
involvement of the 4,5-p-bond in the conjugation appears to be
more important in affecting basicity than withdrawing/releasing
effects of 4,5-substituents. Relative to HIm-pt, the imidazole base
of the 4,5-phenanthroline-substituted HIm-phen gave stronger
Lewis basicity despite the anticipated electron-withdrawing influ-
ence of the phenanthrolineyl heteroatoms on the imidazole ring
relative to 4,5-phenanthrene group. The experimental observations
suggest that impact of the 4,5-phenanthrolinely N-heteroatoms at
causing loss of electron delocalization, which then reduces the

A.O. Eseola et al. / Journal of Molecular Structure 984 (2010) 117–124
123
Table 2
Selected IR and NMR signals and DFT derived properties determined at the B3LYP/6-311 + Gꢀ level.
Compounds
IR and 1H NMR
Calculated dipoles, angles and Mulliken atomic charges
mC@C,C@N (cmꢂ1
)
dN–H (ppm)
DM (D)b
Co-planarity (°)c
N(1)
N(3)
N(1)–N(3)
HIm-dp
HIm-pt
HIm-phen
HIm-n
MeIm-n
EtIm-ba
EtIm-q
1601 m
1603 m
1607 m
1619 m
1618 m
1617 m
1615s
9.50(vbr)
6.92
5.92
8.24
2.12
4.47
7.53
6.81
0.39
0.43
5.19
15.80
44.56
34.04
80.43
ꢂ0.831
ꢂ0.887
ꢂ0.886
ꢂ0.838
ꢂ0.720
ꢂ0.714
ꢂ0.712
ꢂ0.390
ꢂ0.348
ꢂ0.347
ꢂ0.412
ꢂ0.404
ꢂ0.510
ꢂ0.380
ꢂ0.441
ꢂ0.539
ꢂ0.539
ꢂ0.426
ꢂ0.316
ꢂ0.204
ꢂ0.332
11.35(br)
a
–
10.22(br)
e
–
–
–
e
e
vbr = very broad; br = broad.
a
Not observed.
DM = Dipole moment in Debye.
Angle between planes of imidazole and 2-aryl rings.
The NH proton is absent.
b
c
e
Fig. 2. Frontier molecular orbital diagram for the HOMO – 1, HOMO and LUMO states of the investigated molecules.
between values for N(1) and N(3) were compared with computed
dipole moments. It is considered that the dipole is either across
the imidazole ring from N(1) to N(3) or along the length of the mol-
ecule from C(2) to the C(4)C(5) axis. While it is noteworthy that the
DFT derived magnitude of electron charge densities on the imidaz-
ole nitrogen donor N(3) generally yielded good correlation with
observed Lewis basicity (Tables 1 and 2), N(1)–N(3) did not give
a clear correlation with computed dipole moments. In fact, N(1)–
N(3) values for HIm-n (ꢂ0.426), MeIm-n (ꢂ0.316) and EtIm-ba
(ꢂ0.204) gave inverse relationship with computed dipole mo-
ments, which are 2.12 D, 4.47 D and 7.53 D respectively. Therefore,
it could be concluded that electronic dipole in the ground state of
the molecules is not necessarily across the imidazole ring. The
diversity of Frontier orbital alignments as shown in Fig. 2 shows
that diverse molecular dipole orientation should be expected. In
fact, EtIm-q showed a quinoline based HOMO and LUMO elec-
tronic character. DFT results gave two energetically close HOMO
and HOMO – 1 alternative orbital alignment, which occurred as
ground state in the series. Furthermore, a poor electronic conjuga-
tion in HIm-phen is supported by the scanty distribution of active
orbitals in HOMO – 1, HOMO and LUMO states (Fig. 2).
The lower dipole moment obtained for HIm-pt relative to val-
ues for HIm-dp and HIm-phen agrees with a greater spread of
charges in HIm-pt and supports the proposed prominence of the
influence on Lewis basicity by
p-electron conjugation between
imidazole and aryl-substituents over inductive effect of the
substituents.
Since the extent of co-planarity of joined aromatic rings may be
considered to indicate extent of conjugation between the rings, the
optimized structures were examined for structure correlations. It is
worth noting that the extent of co-planarity of the imidazole ring
and 2-aryl aromatic ring was high for cases where the lower pKas
resulted while loss of co-planarity characterized the molecules
with higher donor strengths. Loss of co-planarity by 5.19° may
have contributed to increase in donor strength of HIm-phen for
which calculated results suggested there is scarce difference in

124
A.O. Eseola et al. / Journal of Molecular Structure 984 (2010) 117–124
charge densities on imidazole heteroatoms relative to HIm-pt
(Tables 1 and 2). This observation supports the thinking that extent
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2010.09.015.
of
p-conjugation is a relevant deciding factor for Lewis basicity
trends relative to the electron withdrawing/releasing capacities
of substituents (HIm-pt, 2.67 0.07, 0.43°; HIm-phen,
3.80 0.04, 5.19°; Tables 1 and 2).
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A series of imidazole based compounds HIm-dp, HIm-pt, HIm-
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A.O.E. is grateful to Dr. J. Rapha for supports, Redeemer’s Uni-
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Appendix A. Supplementary material
Contained in the supplementary data are (S1) a more compre-
hensive presentation of variable pH spectral overlays in acidic,
alkaline and pH 1–14 ranges, and (S2) 1H NMR spectra of EtIm-q.
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