A study of the effects of subunit pre-orientation for diarylpyrrole esters; design of new aryl-heteroaryl fluorescent sensors

Article abstract of DOI:10.1039/b507669b

The synthesis, single crystal X-ray structures, spectroscopic properties and molecular mechanics calculations of three systematically substituted 3,5-diaryl-1H-pyrrole-2-carboxylic acid ethyl esters 1a-c are described. The goal is to develop design princi

Full text of DOI:10.1039/b507669b

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P A P E R
A study of the effects of subunit pre-orientation for diarylpyrrole
esters; design of new aryl-heteroaryl fluorescent sensors
John Killoran,a John F. Gallagher,b Paul V. Murphya and Donal F. O’Shea*a
a Centre for Synthesis and Chemical Biology, Conway Institute, Department of Chemistry,
University College Dublin, Belfield, Dublin 4, Ireland. E-mail: donal.f.oshea@ucd.ie;
Tel: þ353-(0)1-7162425
b School of Chemical Sciences, Dublin City University, Dublin 9, Ireland
Received (in Durham, UK) 31st May 2005, Accepted 11th August 2005
First published as an Advance Article on the web 7th September 2005
The synthesis, single crystal X-ray structures, spectroscopic properties and molecular mechanics calculations
of three systematically substituted 3,5-diaryl-1H-pyrrole-2-carboxylic acid ethyl esters 1a–c are described. The
goal is to develop design principles for the generation of new class of fluorescent switches constructed from
an aryl-heteroaryl architecture containing a virtual (C0) spacer. The spectroscopic effects of the electron
donor p-dimethylamino substituent of 1b and the combined steric and electron donor impact of the
o-methyl-p-dimethylamino groups of compound 1c were investigated to determine the required structural
motifs to achieve orthogonal pre-orientation of the sensor subunits.
framework linking the receptor and fluorphore subunits can
Introduction
cause a twist of the components away from co-planarity. If a
near orthogonal conformation exists, the electron system of the
receptor remains decoupled from that of the fluorophore due
to restricted p-orbital overlap (Fig. 1, model B). This approach
is particularly suited to biaryl systems as they are characterised
by an inherent restricted flexibility about the single biaryl bond
and switching efficiency can often be controlled by the degree
of interannular twist.
A further design can comprise an integrated, or intrinsic,
fluorophore-receptor approach in which there is no electronic
separation of receptor and fluorophore and switching is modu-
lated by an internal charge transfer (ICT) process as depicted
by model C (Fig. 1). Recently combination sensors comprising
models A and C have been reported as potential two-dimen-
sional fluorescent sensors.6
We are currently interested in developing new visible red and
near infrared (NIR) sensors based upon the BF2 chelated
tetraarylazadipyrromethene fluorophore (Fig. 2). We have
recently reported this chromophore class to have highly sought
after absorption and emission characteristics in the 650–750
nm region of the spectrum which could facilitate their applica-
tion as in vitro and in vivo biomedical diagnostic agents.7 NIR
dyes are suitable for such applications due to efficient penetra-
tion of light through tissue and the low auto-fluorescence of
endogenous chromophores in this spectral region. Our current
design approach is to adopt an aryl-heteroaryl subunit pre-
orientation approach (model B) using a substituted aryl
ring containing the receptor linked to a pyrrole ring of the
fluorophore.
In spite of its long history the development of molecular based
fluorescent sensors continues to be a very active area of
research.1 Specifically, in the field of molecular biology the
use of high sensitivity fluorescence detection has become a
common tool for gaining a greater understanding of the
molecular processes in biological systems.2 The success of this
strategy is underlined by the increasing number of assay
systems that are based upon a molecular recognition event
coupled with fluorescence output. The design of fluorescent
probes, with the fluorescence switching properties controlled
by an excited state electron transfer mechanism, typically adopts
a modular building block approach such as the receptor–spacer–
fluorophore architecture.3 The function of the receptor is to
detect the targeted analyte, whereas the role of the fluorophore
is to quantify and communicate this detection to the observer.
The purpose of the spacer unit, the least structurally complex
component, is to covalently link the fluorophore to the recep-
tor whilst keeping the ground state electronic systems of the
receptor and the fluorophore disconnected. The spacer com-
ponent most commonly comprises a saturated methylene unit
(C1 spacer), which effectively decouples the system (model A,
Fig. 1).4 The electronic separation of receptor and fluorophore
can also be accomplished by a virtual spacer (C0), though this
approach is significantly less exploited (model B, Fig. 1).3a,5
When using a virtual spacer, the receptor module is covalently
linked directly to the fluorophore but their electronic systems
remain disconnected as a result of a forced orthogonal con-
formation between the receptor and fluorophore. The s bond
In the course of this work we have generated an intermediate
system for study, the 3,5-diaryl-1H-pyrrole-2-carboxylic acid
Fig. 1 Schematic of fluorescent sensor designs. Rectangle ¼ fluoro-
phore; circle ¼ receptor; oval ¼ orthogonal receptor.
Fig. 2 BF2 Chelated tetraarylazadipyrromethenes.
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 5
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tures would facilitate a correlation of structural differences
with data available from spectroscopic characteristics and
molecular mechanics calculations and aid in the general design
of future sensors. Crystals were grown by the slow room
temperature evaporation of ethanolic solutions of each com-
pound. Compound 1a crystallised in the monoclinic system,
space group P21/c (No. 14) (Z0 ¼ 1) while both derivatives
1b (Z0 ¼ 2, two independent molecules A and B per asymmetric
unit) and 1c (Z0 ¼ 1) crystallised in the triclinic system
ꢀ
Fig. 3 3,5-Diaryl-1H-pyrrole-2-carboxylic acid ethyl esters.
(P1, No. 2)w.
The major difference observed between the three systems was
the inter-planar angle between the C3 substituted aromatic ring
{C31,ꢀ ꢀ ꢀ,C36} and the central pyrrole ring {N1,C1ꢀ ꢀ ꢀ,C4} which
varies from 43.42(7)1 in 1a to 32.98(10)/37.40(7)1 (A/B) in 1b to
the almost orthogonal 82.87(4)1 in 1c (Fig. 4, Table 1). This
indicates that the inclusion of ortho methyl groups in 1c would
be a more effective design for achieving an electronically
disconnected system between the aryl-heteroaryl system when
compared to 1b.
ethyl esters 1a–c which would assist in the overall design of our
NIR analogues and has revealed interesting properties of their
own (Fig. 3). A study of these compounds has shown their
potential to determine the effects of subunit pre-orientation in
an aryl-heteroaryl system and serve as useful design tools for
the more complex BF2 chelated tetraarylazadipyrromethene
systems.
Further analysis of the three structure reveals that for the
unsubstituted phenyl ring at C1, the inter-planar angle with the
central pyrrole is 25.39(9)1 in 1a; 17.23(12)/30.80(9)1 for 1b and
4.10(9)1 for 1c. As expected, a smaller variance in this inter-
planar angle was found between the three systems. However,
the orientation of this phenyl ring does have an important
secondary role to play in the intermolecular hydrogen bonding
in the solid state (discussed later).
Results and disscussion
Synthesis
To pursue our synthetic strategy we required a robust versatile
synthesis of 2,4-diarylpyrroles. Despite their synthetic impor-
tance, direct methods for making 2,4-diarylpyrroles are limited
especially if two different aryl substituents are required. Routes
to symmetrical substituted 2,4-diarylpyrroles include SmI2
mediated reductive dimerisation of phenacyl azides,8 reaction
of hexacarbonylmolybdenum with 3-aryl-2H-azirines,9 and
Grignard mediated dimerization of acetophenone oximes.10
Rhodium and zirconium catalysed reaction of alkynes, amines
and carbon monoxide have been reported as procedures to
unsymmetrically substituted derivatives but these methods
require high pressure CO conditions.11,12 Our approach fol-
lowed a literature methodology which exploited a reductive
cyclisation of electron deficient g-nitroketones with formami-
dinesulfinic acid.13 The starting point for our synthesis were the
1,3-diarylpropenones (chalcones) 2. Compound 2a was com-
mercially available and 2b–c were synthesised by an aldol/
dehydration reaction of the corresponding aldehyde and aceto-
phenone. The generation of 3 was achieved by the addition of
nitroacetic acid ethyl ester to 1,3-diarylpropenones 2. Reduc-
tive cyclization of 3 with formamidinesulfinic acid provided the
ester substituted diarylpyrroles 1a–c in moderate yields
(Scheme 1).
At the substituted pyrrole carbon atom C3, the C4–C3–C31
angles are 130.73(15)1, 131.48(19)/131.34(18)1 and 129.06(11)1
A in 1a, 1b and 1c respectively, a difference of 2.51. In contrast
at C4 for the related C3–C4–C5 angles there is a larger
difference of 41 (Table 1). This can be explained by the
substitution pattern at C3 and C4, whereby the increasing
steric bulk of the substituted phenyl ring along the 1a–c series
influences the bond angles at C4. In 1c, the orthogonal
orientation of the aryl ring relative to the pyrrole facilitates
the C4–C3–C31 and C3–C4–C5 angles to close relative to 1a
and 1b. In contrast the differences in the internal C2–C3–C4/
C3–C4–N1 angles are, however, only 0.4/0.61 between 1a–c.
The ipso angles in the substituted phenyl group at C3, e.g. C32–
C31–C36, vary as 118.37(18)1, 116.16(19)1/116.08(18)1
and 119.13(10)1, a 31 difference in the substituted aromatic
rings –C6H5, –C6H4(NMe2) and –C6H2(Me)2(NMe2). The
smaller angle in 1b derives from the influence of the NMe2
moiety as it is intermediate in structure between 1a and 1c.
Bond length analysis of the pyrrole ring in 1a–c reveals that
there are few significant differences between the three struc-
tures (Table 2). But analysis of the aromatic C–C bond lengths
of both the substituted and unsubstituted aryl rings in 1b show
that the two shortest C–C bonds are the C32–C33/C35–C36
pair with 1.376(3)/1.376(3) A and 1.383(3)/1.378(3) A in mo-
lecules A/B, in comparison to the range of 1.388(3) to 1.397(3)
A for the eight other C–C distances in both C6 rings. No
significant C–C differences are discernible in the other four
aromatic rings of either 1a or 1c. The C–NMe2 bond lengths in
1b are 1.389(3)/1.390(3) A with twist angles of 6.1(3)1/
14.80(12)1 between the Me2N and C6 planes. This provides
supporting evidence for some delocalisation in 1b along the
para-substituted –C6H4–NMe2 moiety.
X-Ray crystallographic study
Compounds 1a–c were examined by single crystal X-ray dif-
fraction in order to determine the nature of the inter-planar
angle between the aryl-pyrrole rings and compare their mole-
cular and crystal structures. In addition, the solid state struc-
Hydrogen bonding and crystal engineering studies continue
to attract much interest in a diverse range of areas of structural
science with potential applications in pharmaceuticals, poly-
morphism, medicinal chemistry, materials for optical/switch-
ing devices, designer supramolecular systems and controlling
crystal growth.14 Of increasing importance is the nature of the
weak interaction e.g. C–Hꢀ ꢀ ꢀO, C–Hꢀ ꢀ ꢀp(arene) and how these
interactions can be manipulated and controlled in the 3-D
crystal structure.15 In our series each pyrrole derivative asso-
ciated through
into dimeric units resulting in the formation of a hydrogen
N–Hꢀ ꢀ ꢀO
C
hydrogen bonding
(ester)
Q
(pyrrole)
Scheme 1
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 2 5 8 – 1 2 6 5
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Table 1 Selected bond angles for 1a–c in [1]
1a
1ba
1c
Aryl–pyrrole twist 43.42(7)
32.98(10)/37.40(7)
82.87(4)
N1–C1–C2
N1–C4–C3
C1–N1–C4
C1–C2–C3
C2–C3–C4
C3–C4–C5
C4–C3–C31
C5–O2–C6
C32–C31–C36
a
106.77(14) 106.50(18)/107.14(17) 106.96(10)
107.70(14) 107.90(18)/107.99(17) 108.29(10)
110.27(14) 110.34(18)/109.87(17) 109.76(9)
109.32(14) 109.72(19)/109.35(18) 109.00(10)
105.93(14) 105.53(18)/105.62(17) 105.97(10)
134.69(15) 135.3(2)/134.32(18)
131.37(11)
130.73(15) 131.48(19)/131.34(18) 129.06(11)
118.13(14) 116.29(17)/117.62(17) Disordered
118.37(18) 116.16(19)/116.06(18) 119.13(10)
Two independent molecules A/B are present.
Table 2 Selected bond lengths for 1a–c in [A]
1a
1ba
1c
N1–C1
N1–C4
C1–C2
C2–C3
C3–C4
C4–C5
C1–C11
C3–C31
N34–C34
a
1.358(2)
1.373(2)
1.379(2)
1.402(2)
1.394(2)
1.454(2)
1.466(2)
1.483(2)
—
1.361(3)/1.361(3)
1.375(3)/1.378(2)
1.378(2)/1.379(3)
1.407(3)/1.408(3)
1.394(3)/1.399(3)
1.452(3)/1.449(3)
1.462(3)/1.467(3)
1.486(3)/1.477(3)
1.389(3)/1.390(3)
1.3631(15)
1.3758(14)
1.3873(16)
1.4057(16)
1.3913(16)
1.4525(17)
1.4678(16)
1.4860(15)
1.3894(15)
Two independent molecules A/B are present.
N–Hꢀ ꢀ ꢀO C hydrogen bonded ring system thus generating an
Q
additional hydrogen bonded motif with graph set R12(7). In the
A/B hydrogen bonded dimeric unit in 1b the intramolecular
inter-planar angles that the C1-phenyl ring makes with the
pyrrole moiety are 17.23(12)1 (A) and 30.80(9)1 (B).
The former (a reduction from 25.39(9)1 in 1a) enables the
formation of
a
C12A–H12Aꢀ ꢀ ꢀO1B interaction with
C12Aꢀ ꢀ ꢀO1B, 3.445(3) A and H12Aꢀ ꢀ ꢀO1B 2.57 A (C–Hꢀ ꢀ ꢀO
angle of 1571), but the phenyl/pyrrole angle difference of 151
between molecules A and B precludes the formation of
a
second and reciprocal C12B–H12Bꢀ ꢀ ꢀO1A interaction
(Fig. 6). The contact data from B - A are 3.616(3) A, 2.96
A and 1291, thus ruling out this possible interaction being
considered even as a contact. There are no p-stacking or
C–Hꢀ ꢀ ꢀp (arene) interactions of note in 1b apart from a myriad
of contacts and van der Waals interactions.
In 1c the centrosymmetric hydrogen bonded dimer contains
two C–Hꢀ ꢀ ꢀO additional interactions involving C12–H12ꢀ ꢀ ꢀ
O1ii/C12–H12iiꢀ ꢀ ꢀO1 as a centrosymmetric related pair, in
contrast to one C-Hꢀ ꢀ ꢀO in 1b and none in 1a (Table 3).
Although the interplanar (perpendicular) distances are reason-
ably short between adjacent dimers the planes do not align to
give an overlapping p-stack in the crystal structure. The
distance data for 1c are C12ꢀ ꢀ ꢀO1ii 3.3707(16) A, H12ꢀ ꢀ ꢀO1ii,
Fig. 4 ORTEP diagrams of 1a, 1b and 1c with displacement ellipsoids
depicted at the 30% probability level. Hydrogen bonds and contacts
are depicted with dashed lines. 1a and 1c with a symmetry equivalent
molecule at ꢁx, ꢁy, ꢁz and 1 ꢁ x, 1 ꢁ y, 1 ꢁ z, respectively.
bonded ring with graph set R22(10), (Fig. 5).16 The strong
intermolecular N–Hꢀ ꢀ ꢀO hydrogen bonding is centrosym-
metric in 1a and 1c with one molecule per asymmetric unit,
whereas it comprises two independent A/B molecules in the
form of a hydrogen bonded dimer in 1b (Z ¼ 4 in space group
ꢀ
P1, No. 2w). The hydrogen bonding Nꢀ ꢀ ꢀO distances differ
from 2.9480(18) A in 1a; 3.068(2) and 2.995(2) A in 1b to
2.9888(13) A in 1c. An overview of the hydrogen bonding is
represented in Fig. 5 with full details presented in Table 3.
The crystal structure of 1a shows that there are no additional
intermolecular hydrogen bonding interactions assisting the
N–Hꢀ ꢀ ꢀO C hydrogen bonded ring formed between each
Q
molecule in the dimeric unit (Table 3). In the crystal structure
Fig. 5 Schematic drawing of the intermolecular hydrogen bonding
within the dimeric species in 1a–c.
of 1b a C–Hꢀ ꢀ ꢀO interaction is present in tandem with the
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on a pyrrole ring system, while XETXID,19 ethyl 3-methyl-5-
phenylpyrrole-2-carboxylate differs from 1a by replacing a
phenyl with a methyl group. This study of 1a–c highlights that
functional groups at remote positions in a molecular system
can introduce subtle differences in both the molecular and
crystal structures as manifested in bond length/angles differ-
ences and overall intermolecular hydrogen bonding.
Table 3 Intermolecular hydrogen bonding, contact and distance
parameters for 1a–c
1a
1ba
1c
N1ꢀ ꢀ ꢀO1i (A)
H1ꢀ ꢀ ꢀO1i (A)
N1–H1–O1i (1)
C12ꢀ ꢀ ꢀO1i (A)
H12ꢀ ꢀ ꢀO1i (A)
C12–H12ꢀ ꢀ ꢀO1i (1)
C36ꢀ ꢀ ꢀO2 (A)
H36ꢀ ꢀ ꢀO2 (A)
C36–H36ꢀ ꢀ ꢀO2 (1)
C6H5/pyrrole (1)
Subs.C6/pyrroleb (1)
Me2N/C6 (1)
2.9480(18)
2.128(19)
162.6(16)
3.614(2)
3.01
3.068(2)/2.995(2)
2.15(2)/2.09(2)
174(2)/176.4(19)
3.445(3), 3.616(3)
2.57, 2.96
2.9888(13)
2.095(15)
170.3(14)
3.3707(16)
2.43
124
157, 129
169
3.4897(18)
Spectroscopic study
2.928(2)
2.54
105
2.932(2)/2.910(3)
2.44/2.47
113/109
The steady state photophysical properties of 1a–c are shown in
Fig 7. The absorption spectrum of 1a exhibited two distinct
bands with little solvent dependency between non-polar cyclo-
hexane and polar acetonitrile. The fluorescence spectrum of 1a
shows slight solvent dependency with a variance of 6 nm for
the emission maximum in cyclohexane and acetonitrile with
Stoke shifts of 44 and 56 nm respectively (Table 4).
2.87
122
(H40C)
25.39(9)
43.42(7)
—
17.23(12)/30.80(9)
32.98(10)/37.40(7)
6.1(3)/14.80(12)
b
4.10(9)
82.87(4)
17.83(8)
a
Two independent molecules A/B are present. The substituted
{C31,ꢀ ꢀ ꢀ,C36} ring system in all three derivatives. i ¼ symmetry
operator ꢁx, ꢁy, ꢁz in 1a, no symmetry operator in 1b; 1 ꢁ x,
1 ꢁ y,1 ꢁ z in 1c.
The absorption spectrum of 1b displayed a single band again
with little solvent effect. But in contrast to 1a the fluorescence
2.43 A and C12–H12ꢀ ꢀ ꢀO1ii, 1691 which are significantly short-
er than 1b.
The overall trend in the hydrogen bonding (disregarding the
effects of the overall crystal packing) is the presence of the
hydrogen bonded N–Hꢀ ꢀ ꢀO C ring system in all three crystal
Q
structures and the presence of additional 0, 1, 2 orthoC–Hꢀ ꢀ ꢀ
O
C interactions augmenting the central N–Hꢀ ꢀ ꢀO C ring
Q
Q
on progression from the phenyl 1a, 4-substituted aryl 1b to the
2,4,6-substituted aryl ring system 1c. The known tendency for
the strongest hydrogen bond donor to pair with the strongest
acceptor is observed for 1a to 1c with additional weaker
C–Hꢀ ꢀ ꢀO interactions supplementing this interaction. In a
structurally related system we have previously reported dipyr-
romethanes where only N–Hꢀ ꢀ ꢀp(pyrrole) interactions are ob-
served in the absence of stronger hydrogen bond donors/
acceptors.17
There are no close pyrrole analogues of 1a–c available on the
Cambridge Structural Database (CSD) reported to date using
a search for the central pyrrole core with two C6 aromatic rings
attached. However, an example VUGDEG,11,18 5-methyl-N,3-
diphenylpyrrole-2-carboxamide has the general substitution
pattern of three carbon atoms replacing three of the H atoms
Fig. 6 Stereoview diagram of a pair of hydrogen bonded dimers in 1b.
The H atoms on the CH3 and CO2Et groups have been removed for
clarity.
Fig. 7 Normalised absorption and fluorescence spectra of 1a (top), 1b
(middle), 1c (bottom) in cyclohexane (black, blue) and acetonitrile
(green, red).
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Table 4 Spectroscopic data for 1a–ca
lysis. The dihedral angle (j) between the C3 substituted aro-
matic ring and the pyrrole ring was varied by 11 increments
using the dihedral driving feature in Macromodel 8.5 and the
energy calculated after minimization at each incremental stage
using the MM2 force field in the gas phase.22 The results
obtained were plotted as shown in Fig. 8 which provided the
calculated ground state twist potential of 1a–c.
All atoms were constrained during the calculation except for
the rotating aromatic group at the pyrrole C-3 position and
energy minima were calculated at one-degree intervals. 1a and
1b gave similar results with an energy minimum between
38–441 and 33–381 respectively. This was in good agreement
with the experimental C3 aryl-pyrrole inter-planar angle from
their crystal structures. Both 1a and 1b showed a significant
barrier to rotation for j ¼ 901 of 11.6 kJ molꢁ1 and 13 kJ
molꢁ1 respectively. In contrast 1c showed a significantly lower
barrier (2 kJ molꢁ1) to rotation about the 60–1201 range but a
large barrier (60 kJ molꢁ1) to both rings becoming co-planar,
again in agreement with the solid-state structure. The close
agreement of the results of this computational method with our
experimental crystallographic data suggests that this would be
a powerful predictive tool for other systems.
Solvent
lmax abs [nm]
lmax flu [nm]
Stoke shift [nm]
1a
1a
1b
1b
1c
1c
a
C6H12
CH3CN
C6H12
262/306
263/300
296
350
356
400
492
417
524
44
56
104
197
111
220
CH3CN
C6H12
CH3CN
295
306
304
Room temperature.
spectrum showed a pronounced solvatochromic effect with
larger Stokes’ shifts. The wavelength of emission maxima in
cyclohexane (400 nm) and acetonitrile (492 nm) varied by 92
nm with the Stokes’ shift increasing from 104 nm to 197 nm
due to the solvent polarity change. This would be indicative of
a high charge-transfer character of the emitting state. A similar
but even more pronounced effect was observed for the fluor-
escence spectra of 1c. The emission maximum in cyclohexane
was at 417 nm with a larger red shift to 524 nm in acetonitrile.
The increase in Stoke shifts to 111 nm in cyclohexane and
220 nm in acetonitrile is indicative of an increased electronic
decoupling in 1c. In conjunction with the red shifts, broadening
of the bands was also observed and in the case of 1c a
significant diminishing of fluorescence intensity in acetonitrile.
These spectral characteristics are similar in some respects to
those reported for other reported dimethylamino substituted
CT sytems.20 The characteristics of the fluorescence spectra of
1b–c in polar solvent indicates that their fluorescence state is
different from the originally locally-excited (LE) state. The
increasing Stokes’ red shift with increasing solvent polarity
implies that 1b–c in the fluorescent state has a large dipole
moment which is most likely the intramolecular charge transfer
state. One could propose that from a comparison of absorption
and fluorescence characteristic for the series 1a–c that 1a emits
from a less polar LE state whereas 1b–c emit either from a CT
state or a combination of CT and LE. While aromatic amino
esters have been reported as having solvent dependant emis-
sions it is interesting to observe such characteristics from a
pyrrole ester. A previously reported examples exploiting pyr-
role units in a donor–acceptor system used the pyrrole as the
donating group.21 As such the unique architecture of this
system coupled with its interesting spectral properties warrants
a further in depth photophysical study.
Conclusion
We have synthesised a series of diaryl-pyrroles and charac-
terised key parameters to determine their suitability for incor-
poration into fluorescent sensors designed upon the virtual C0
spacer principles. Solution, solid state and computational
evidence for the key characteristics of these systems provides
an excellent platform for the design of future more complex
visible red and NIR analogues.
Experimental
General
1H NMR spectra were recorded on a Varian FT spectrometer
at 300 MHz and 13C NMR spectra at 75 MHz, in CDCl3 with
tetramethylsilane as the internal standard. All chemical shifts
are quoted in d (ppm) and coupling constants in Hz. Melting
points were determined on a Reichert Thermovar melting point
platform and are uncorrected. Mass spectral analyses were
performed on a Micromass Quattro Micro. IR spectra were
recorded on a Mattson Instruments Galaxy series FT-IR 3000
spectometer. Absorption spectra were recorded on a Varian
Cary 50 UV-visible spectrophotometer. Fluorescence spectra
were recorded on a Cary Eclipse spectrofluorometer. The
microanalytical laboratory, University College Dublin, carried
out the elemental analyses.
Computational study
The coordinates from the crystal structures 1a–c provided the
starting structures that were used in the conformational ana-
4-Dimethylamino-2,6-dimethylbenzaldehyde. POCl3 (6.85 g,
44.7 mmol) was added dropwise over 20 minutes to DMF
(13.06 g, 179 mmol) that was cooled on an ice bath. The
solution was allowed to stir for 30 minutes after which it was
added dropwise over 30 minutes to 3,5-dimethylphenyldi-
methylamine (20 g, 134 mmol) under nitrogen and cooled on
an ice bath. The mixture was stirred at room temperature for 8
hours during which time a brown solid formed. Ice (120 g) was
added and the reaction mixture was adjusted to pH 7 with 33%
NaOH solution (15 mL). The mixture was extracted with ether
(5 ꢂ 100 mL), the organic layer was separated, dried over
sodium sulfate and the solvent evaporated. The excess amine
(12.5 mL recovered) was distilled off and the product was
isolated from the resulting residue after recrystallisation from
petroleum spirits (40–60) as a white solid (5.53 g, 70%); mp
84–85 1C (lit mp 83 1C).23 1H NMR (300 MHz, CDCl3) d:
10.35 (s, 1H), 6.30 (s, 2H), 3.03 (s, 6H), 2.59 (s, 6H); 13C NMR
(75 MHz, CDCl3) d: 190.7, 153.1, 144.4, 121.7, 112.2, 40.0,
Fig. 8 Ground state twist potential (j) of 1a (green) 1b (black) and 1c
(blue) derived from MM2 force field in the gas phase.
21.8; IR (KBr disc): uCQ 1666 cmꢁ1; ES-MS (m/z) calcd. for
O
1262
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 2 5 8 – 1 2 6 5

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C11H16N: 178.0 (M þ H)1; found: 178.1; Anal. calcd. for
C11H15N: C, 74.54; H, 8.53; N, 7.90; found: C, 74.42; H, 8.54;
N, 7.76.
filtration. Recrystallisation from ethanol gave the product 3b
1
as a white solid (15.8 g, 74%), mp 102–104 1C. H NMR (300
MHz, CDCl3) d: 7.86–7.90 (m, 2H), 7.49–7.55 (m, 1H), 7.38–
7.44 (m, 2H), 7.10–7.17 (m, 2H), 6.58–6.62 (m, 2H), 5.55, 5.49
(each d, J ¼ 9.4, 8.5 Hz, total 1H), 4.35–4.43 (m, 1H), 4.04–
4.28, (m, 2H), 3.36–3.68 (m, 2H), 2.87 (s, 6H), 1.22, 1.08 (each
t, J ¼ 7.2, 7.2 Hz, total 3H); 13C NMR (75 MHz, CDCl3) d:
196.9, 163.6, 150.4, 136.8, 133.5, 129.3, 129.0, 128.8, 128.3,
124.2, 112.8, 92.2, 92.1, 63.3, 63.0, 41.4, 41.3, 41.1, 40.9, 40.5,
13.9; IR (KBr disc): uCQO 1743, uCQO 1683 cmꢁ1; ES-MS (m/z)
calcd. for C21H25N2O5: 385.0 (M þ H)1; found: 385.2; Anal.
calcd. for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29; found C,
65.47; H, 6.28; N, 7.29%.
3-(4-Dimethylaminophenyl)-1-phenylpropenone (2b). 4-Di-
methylaminobenzaldehyde (10 g, 67 mmol), 1-phenylethanone
(8.05 g, 67 mmol) and four NaOH pellets were dissolved in
methanol (100 mL) and stirred at room temperature for 24
hours during which time a precipitate formed. The precipitate
was isolated by filtration and washed with cold methanol to
give the product 2b as a bright yellow solid, (14.1 g, 84%), mp
111–112 1C (lit. m.p. 110–111 1C).24 1H NMR (300 MHz,
CDCl3) d: 7.98–8.02 (m, 2H), 7.79 (d, J ¼ 15.5 Hz, 1H), 7.43–
7.56 (m, 5H), 7.32 (d, J ¼ 15.5 Hz, 1H), 6.64–6.69 (m, 2H), 3.00
(s, 6H); 13C NMR (75 MHz, CDCl3) d: 190.8, 152.3, 146.0,
139.3, 132.3, 130.6, 128.7, 128.5, 122.9, 117.1, 112.0, 40.3; IR
3-(4-Dimethylamino-2,6-dimethylphenyl)-2-nitro-5-oxo-5-
phenylpentanoic acid ethyl ester (3c). Compound 2c (0.68 g,
2.43 mmol) was dissolved in ethanol (15 mL), diethylamine
(0.04 g, 0.41 mmol) and nitro-acetic acid ethyl ester (0.54 g, 4.1
mmol) were added, and the reaction was heated under reflux
for 24 hours. The reaction mixture was allowed to cool to room
temperature, acidified with 25% acetic acid solution (2 mL)
and diluted with water (10 mL) which resulted in an oil. The
water was removed by evaporation and the resulting residue
was taken up in CH2Cl2 and washed with a saturated sodium
bicarbonate solution (2 ꢂ 25 mL). The organic layer was
separated, dried over sodium sulfate and evaporated to dry-
ness. Purification by dry flash column chromatography on
silica eluting with hexane/ether (2 : 1) gave the unreacted
starter first (0.32 g) and the product 3c second as a straw yellow
oil (0.2 g, 20%). 1H NMR (300 MHz, CDCl3) d: 7.83–7.90 (m,
2H), 7.51–7.55 (m, 1H), 7.39–7.46 (m, 2H), 6.32 (s, 1H), 6.31 (s,
1H), 5.78, 5.69 (each d, J ¼ 11.7, 11.2 Hz, total 1H), 4.99–5.16
(m, 1H), 3.89–4.15 (m, 2H), 3.35–3.73 (m, 2H), 2.87, 2.85 (each
s, total 6H), 2.50, 2.46, 2.40, 2.37 (each s, total 6H), 1.20, 0.92
(each t, total 3H); 13C NMR (75 MHz, CDCl3) d: 196.9, 164.2,
163.3, 149.6, 149.4, 136.8, 133.3, 133.1, 128.3, 122.7, 120.9,
114.1, 114.0, 113.1, 113.0, 90.7, 90.3, 63.2, 62.5, 36.1, 35.1, 41.4,
40.9, 40.3, 40.2, 13.7, 13.3; IR (CH2Cl2): uCQO 1750, uCQO 1689
cmꢁ1; ES-MS (m/z) calcd. for C23H29N2O5: 413.0 (M þ H)1;
found 413.
(KBr disc): uCQ 1649 cmꢁ1
; ES-MS (m/z) calcd. for
O
C17H18NO: 250.0 (M þ H)1; found 252.1; Anal. calcd. for
C17H17NO: C, 81.24; H, 6.82; N, 5.57; found: C, 80.95; H, 6.82;
N, 5.49%.
3-(4-Dimethylamino-2,6-dimethylphenyl)-1-phenylpropenone
(2c). 4-Dimethylamino-2,6-dimethylbenzaldehyde (4.5 g, 25
mmol), 1-phenylethanone (3 g, 25 mmol) and four NaOH
pellets were dissolved in methanol (50 mL) and stirred at room
temperature for 24 hours during which time a precipitate
formed. The precipitate was isolated by filtration and washed
with cold methanol to give the product 2c as a bright yellow
solid, (3.8 g, 54%), mp 93–95 1C. 1H NMR (300 MHz, CDCl3)
d: 8.11 (d, J ¼ 15.8 Hz, 1H), 7.97–7.99 (m, 2H), 7.45–7.55 (m,
3H), 7.14 (d, J ¼ 15.8 Hz, 1H), 6.44 (s, 2H), 2.99 (s, 6H), 2.48
(s, 6H); 13C NMR (75 MHz, CDCl3) d: 191.0, 150.8, 143.6,
140.4, 139.2, 132.4, 128.7, 128.6, 123.2, 122.1, 112.6, 40.3, 22.9;
IR (KBr disc): uCQ 1654 cmꢁ1; ES-MS (m/z) calcd. for
O
C19H22N: 280.0 (M þ H)1; found: 280.1; Anal. calcd. for
C19H21N: C, 81.68; H, 7.58; N, 5.01; found C, 81.75; H, 7.63;
N, 5.31%.
2-Nitro-5-oxo-3,5-diphenylpentanoic acid ethyl ester (3a).
Compound 2a (10 g, 48 mmol) was dissolved in ethanol (80
mL), diethylamine (0.35 g, 4.8 mmol) and nitro-acetic acid
ethyl ester (3.33 g, 25 mmol) were added, and the reaction was
heated under reflux for 18 hours. The reaction mixture was
allowed to cool to room temperature, acidified with 50% acetic
acid solution (5 mL), diluted with water (20 mL) and the
resulting precipitate was isolated by filtration. Recrystallisation
from ethanol gave the product 3a as a white solid (14.3 g,
87%), m.p. 111–113 1C (lit. m.p. 116–117 1C).25 1H NMR (300
MHz, CDCl3) d: 7.86–7.89 (m, 2H), 7.51–7.57 (m, 1H), 7.4–
7.45 (m, 2H), 7.22–7.32, (m, 5H), 5.61, 5.54, (each d, J ¼ 9.5,
8.5 Hz, 1H), 4.45–4.55 (m, 1H), 4.02–4.29 (m, 2H), 3.45–3.74
(m, 2H), 1.22, 1.06 (each t, J ¼ 7.2, 7.2 Hz, total 3H); 13C
NMR (75 MHz, CDCl3) d: 196.6, 196.5, 163.9, 163.4, 138.2,
137.2, 136.7, 133.7, 133.6, 129.1, 129.1, 128.9, 128.7, 128.3,
128.3, 128.2, 91.8, 91.7, 63.4, 63.2, 42.1, 41.7, 41.0, 40.7, 13.9,
13.8; IR (KBr disc): uCQO 1751, uCQO 1682 cmꢁ1; ES-MS (m/z)
calcd. for C19H20NO5: 342.0 (M þ H)1; found: 342.1; Anal.
calcd. for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found C,
66.79; H, 5.61; N, 4.11%.
3,5-Diphenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1a).
Compound 3a (10 g, 29 mmol) was dissolved in dry ethanol
(50 mL), treated with formamidine sulfinic acid (10 g, 92 mmol)
and the suspension was heated under reflux under nitrogen for
14 hours. The reaction mixture was allowed to cool to room
temperature and the solvent was evaporated to a brown
residue. Recrystallisation from ethanol gave the product 1a
as a crystalline solid (3.32 g, 39%), m.p. 139–140 1C (lit. m.p.
138–139 1C).26 1H NMR (300 MHz, CDCl3) d: 9.51 (bs, 1H),
7.57–7.62 (m, 4H), 7.28–7.44 (m, 6H), 6.61 (d, 1H, J ¼ 3.0 Hz),
4.26 (q, J ¼ 7.2 Hz, 2H), 1.23 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) d: 161.6, 135.7, 135.4, 133.7, 131.4, 129.8, 129.3,
128.1, 127.9, 127.3, 125.1, 118.9, 110.2, 60.6, 14.4; IR (KBr
disc): uNꢁH 3313, uCQO 1662 cmꢁ1; UV-visible (EtOH): lmax
¼
263, 308 nm; ES-MS (m/z) calcd. for C19H17NO2: 292.0 (M þ
H)1; found: 292.1; Anal. calcd. for C19H17NO2: C, 78.33; H,
5.88; N, 4.81; found C, 78.41; H, 5.89; N, 4.79%.
3-(4-Dimethylaminophenyl)-5-phenyl-1H-pyrrole-2-carboxy-
lic acid ethyl ester (1b). Compound 3b (10 g, 26 mmol) was
dissolved in dry ethanol (100 mL), treated with formamidine
sulfinic acid (9.5 g, 88 mmol) and the suspension was heated
under reflux under nitrogen for 14 hours. The mixture was
allowed to cool to room temperature and the solvent was
evaporated to a brown residue. Recrystallisation from ethanol
gave the product 1b as a crystalline solid (3.4 g, 39%), m.p. 135
3-(4-Dimethylaminophenyl)-2-nitro-5-oxo-5-phenylpentanoic
acid ethyl ester (3b). Compound 2b (14.1 g, 56 mmol) was
dissolved in ethanol (100 mL), diethylamine (0.41 g, 5.6 mmol)
and nitro-acetic acid ethyl ester (11.22 g, 84 mmol) were added,
and the reaction was heated under reflux for 24 hours. The
reaction mixture was allowed to cool to room temperature,
acidified with 50% acetic acid solution (15 mL), diluted with
water (100 mL) and the resulting precipitate was isolated by
1
–137 1C. H NMR (300 MHz, CDCl3) d: 9.34 (bs, 1H), 7.51–
7.61 (m, 4H), 7.38–7.43 (m, 2H), 7.27–7.32 (m, 1H), 6.74–6.79
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 2 5 8 – 1 2 6 5
1263

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(m, 2H), 6.59 (d, 1H, J ¼ 3.08), 4.29 (q, 2H, J ¼ 7.2 Hz), 2.98
(s, 6H), 1.29 (t, 3H, J ¼ 7.2 Hz); 13C NMR (75 MHz, CDCl3) d:
161.6, 150.1, 135.5, 134.2, 131.6, 130.5, 129.2, 128.0, 125.0,
123.4, 118.3, 112.1, 109.8, 60.4, 40.9, 14.6; IR (KBr disc): uNꢁH
refinement: the rotational disorder in the methyl groups of 1c
was treated using the AFIX 127 command in SHELXL97.
3342, uCQ 1664 cmꢁ1; UV-visible (EtOH): lmax ¼ 294 nm;
O
Crystallographic data
ES-MS (m/z) calcd. for C21H22N2O: 335.0 (M þ H)1;
found: 335.1; Anal. calcd. for C21H22N2O2: C, 75.42; H, 6.63;
N, 8.38; found C, 75.41; H, 6.62; N, 8.26%.
1a, Chemical formula C19H17NO2, colourless, molecular
weight 291.34 g molꢁ1, monoclinic, space group P21/c (No.
14), a ¼ 10.5232(12), b ¼ 7.5048(4), c ¼ 20.2461(15) A, b ¼
102.020(7)1, V ¼ 1563.9(2) A3, Z ¼ 4, T ¼ 294(1) K, density ¼
1.237 g cmꢁ3 (calc.), F(000) ¼ 616, m ¼ 0.080 mmꢁ1, 4173
reflections to 2y ¼ 521, 3081 unique (with 2189 I 4 2sI), 204
parameters, R-factor is 0.045, wR2 ¼ 0.102 (based on F2 for
with I 4 2sI) using SHELXL97, Gof ¼ 1.03, density range in
3-(4-Dimethylamino-2,6-dimethylphenyl)-5-phenyl-1H-pyrrole-
2-carboxylic acid ethyl ester (1c). (4-Dimethylamino-2,6-
dimethylphenyl)-2-nitro-5-oxo-5-phenylpentanoic acid ethyl
ester 3c (1 g, 2.4 mmol) was dissolved in dry ethanol (40
mL), treated with formamidine sulfinic acid (1.05 g, 9.7 mmol)
and the suspension was heated under reflux under nitrogen for
24 hours. The mixture was allowed to cool to room tempera-
ture and the solvent was evaporated to a brown residue.
Recrystallisation from ethanol gave the product 1c as a yellow
coloured crystalline solid (0.2 g, 22%), mp 157–160 1C. 1H
NMR (300 MHz, CDCl3) d: 9.59 (bs, 1H), 7.60–7.63 (m, 2H),
7.38–7.43 (m, 2H), 7.26–7.31 (m, 1H), 6.52 (s, 2H), 6.41 (d, J ¼
2.8 Hz, 1H), 4.13 (q, J ¼ 7.1 Hz, 2H), 2.94 (s, 6H), 2.09 (s, 6H),
1.07 (t, J ¼ 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 161.6,
149.7, 137.3, 135.5, 132.0, 131.5, 129.0, 127.6, 124.7, 124.5,
120.2, 111.6, 110.5, 59.9, 40.9, 21.3, 14.1; IR (KBr disc): uNꢁH
3328, uCQO 1677 cmꢁ1; UV-visible (EtOH): lmax ¼ 307 nm; ES-
MS (m/z) calcd. for C23H26N2: 363.0 (M þ H)1; found: 363.2;
Anal. calcd. for C23H26N2: C, 76.21; H, 7.23; N, 7.73; found C,
75.99; H, 7.30; N, 7.79%.
final Dmap is ꢁ0.19 to þ0.21 e. Aꢁ3
.
1b, Chemical formula C21H22N2O2, colourless, molecular
weight 334.41 g molꢁ1, triclinic, space group P1 (No. 2), a ¼
ꢀ
9.8173(11), b ¼ 13.3363(11), c ¼ 15.9016(10) A, a ¼ 67.237(5)1,
b ¼ 80.480(8)1, g ¼ 72.421(8)1, V ¼ 1827.3(3) A3, Z ¼ 4, T ¼
294(1) K, density ¼ 1.216 g cmꢁ3 (calc.), F(000) ¼ 712, m ¼
0.079 mmꢁ1, 8324 reflections to 2y ¼ 521, 7032 unique (with
4257 I 4 2sI), 468 parameters, R-factor is 0.054, wR2 ¼ 0.119
(based on F2 for with I 4 2sI) using SHELXL97, Gof ¼ 1.03,
density range in final Dmap is ꢁ0.32 to þ0.34 e. Aꢁ3
.
1c, Chemical formula C23H26N2O2, yellow, molecular
weight 362.46 g molꢁ1, triclinic, space group P1 (No. 2), a ¼
ꢀ
7.6973(5), b ¼ 9.3729(6), c ¼ 14.0807(10) A, a ¼ 83.347(1)1,
b ¼ 82.391(1)1, g ¼ 79.132(1)1, V ¼ 984.54(11) A3, Z ¼ 2,
T ¼ 150(2) K, density ¼ 1.223 g cmꢁ3 (calc.), F(000) ¼ 388,
m ¼ 0.078 mmꢁ1, 16869 reflections to 2y ¼ 56.51, 4591 unique
(with 3988 I 4 2sI), 274 parameters, R-factor is 0.048, wR2 ¼
0.127, (based on F2 for with I 4 2sI) using SHELXL97, Gof ¼
1.04, density range in final Dmap is ꢁ0.28 to þ0.28 e. Aꢁ3
.
X-Ray data collection, structure solution and refinement
Crystallographic data (excluding structure factors) for 1a–c
have been deposited with the Cambridge Crystallographic
Data Centre.w
Data were collected on a Siemens-Bruker P4 diffractometer for
the structures 1a and 1b at room temperature (294 K) and
processed using the XSCANS suite of programs.27 A study at
294 K of 1c has been deposited with the CSD as 233395w but
has not been referred to in the text. A low-temperature study
was undertaken of 1c at 150 K using a Bruker APEX diffract-
ometer and data were processed using the SMART suite of
programs.28 Mo-Ka radiation (0.71073 A) was used in all
structural studies with graphite monochromator. Compound
1a crystallizes in the monoclinic system, space group P21/c
(No. 14) (Z0 ¼ 1) while both derivatives 1b (Z0 ¼ 2, two
independent molecules A and B per asymmetric unit) and 1c
UV-visible and fluorescence procedures
Solvents used were spectrophotometric grade chloroform,
which was distilled over potassium carbonate prior to use,
spectrophotometric grade acetonitrile and HPLC grade cyclo-
hexane. Stock solutions (5 ꢂ 10ꢁ5 M) of each diarylpyrrole
ester 1a–c were prepared in chloroform. For UV-visible ana-
lysis a 1 in 10 dilution from the stock solution into cyclohexane
and acetonitrile was performed to give solutions of 5 ꢂ 10ꢁ6 M
concentration. In all cases the UV-visible spectra were deter-
mined from a 1 cm path quartz cell at room temperature.
Baseline corrected UV-visible spectra were collected between
250 and 500 nm. All UV-visible spectra were normalised to 1 at
their position of maximum absorbance. For fluorescence ana-
lysis the respective 5 ꢂ 10ꢁ6 M UV-visible solutions were
diluted by a factor of 10 with acetonitrile and cyclohexane to
give solutions of 5 ꢂ 10ꢁ7 M concentration. In all cases
fluorescence was determined at room temperature from a
1 cm path quartz cell with excitation and emission slit widths
of 5 nm and a PMT detector voltage of 600 volts. Baseline
corrected fluorescence spectra for 1a–b were obtained by
exciting solutions at 285 nm and collecting the fluorescence
between 295 and 600 nm. Baseline correction for the poorly
emitting 1c did not give satisfactory spectra. Therefore in order
to avoid 2nd order solvent scattering interference for 1c, the
solutions were excited at 310 nm and the fluorescence collected
between 320 and 600 nm. All fluorescence spectra were normal-
ised to 1 at their position of maximum emission.
0
ꢀ
(Z ¼ 1) crystallize in the triclinic system (P1, No. 2). Solution
and refinement was undertaken using SHELXS97 and
SHELXL97.29 The graphics were generated with ORTEX30
and PLATON.31
No disorder is present in 1a, but in the asymmetric unit of 1b
a minor component of rotational disorder was detected in three
of the methyl groups in the two Me2N moieties of the inde-
pendent A and B molecules. These were treated accordingly by
using six partial occupancy H atom sites with AFIX 127 in
SHELXL97 to give site occupancies of 0.81 : 0.19, 0.74 : 0.26
and 0.88 : 0.12. Data for 1c were collected on a Bruker APEX
CCD diffractometer at 150 K. Carboxylate disorder is ob-
served in 1c but with site occupancy factors of 0.608(4) and
0.392(4) for the major and minor orientations, respectively,
and one of the methyl groups C37 has rotational disorder with
respect to the three hydrogen atoms resulting in major : minor
orientations of 0.61(2) and 0.39(2).
All non hydrogen atoms were refined using anisotropic
displacement parameters and hydrogen atoms were treated as
riding atoms using the SHELXL97 defaults at the appropriate
temperature whereas the N–H hydrogen atoms were refined
with isotropic displacement parameters. The carboxylate dis-
order in 1c was treated using appropriate soft DFIX/DELU/
ISOR restraints in the final cycles of full matrix least squares
w CCDC reference numbers 233393–233396. See http://dx.doi.org/
10.1039/b507669b for crystallographic data in CIF or other electronic
format.
1264
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11 E. M. Campi, G. D. Fallon, W. R. Jackson and Y. Nilsson, Aust.
J. Chem., 1992, 45, 1167.
Acknowledgements
12 S. L. Buchwald, M. W. Wannamaker and B. T. Watson, J. Am.
Chem. Soc., 1989, 111, 776.
´
13 B. Quiclet-Sire, I. Thevenot and S. Z. Zard, Tetrahedron Lett.,
This work was funded under the Program for Research in
Third-Level Institutions administered by the HEA. J. F. G.
thanks Dublin City University for the purchase of a Siemens
P4 diffractometer and computer system. Thanks to Dr D. Rai
of the CSCB Mass Spectrometry Centre for mass analyses and
Dr H. Mueller-Bunz of the UCD Crystallographic Centre for
collecting a low temperature dataset for 1c.
1995, 36, 9469.
14 G. R. Desiraju and T. Steiner, The Weak Hydrogen Bond in
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