Five (1H-pyrrol-2-yl)pyridines

Article abstract of DOI:10.1107/S0108270103007042

The title (1H-pyrrol-2-yl)pyridines, C₉H₈N₂, substituted at the ortho, meta, and para positions of the pyridine ring all have hydrogen-bonded arrangements with geometrically similar, nearly linear, N(pyrrole)-H...N(pyridine) hydrogen bonds of average length. The graph sets for the ortho, meta, and three para polymorphs are R₂²(10), C(6), C(7), C(7), and R₄⁴(28), respectively.

Full text of DOI:10.1107/S0108270103007042

organic compounds
Acta Crystallographica Section C
Crystal Structure
The disordered rings in (IIIC) are tilted in opposite directions
to the plane of the pyrrole ring.
Communications
In all ®ve structures, the molecules are held together by
N8ÐHÁ Á ÁN1 hydrogen bonds. The metrical parameters for
these bonds are given in Table 1. All of the NÐHÁ Á ÁN bonds
are close to linear and of average length.
ISSN 0108-2701
Five (1H-pyrrol-2-yl)pyridines
In (I), there is an intramolecular N8ÐHÁ Á ÁN1 contact, with
ꢀ
Ê
Ê
NÐHÁ Á ÁN = 93 , HÁ Á ÁN = 2.06 A, and NÁ Á ÁN = 2.786 (2) A.
Although the NÁ Á ÁN distance in this contact is shorter than the
intermolecular NÁ Á ÁN distances in all of the compounds, the
Wayland E. Noland, Kevin P. Cole and Doyle Britton*
ꢀ
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455-0431,
geometry of the arrangement, with an NÐHÁ Á ÁN angle of 93 ,
USA
suggests that it is less important. The intermolecular
hydrogen-bond arrangement is shown in Fig. 1. Two molecules
form a dimer across a twofold axis. In graph-set notation
Correspondence e-mail: britton@chem.umn.edu
Received 2 October 2002
Accepted 26 March 2003
Online 30 April 2003
2
2
(
Etter et al., 1990), this is an R (10) arrangement.
The title (1H-pyrrol-2-yl)pyridines, C H N , substituted at the
9
8
2
ortho, meta, and para positions of the pyridine ring all have
hydrogen-bonded arrangements with geometrically similar,
nearly linear, N(pyrrole)ÐHÁ Á ÁN(pyridine) hydrogen bonds
of average length. The graph sets for the ortho, meta, and three
2
2
4
4
para polymorphs are R (10), C(6), C(7), C(7), and R (28),
respectively.
Comment
Pyrroles and other simple heteroaromatic nuclei are of
interest in biology and medicine, and are used widely as
ligands for transition metal complexes, including porphyrins
and synthetic analogs (Klappa et al., 2002). Polypyrroles are of
interest as conducting polymers (Wilson, 1977; de Jesus, 1996;
Kanatzidis, 1990). We became interested in the (1H-pyrrol-2-
yl)pyridines substituted in the ortho, (I), meta, (II), and para,
Figure 1
The intermolecular HÁ Á ÁN contacts (dashed lines) in (I). Displacement
ellipsoids are shown at the 50% probability level and H atoms are shown
as small spheres of arbitrary radius.
(
III), positions with respect to the N atom of the pyridine
nucleus. We report here the crystal structures of (I), (II), and
three polymorphs of (III), viz. (IIIA), (IIIB) and (IIIC). There
are two molecules in the asymmetric unit of each of the three
polymorphs of (III).
The atomic labeling and the anisotropic displacement
ellipsoids for the ®ve structures are shown as part of the
packing diagrams in Figs. 1±5. The bond lengths and angles are
normal, and vary slightly in the pyridine rings, depending in a
reasonable way on the point of attachment of the pyrrole ring,
and agreed, within experimental error, in all eight determi-
nations of the pyrrole-ring geometry.
The rings were all planar, with dihedral angles between the
ꢀ
ꢀ
Figure 2
rings as follows: (I) 15.5 (2) , (II) 13.6 (2) , (IIIA) 14.8 (2) and
ꢀ
The intermolecular HÁ Á ÁN contacts (dashed lines) in (II). Displacement
ellipsoids are shown at the 50% probability level and H atoms are shown
as small spheres of arbitrary radius.
ꢀ
1
3.3 (2) , (IIIB) 12.1 (2) and 5.0 (2) , and (IIIC) 16.8 (5)/
ꢀ
8
.3 (5) (two orientations of the disordered ring) and 0.8 (2) .
Acta Cryst. (2003). C59, o263±o267
DOI: 10.1107/S0108270103007042
# 2003 International Union of Crystallography o263

organic compounds
The hydrogen bonding in (II) is shown in Fig. 2. There are
chains, with graph set C(6), lying along the [101] direction,
with the molecules related by the n glide.
The hydrogen bonding in polymorph A of (III) is shown in
Fig. 3. There are chains, with graph set C(7), parallel to the b
axis alternating between the crystallographically independent
A and B molecules. The A and B molecules are not related by
any pseudosymmetry. Pairs of molecules in the chain are
related by translation along b. Although the molecules are
crystallographically independent, there is no signi®cant
difference in their hydrogen-bonding behavior.
The hydrogen bonding in polymorph B of (III) is shown in
Fig. 4. There are chains, with graph set C(7), parallel to the c
axis alternating between the crystallographically independent
A and B molecules. As in (IIIA), there is no pseudosymmetry
relating the two independent molecules and no signi®cant
difference in their hydrogen-bonding behavior. Adjacent pairs
of A and B molecules in the chain are related by the c glide.
The bonding in polymorph C of (III) is shown in Fig. 5.
4
There are four-membered rings, with graph set R (28),
4
surrounding a center of symmetry, with alternating crystal-
lographically independent A and B molecules. As a conse-
quence of the molecular ring, the A and B molecules are
related by a pseudo-fourfold symmetry axis, but this does not
lead to more extended pseudosymmetry.
Figure 4
The intermolecular HÁ Á ÁN contacts (dashed lines) in polymorph B of
(III). Displacement ellipsoids are shown at the 50% probability level and
H atoms are shown as small spheres of arbitrary radius.
Figure 5
Figure 3
The intermolecular HÁ Á ÁN contacts (dashed lines) in polymorph C of
(III). Displacement ellipsoids are shown at the 50% probability level and
H atoms are shown as small spheres of arbitrary radius. The disorder in
the pyridine ring of molecule A is shown only in the labeled molecule.
The intermolecular HÁ Á ÁN contacts (dashed lines) in polymorph A of
(III). Displacement ellipsoids are shown at the 50% probability level and
H atoms are shown as small spheres of arbitrary radius.
ꢁ
o264 Noland, Cole and Britton
Five C H N
9 8 2
polymorphs
Acta Cryst. (2003). C59, o263±o267

organic compounds
A comparison of the cell volumes of (IIIA), (IIIB), and
3
IIIC) [1495.6 (7), 1513.8 (7), and 1488.0 (7) A , respectively]
Table 1
Distances and angles ( AÊ , ) for the N8ÐHÁ Á ÁN1 contacts in the ®ve title
ꢀ
Ê
(
compounds (I)±(IIIC).
suggests that at low temperature the (IIIC) form is the most
stable and the (IIIB) form the least stable (Dunitz, 1995).
D
A
DÐH
DÐHÁ Á ÁA
HÁ Á ÁA
DÁ Á ÁA
i
(
(
I)
II)
N8
N8
N1
N1
0.91
0.93
0.97
0.93
0.96
0.95
0.91
0.95
0.95
163
169
171
161
168
167
174
174
169
2.06
1.99
1.95
2.03
1.94
1.99
2.07
2.08
2.02
2.949
2.901
2.913
2.920
2.891
2.920
2.976
3.021
2.956
ii
Experimental
(IIIA)
(
(
N8A
N8B
N8A
N8B
N8A
N8B
N8B
N1B
iii
N1
N1B
N1A
N1B
N1A
N1A
IIIA)
IIIB)
The (1H-pyrrol-2-yl)pyridines (I)±(III) are well known compounds,
and (I) is an inhibitor of prolyl 4-hydroxylase (Dowell et al., 1993).
We chose methods that were (i) inexpensive, (ii) relatively high-
yielding, and (iii) easily applied to acetophenones in order to
generate a large variety of 2-aryl-1H-pyrroles for medicinal chemistry
studies. Avariation of the Knorr pyrrole synthesis (see Scheme below,
method A) was suitable for easy formation of (II) and (III) (Kruse et
al., 1987). The starting methyl ketones are, in general, inexpensive
and readily available, and the intermediates require minimal puri®-
cation. The synthesis of (I) was more dif®cult. Method A failed due to
a very poor yield in the alkylation step and failure of the N,N-di-
methylhydrazone to hydrolyze under several conditions. The problem
was solved by preparing and utilizing 1-aryl-4-(N,N-dimethyl-
hydrazono)-2-buten-1-ones (Severin et al., 1975) in two steps (see
Scheme below, method B). The aldol step is rapid, but the cyclization
step proceeded in lower yield, due in part, at least, to loss of product
iv
(IIIB)
(
(
(
IIIC)
IIIC)
IIIC)
v
0
v
Ê
ꢀ
²
0
Note: the s.u. values are N8ÐH and HÁ Á ÁN1 = 0.02 A, N8ÐHÁ Á ÁN1 = 1 and N8Á Á ÁN1 =
Ê
.002±0.003 A.
1
2
1
1
1
Symmetry codes: (i) 1 � y, 1 � x, � z; (ii) � 2 + x, 2 � y, � 2
+
z;
1
1
(iii) x, � 1 + y, z; (iv) x,
� y, � + z; (v) � x, 1 � y, 1 � z.
2
2
Compound (I)
Crystal data
C
H
9 8
N
2
Mo Kꢀ radiation
M
r
= 144.17
Tetragonal, P4 2 2
Cell parameters from 3961
re¯ections
3 1
Ê
a = 8.123 (2) A
c = 23.502 (6) A
Ê
V = 1550.7 (7) A
Z = 8
D
ꢀ
ꢁ = 2.6±26.4
ꢂ = 0.08 mm
T = 173 (2) K
Ê
� 1
3
(
I) because of its extremely high volatility. The literature melting
points follow the usual pattern for aromatic compounds, with the
para-isomer having the highest melting point, viz. 447±448 K (CCl
Afonin et al., 2000); cf. the meta-isomer melting point of 373±375 K
benzene±petroleum ether; Pictet & Crepieux, 1895) and the ortho-
isomer melting point of 361±362 K (petroleum ether; Petrova et al.,
997). The R values (SiO , 1:1 EtOAc, hexanes) among the isomers
Prism, colorless
0.50 Â 0.20 Â 0.20 mm
� 3
x
= 1.235 Mg m
4
;
Data collection
(
Siemens SMART area-detector
diffractometer
1115 independent re¯ections
1052 re¯ections with I > 2ꢃ(I)
!
scans
Absorption correction: multi-scan
SADABS; Sheldrick, 1996;
Blessing, 1995)
min = 0.97, Tmax = 0.99
8 079 measured re¯ections
Rint = 0.048
max = 27.5
h = � 10 ! 10
k = � 10 ! 10
l = � 30 ! 30
1
F
2
ꢀ
ꢁ
rose sharply from para (0.04) to meta (0.16) to ortho (0.49).
(
T
1
Re®nement
2
2
2
2
Re®nement on F
2
o
w = 1/[ꢃ (F ) + (0.044P)
2
R[F > 2ꢃ(F )] = 0.044
wR(F ) = 0.100
S = 1.16
+ 0.304P]
where P = (F
(Á/ꢃ)max = 0.006
Áꢄmax = 0.13 e A
Áꢄmin = � 0.16 e AÊ
2
2
2
c
o
+ 2F
)/3
Ê
� 3
1
1
115 re¯ections
04 parameters
� 3
H atoms: see below
Compound (II)
Crystal data
�
3
C H
9 8
N
2
D
x
= 1.293 Mg m
M
r
= 144.17
Monoclinic, P2
Mo Kꢀ radiation
1
/n
Cell parameters from 2058
re¯ections
The initial attempt to grow crystals of (III) was carried out by
recrystallization of a slightly impure sample (light brown in color)
from methanol. The crystals were a mixture of dendrites and tear-
shaped crystals. The sample was puri®ed further; new crystals grown
from acetonitrile appeared to be satisfactory for X-ray diffraction and
the structure of (IIIA) was determined. It was then decided to check
the unit cells of the original crystals. A needle, cut from a dendrite,
had a different cell; the structure was determined as (IIIB). A tear-
shaped crystal had a still different cell; the structure was determined
as (IIIC). The melting point of (IIIA) was 445±447 K, in agreement
with the literature value. The melting points of (IIIB) and (IIIC) were
essentially the same, viz. 444±446 and 442±443 K, respectively,
although both samples had shown some decomposition at about
Ê
a = 5.3537 (13) A
b = 11.654 (3) AÊ
Ê
c = 11.990 (3) A
ꢅ = 98.10 (1)
V = 740.6 (3) A
Z = 4
ꢀ
ꢁ = 2.4±27.0
� 1
ꢂ = 0.08 mm
T = 174 (2) K
ꢀ
Ê
3
Needle, colorless
0.35 Â 0.15 Â 0.05 mm
Data collection
Siemens SMART area-detector
diffractometer
! scans
Absorption correction: multi-scan
1681 independent re¯ections
1232 re¯ections with I > 2ꢃ(I)
Rint = 0.030
ꢀ
ꢁmax = 27.5
(
SADABS; Sheldrick, 1996;
Blessing, 1995)
min = 0.97, Tmax = 0.99
4676 measured re¯ections
h = � 6 ! 6
k = � 11 ! 15
l = � 15 ! 14
T
430 K.
ꢁ
Acta Cryst. (2003). C59, o263±o267
Noland, Cole and Britton
Five C H N
9 8 2
polymorphs o265

organic compounds
Re®nement
Re®nement
2
2
2
2
2
2
2
2
Re®nement on F
2
w = 1/[ꢃ (F
o
) + (0.058P)
Re®nement on F
2
o
w = 1/[ꢃ (F ) + (0.039P)
2
2
R[F > 2ꢃ(F )] = 0.044
wR(F ) = 0.114
S = 1.02
+ 0.116P]
where P = (F
(Á/ꢃ)max = 0.001
R[F > 2ꢃ(F )] = 0.047
wR(F ) = 0.098
+ 0.333P]
where P = (F
(Á/ꢃ)max = 0.004
Áꢄmax = 0.21 e A
Áꢄmin = � 0.17 e AÊ
2
2
2
c
2
2
2
c
o
+ 2F
)/3
o
+ 2F
)/3
S = 1.03
3452 re¯ections
207 parameters
Ê
� 3
Ê
� 3
� 3
1
1
681 re¯ections
05 parameters
Áꢄmax = 0.19 e A
Ê
� 3
Áꢄmin = � 0.17 e A
H atoms treated by a mixture of
independent and constrained
re®nement
Extinction correction: SHELXTL
Extinction coef®cient: 0.022 (6)
H atoms treated by a mixture of
independent and constrained
re®nement
Compound (IIIC)
Compound (IIIA)
Crystal data
Crystal data
�
3
�
3
C H N
8
D = 1.287 Mg m
x
C
9
H
8
N
2
D
x
= 1.281 Mg m
9
2
M
r
= 144.17
Monoclinic, P2
Mo Kꢀ radiation
Cell parameters from 2761
re¯ections
M
Monoclinic, P2
Ê
a = 7.402 (2) A
b = 11.480 (3) A
Ê
c = 17.705 (4) A
ꢅ = 96.23 (1)
V = 1495.6 (7) A
Z = 8
r
= 144.17
Mo Kꢀ radiation
Cell parameters from 2036
re¯ections
/n
1
/c
1
Ê
a = 5.1519 (13) A
ꢀ
b = 19.739 (5) A
Ê
c = 14.694 (4) A
ꢅ = 95.26 (1)
V = 1488.0 (7) A
Z = 8
Ê
ꢁ = 2.8±26.2
ꢀ
Ê
ꢁ = 2.9±25.4
ꢂ = 0.08 mm
T = 173 (2) K
� 1
ꢂ = 0.08 mm
T = 173 (2) K
� 1
ꢀ
ꢀ
3
Ê
3
Irregular, pale yellow
0.45 Â 0.15 Â 0.05 mm
Ê
Needle, colorless
0.50 Â 0.10 Â 0.06 mm
Data collection
Data collection
Siemens SMART area-detector
diffractometer
2920 independent re¯ections
1985 re¯ections with I > 2ꢃ(I)
Siemens SMART area-detector
diffractometer
3412 independent re¯ections
1933 re¯ections with I > 2ꢃ(I)
!
scans
Absorption correction: multi-scan
SADABS; Sheldrick, 1996;
Blessing, 1995)
min = 0.98, Tmax = 1.00
607 measured re¯ections
Rint = 0.042
!
scans
Absorption correction: multi-scan
SADABS; Sheldrick, 1996;
Blessing, 1995)
min = 0.97, Tmax = 0.99
224 measured re¯ections
Rint = 0.052
ꢀ
ꢀ
ꢁmax = 26.0
ꢁ
max = 27.5
(
h = � 6 ! 6
(
h = � 9 ! 9
k = � 21 ! 24
l = � 18 ! 14
k = � 14 ! 14
l = � 14 ! 22
T
T
8
9
Re®nement
Re®nement
2
2
2
2
2
2
2
2
Re®nement on F
2
w = 1/[ꢃ (F
where P = (F
(Á/ꢃ)max = 0.001
o
) + (0.058P) ]
Re®nement on F
2
o
w = 1/[ꢃ (F ) + (0.034P)
2
2
2
2
R[F > 2ꢃ(F )] = 0.058
wR(F ) = 0.111
+ 0.258P]
where P = (F
(Á/ꢃ)max = 0.002
R[F > 2ꢃ(F )] = 0.047
wR(F ) = 0.118
S = 0.92
o c
+ 2F )/3
2
2
2
c
2
o
+ 2F
)/3
Ê
� 3
S = 1.09
2920 re¯ections
227 parameters
Áꢄmax = 0.22 e A
� 3
Ê
� 3
Ê
Áꢄmax = 0.15 e A
3
2
412 re¯ections
08 parameters
Áꢄmin = � 0.21 e A
Ê
� 3
Extinction correction: SHELXTL
Extinction coef®cient: 0.0061 (13)
Áꢄmin = � 0.12 e A
H atoms treated by a mixture of
independent and constrained
re®nement
H atoms treated by a mixture of
independent and constrained
re®nement
Extinction correction: SHELXL97
Extinction coef®cient: 0.0059 (13)
In all of the determinations, the H atoms were placed in idealized
positions with respect to the attached atoms, except for those on the
pyrrole N atoms, which were re®ned with isotropic displacement
parameters. The ortho compound, (I), occurred in a non-centro-
symmetric space group. However, with no atoms heavier than
nitrogen in the structure, the absolute con®guration could not be
determined. The Friedel pairs were averaged for the ®nal re®nement.
Disorder was found for the pyridine rings of molecule A in the (IIIC)
polymorph; re®nement using an ordered model with large anisotropic
displacement parameters increased R from 0.057 to 0.061. The
disorder parameter 0.475 (7) for the lesser component is not
convincingly different from complete disorder. An intermolecular
Compound (IIIB)
Crystal data
�
3
C
H N
9 8 2
D
x
= 1.265 Mg m
M
Monoclinic, P2
r
= 144.17
Mo Kꢀ radiation
Cell parameters from 2651
re¯ections
1
/c
Ê
a = 15.139 (4) A
Ê
b = 5.4945 (14) A
ꢀ
ꢁ = 2.2±25.8
ꢂ = 0.08 mm
T = 173 (2) K
Ê
c = 18.736 (5) A
� 1
ꢀ
ꢅ = 103.76 (1)
V = 1513.8 (7) A
Z = 8
Ê
3
Needle, pale yellow
0.50 Â 0.05 Â 0.05 mm
Ê
0
0
Data collection
contact distance of 3.116 A between atoms C2A and C5A in the next
molecule along the a direction suggests that the two orientations
probably alternate in adjacent molecules in this direction but are
random between molecules in other directions.
Siemens SMART area-detector
diffractometer
3452 independent re¯ections
2385 re¯ections with I > 2ꢃ(I)
!
scans
Absorption correction: multi-scan
SADABS; Sheldrick, 1996;
Blessing, 1995)
min = 0.98, Tmax = 1.00
4 309 measured re¯ections
Rint = 0.049
ꢀ
ꢁ
max = 27.5
For all compounds, data collection: SMART (Siemens, 1995); cell
re®nement: SAINT (Siemens, 1995); data reduction: SAINT;
program(s) used to solve structure: SHELXTL (Sheldrick, 1994);
program(s) used to re®ne structure: SHELXTL; molecular graphics:
(
h = � 19 ! 19
k = � 7 ! 7
T
l = � 24 ! 24
1
ꢁ
o266 Noland, Cole and Britton
Five C H N
9 8 2
polymorphs
Acta Cryst. (2003). C59, o263±o267

organic compounds
SHELXTL; software used to prepare material for publication:
SHELXTL.
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We thank the Wayland E. Noland Research Fellowship
Fund of the University of Minnesota Foundation for ®nancial
support of KPC.
3141±3151.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: KB1000). Services for accessing these data are
described at the back of the journal.
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ꢁ
Acta Cryst. (2003). C59, o263±o267
Noland, Cole and Britton
Five C H N
9 8 2
polymorphs o267