Crystal Structure Determination and Hydrogen-Bonding Patterns in 2-Pyridinecarboxamide

doi:10.4236/csta.2012.13006

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Crystal Structure Theory and Applications, 2012, 1, 30-34

http://dx.doi.org/10.4236/csta.2012.13006 Published Online December 2012 (http://www.SciRP.org/journal/csta)

Crystal Structure Determination and Hydrogen-Bonding

Patterns in 2-Pyridinecarboxamide

Gerzon E. Delgado*, Asiloé J. Mora, Marilia Guillén-Guillén, Jeans W. Ramírez, Jines E. Contreras

Laboratorio de Cristalografía, Departamento de Química, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela

Email: *[email protected]

Received September 17, 2012; revised October 18, 2012; accepted October 26, 2012

ABSTRACT

The title compound, 2-pyridinecarboxamide, C6H6N2O, crystallize in the monoclinic system with space group P21/n

(N˚14), Z = 4, and unit cell parameters a = 5.2074(1) Å, b = 7.1004(1) Å, c = 16.2531(3) Å,



= 100.260(1)˚. The crys-

tal structure of the title compound, was reported previously from Weissenberg photographic data with R = 0.127. It has

now been redetermined, providing a significant increase in the precision of the derived geometric parameters. The crys-

tal packing is governed by N--H···O hydrogen bond-type intermolecular interactions, forming infinite one-dimensional

chains with graph-set notation C(4), R22(8) and R24(8).

Keywords: Pyridinecarboxamides; Picolinamide; X-Ray Crystal Structure; Hydrogen Bonding

1. Introduction

The three isomers of pyridinecarboxamide; 2-pyridine

carboxamide or picolinamide, 3-pyridinecarboxamide or

nicotinamide and 4-pyridinecarboxamide or isonicotina-

mide are a class of medicinal agents which can be classi-

fied as GRAS (generally regarded as safe) compounds. In

particular, nicotinamide (niacinamide, Vitamin B3) and

picolinamide show important biological activity with a

coenzyme called NAD (nicotinamide adenine dinucleo-

tide), which plays important roles in more than 200

amino acid and carbohydrate metabolic reactions [1]. In

general pyridinecarboxamides are excellent co-crystal-

lizing compound. The amide group has two hydrogen

bond donors and two lone pairs on the carbonyl O atom.

A second hydrogen bond acceptor is the lone pair on the

N atom of the pyridine ring. This makes these molecules

very versatile for a variety of hydrogen bonded interac-

tions, especially in pharmaceutical co-crystals [2-13].

The molecular structures and vibrational spectra of the

three isomers has been the subject of recent theoretical

studies [14,15], and from the crystal structure point of

view, all isomer compounds exhibit polymorphism [12].

Nicotinamide has four polymorphs, the most stable crys-

tallize in a monoclinic form [16], Isonicotinamide has

three polymorphs in monoclinic and orthorhombic forms

[17], and Picolinamide exists under two polymorphic

structures [18]. The polymorph form with crystal struc-

ture in the Crystal Structure Database [19], was reported

using Weissenberg photographic data and R = 0.127 [18].

The present paper reports a redetermination of the crystal

structure of 2-pyridinecarboxamide (picolinamide), with

greater precision and accuracy. An analysis of the hy-

drogen-bonding patterns is also included.

2. Experimental

2.1. Crystallization of the Title Compound

Picolinamide crystals were obtained in an attempt to pre-

pare 2-pyridinecarboxamide—amino acid co-crystals, in

a 1:1 ethanol-water solution. Colorless crystals suitable

for X-ray diffraction analysis were grown by slow eva-

poration from this solution (m.p. 375 K).

2.2. FT-IR and NMR Analysis

Melting point was determined on an Electrothermal Mo-

del 9100 apparatus. The FT-IR absorption spectrum was

obtained as KBr pellet using a Perkin-Elmer 1600 spec-

trometer. 1H and 13C NMR spectra were determined on a

Bruker Avance 400 model spectrometer.

FT-IR: 1392 cm–1 (t, C-N), 1666 cm–1 (t, C = O), 3419

cm–1 (t, N-H)]. 1H NMR (400 MHz, DMSO d6 ): δ 8.63

(d, H6, J = 4.8 Hz), 8.12 (s, H3), 8.05 (d, H1A, J= 7.9

Hz), 7.98 (dt, H4, J1= 15.4 Hz, J2 = 7.6 Hz, J3 = 1.7 Hz),

7.65 (s, H5), 7.55 - 7.61 (m, H1B). 13C NMR (100 MHz,

DMSO d6 ): δ 166.0 (C1), 150.3 (C2), 148.4 (C6), 137.6

(C4), 126.4 (C5), 121.9 (C3).

2.3. X-Ray Powder Diffraction

*Corresponding author. X-ray powder diffraction pattern was collected, at room

G. E. DELGADO ET AL. 31

temperature, in a Phillips PW-1250 goniometer using

monocromatized CuKα radiation (λ = 1.5418 Å). A small

quantity of picolinamide was ground mechanically in an

agate mortar and pestle and mounted on a flat holder

covered with a thin layer of grease. The specimen was

scanned from 10˚ - 60˚ 2



, with a step size of 0.02˚ and

counting time of 15 s. Silicon was used as an external

standard.

X-ray powder pattern of picolinamide is shown in

Figure 1. The 20 first measured reflections were com-

pletely indexed using the program Dicvol04 [20], which

gave a unique solution in a monoclinic cell with parame-

ters a = 5.19 Å, b = 7.09 Å, c = 16.41 Å,



= 100.26˚. In

order to confirm the unit cell parameters, a Le Bail re-

finement [21] of the whole diffraction pattern without

structural was carried out using the Fullprof program

[22]. Figure 1 shows a very good fit between the ob-

served and calculated patterns.

2.4. X-Ray Single-Crystal Crystallography

Colorless rectangular crystal (0.37 × 0.20 × 0.20 mm3)

was used for data collection. Diffraction data were col-

lected at 298(2) K by ω-scan technique on a Bruker

SMART APEX II CCD diffractometer [23] equipped

with CuKα radiation (λ = 1.5418 Å). The unit cell pa-

rameters were determined by the least-squares methods

using 1292 reflections in the 2



range 5.5˚ - 55.6˚. The

data were corrected for Lorentz-polarization and absorp-

tion effects [24]. The structure was solved by direct

methods using the SHELXS program [25] and refined by

a full-matrix least-squares calculation on F2 using

SHELXL [25].

All H atoms were placed at calculated positions and

treated using a riding model, fixing the C-H distances at

0.96 Å and Uiso(H) = 1.2Ueq(C)], the N-H distance at

0.86 Å and Uiso(H) = 1.2Ueq(N)]. The final Fourier maps

showed no peaks of chemical significance.

Figure 2 shows the molecular structure and the atom-

Figure 1. X-ray powder diffraction data for Picolinamide.

The powder pattern was refined without structural model

to confirm the unit cell parameters.

labeling scheme of picolinamide. Table 1 shows the

crystallographic data and structure refinement parameters.

Selected bond distances, bond and torsion angles are

listed in Table 2. Hydrogen bonds geometry is listed in

Table 3.

Figure 2. Molecular structure of the title compound show-

ing the atomic numbering scheme. Displacement ellipsoids

are drawn at 30% probability level. H atoms are shown as

spheres of arbitrary radii.

Table 1. Crystal data, data collection and structure refine-

ment.

Chemical formula C6H6N2O

Formula weight 122.13

Temperature (K) 296

Radiation (Å) CuK



(1.5418)

Crystal system Monoclinic

Space group P21/n(14)

a (Å) 5.2074(1)

b (Å) 7.1004(1)

c (Å) 16.2531(3)



(˚) 100.260(1)

V (Å3) 591.34(2)

Z 4

dx (g cm–3) 1.372

F(000) 256

µ (mm–1) CuK



0.807

Crystal size (mm3) 0.37 × 0.20 × 0.20



range for data collection(˚) 5.5 - 57.4

hkl range –5 ≤ h ≤ 4; –7 ≤ k ≤ 7; –17 ≤ l ≤ 17

Reflections

Collected 2946

Unique (Rint) 777 (0.015)

With I > 2



(I) 663

Refinement method Full-matrix least-squares on F2

Number of parameters 83

R(F2) [I > 2



(I)] 0.0389

wR(F2) [I > 2



(I)] 0.1119

Goodness of fit on F2 1.06

Max/min 



(e·Å–3) 0.15/–0.12

G. E. DELGADO ET AL.

Table 2. Selected geometrical parameters (Å, ˚).

C1-O1 1.253(2) C1-N1 1.317(2)

C1-C2 1.496(2) C2-C3 1.386(2)

C2-N2 1.370(2) C6-N2 1.334(2)

O1-C1-N1 124.0(1) O1-C1-C2 120.7(1)

N1-C1-C2 115.4(1) C1-C2-N2 117.2(1)

N1-C1-C2-N2 –18.1(2) O1-C1-C2-N2 162.4(2)

N1-C1-C2-C3 162.0(2) O1-C1-C2-C3 –17.5(2)

Table 3. Hydrogen bonds ge ome t ry (Å, ˚).

D--H···A D--H H···A D···A D--H···A

N1---H1A···O1(i) 0.86 2.08 2.923 (2) 166

N1---H1B···O1(ii) 0.86 2.41 3.033 (2) 130

Symmetry codes: (i)1 – x, 2 – y, 1 – z; (ii)1 + x, y, z.

Crystallographic data for the structure reported here

have been deposited with the Cambridge Crystallo-

graphic Data Centre (Deposition No. CCDC-913526).

The data can be obtained free of charge via

http://www.ccdc.cam.ac.uk/perl/catreq.cgi.

3. Results and Discussion

A search in the Cambridge Structural Database (Version

5.33, August 2012) [19] shows only 5 structures with the

picolinamide moiety. In the structures with code EY-

IXAL [26], FUGDER [27] and POVZEF [28] the picoli-

namide is a cation forming salts, and in EXAPEZ [29]

picolinamide is a neutral molecule forming a co-crystal.

PICAMD [18] corresponds with the earlier determination

of the single amide molecule.

In our study, the pyridine ring is essentially planar,

with maximum deviations of 0.010 in C4 and –0.010 in

N2 (Figure 2). The dihedral angle formed between the

pyridine ring and the amide plane is 18.26(9)˚. This value

is similar with the observed in the other picolinamide

cations EYIXAL, FUGDER and POVZEF, but higher

that 6.4(2) Å observed in the neutral molecule of co-cry-

stal EXAPEZ.

Picolinamide molecule adopts a syn conformation with

the heterocyclic N and amide N on same sides of the

molecule [torsion angle N1-C1-C2-N2 = –18.1 (2)˚].

This conformation is also observed only in the co-crystal

EXAPEZ. When picolinamide is in cations form, EY-

IXAL, FUGDER and POVZEF, the molecule adopts an

anticonformation.

The crystal structure of picolinamide displays an ex-

tended hydrogen-bond network generated by amide-am-

ide synthons. Each picolinamide molecule is involved in

two intermolecular N--O···H hydrogen bonds (Figure 3).

Figure 3. A portion of the crystal packing viewed in the ba

plane. Intermolecular hydrogen bonds, N--H···O with sym-

metry (i) 1 – x, 2 – y, 1 – z and (ii) 1 + x, y, z, are indicated

by dashed lines.

Figure 4. Crystal packing diagram in the ca plane. Inter-

molecular hydrogen bonds, N--H···O, are indicated by

dashed lines. H atoms not involved in hydrogen bonding

have been omitted for clarity.

These units are linked together through a complementary

amide dimer R22(8) motif [30,31], formed by N1--

H1A···O1 at (1 – x, 2 – y, 1 – z). The chains are linked

through a second complementary interaction formed by

N1--H1B···O1 at (1 + x, y, z), resulting in the formation

of ladders of alternating R24(8) rings, and chain running

in the [100] direction with graph-set C(4). The combina-

tion of these interactions generates an extended corru-

gated hydrogen-bonded sheet in the ca plane (Figure 4).

4. Conclusion

Crystal structure of picolinamide has been redetermi-

nated with greater precision and accuracy. The molecular

structure and crystal packing are stabilized by intermo-

lecular N--O···H hydrogen bonds into an infinite one-

dimensional network.

5. Acknowledgements

This work was supported by CDCHTA-ULA (grants

G. E. DELGADO ET AL. 33

C-1755-B and C-1784-B), FONACIT (grant LAB-

97000821) and INZIT (grant LOCTI-2007-0003).

REFERENCES

[1] R. A. Olsen, L. Liu, N. Ghaderi, A. Johns, M. E. Hatcher

and L. J. Mueller, “The Amide Rotational Barriers in Pi-

colinamide and Nicotinamide: NMR and Ab Initio Stu-

dies,” Journal of American Chemical Society, Vol. 125,

No. 33, 2003, pp. 10125-10132. doi:10.1021/ja028751j

[2] C. B. Aakeroy, A. M. Beatty, B. A. Helfrich and M.

Nieuwenhuyzen, “Do Polymorphic Compounds Make

Good Cocrystallizing Agents? A Structural Case Study

That Demonstrates the Importance of Synthon Flexibi-

lity,” Crystal Growth & Design, Vol. 3, No. 2, 2003, pp.

159-165. doi:10.1021/cg025593z

[3] P. Vishweshwar, A. Nangia and V. M. Lynch, “Molecular

Complexes of Homologous Alkanedicarboxylic Acids

with Isonicotinamide: X-Ray Crystal Structures, Hydro-

gen Bond Synthons, and Melting Point Alternation,”

Crystal Growth & Design, Vol. 3, No. 5, 2003, pp. 783-

790. doi:10.1021/cg034037h

[4] A. Lemmerer, N. B. Bathori and S. A. Bourne, “Chiral

Carboxylic Acids and Their Effects on Melting-Point

Behaviour in Co-Crystals with Isonicotinamide,” Acta

Crystallographica, Vol. B64, No. 6, 2008, pp. 780-790.

doi:10.1107/S0108768108034526

[5] J. Lu and S. Rohani, “Preparation and Characterization of

Theophylline-Nicotinamide Cocrystal,” Organic Process

Research & Development, Vol. 13, No. 6, 2009, pp.

1269-1275. doi:10.1021/op900047r

[6] A. Lemmerer, C. Esterhuysen and J. Bernstein, “Synthe-

sis, Characterization, and Molecular Modeling of a Phar-

maceutical Co-Crystal: (2-Chloro-4-Nitrobenzoic Acid):

(Nicotinamide),” Journal of Pharmaceutical Science, Vol.

99, No. 9, 2010, pp. 4054-4071. doi:10.1002/jps.22211

[7] L. J. Thompson, R. S. Voguri, A. Cowell, L. Male and M.

Tremayne, “The Cocrystal Nicotinamide—Succinic Acid

(2/1),” Acta Crystallographica, Vol. C66, 2010, p. o421.

doi:10.1107/S0108270110027319

[8] V. R. Hathwar, R. Pal and T. N. Guru Row, “Charge

Density Analysis of Crystals of Nicotinamide with Sali-

cylic Scid and Oxalic Acid: An Insight into the Salt to

Cocrystal Continuum,” Crystal Growth & Design, Vol.

10, No. 8, 2010, pp. 3306-3310. doi:10.1021/cg100457r

[9] N. B. Bathori, A. Lemmerer, G. A. Venter, S. A. Bourne

and M. R. Caira, “Pharmaceutical Co-Crystals with Isoni-

cotinamide; VitaminB3, Clofibric Acid, and Diclofenac;

and Two Isonicotinamide Hydrates,” Crystal Growth &

Design, Vol. 11, No. 1, 2011, pp. 75-87.

doi:10.1021/cg100670k

[10] L. Fabian, N. Hamill, K. S. Eccles, H. A. Moynihan, A. R.

Maguire, L. McCausland and E. Lawrence, “Cocrystals of

Fenamic Acids with Nicotinamide,” Crystal Growth &

Design, Vol. 11, No. 8, 2011, pp. 3522-3528.

doi:10.1021/cg200429j

[11] B. Lou and S. Hu, “Different Hydrogen-Bonded Interac-

tions in the Cocrystals of Nicotinamide with Two Aro-

matic Acids,” Journal of Chemical Crystallography, Vol.

41, No. 11, 2011, pp. 1663-1668.

doi:10.1007/s10870-011-0154-z

[12] R. A. E. Castro, J. D. B. Ribeiro, T. M. R. Maria, M. Ra-

mos Silva, C. Yuste-Vivas, J. Canotilho and M. E. S. Eu-

sebio, “Naproxen Cocrystals with Pyridinecarbox-Amide

Isomers,” Crystal Growth & Design, Vol. 11, No. 12,

2011, pp. 5396-5404. doi:10.1021/cg2009946

[13] S. Tothadi and G. R. Desiraju, “Unusual Co-Crystal of

Isonicotinamide the Structural Landscape in Crystal En-

gineering,” Philosophical Transactions of the Royal So-

ciety, Vol. A370, No. 1969, 2012, pp. 2900-2915.

doi:10.1098/rsta.2011.0309

[14] E. Akalin and S. Akyuz. “Vibrational Analysis of Free

and Hydrogen Bonded Complexes of Nicotinamide and

Picolinamide,” Vibrational Spectroscopy, Vol. 42, No. 2,

2006, pp. 333-340. doi:10.1016/j.vibspec.2006.05.015

[15] M. Bakilera, O. Bolukbasi and A. Yilmaz, “An Experi-

mental and Theoretical Study of Vibrational Spectra of

Picolinamide, Nicotinamide, and Isonicotinamide,” Jour-

nal of Molecular Structure, Vol. 826, No. 1, 2007, pp.

6-16. doi:10.1016/j.molstruc.2006.04.021

[16] Y. Miwa, T. Mizuno, K. Tsuchida, T. Taga and Y. Iwata,

“Experimental Charge Density and Electrostatic Potential

in Nicotinamide,” Acta Crystallographica, Vol. B55, No.

1, 1999, pp. 78-84. doi:10.1107/S0108768198007848

[17] J. Li, S. A. Bourne and M. R. Caira, “New Polymorphs of

Isonicotinamide and Nicotinamide,” Chemical Commu-

nications, Vol. 47, No. 5, 2011, pp. 1530-1532.

doi:10.1039/c0cc04117c

[18] T. Takano, Y. Sasada and M. Kakudo, “The Crystal and

Molecular Structure of Picolinamide,” Acta Crystallo-

graphica, Vol. 21, No. 4, 1966, pp. 514-522.

doi:10.1107/S0365110X66003396

[19] F. H. Allen, “The Cambridge Structural Database: A Quar-

ter of a Million Crystal Structures and Rising,” Acta

Crystallographica, Vol. B58, No. 1, 2002, pp. 380-388.

doi:10.1107/S0108768102003890

[20] A. Boultif and D. Löuer, “Powder Pattern Indexing with

the Dichotomy Method,” Journal of Applied Crystallo-

graphy, Vol. 37, No. 5, 2004, pp. 724-731.

doi:10.1107/S0021889804014876

[21] A. Le Bail, H. Duroy and J. L. Fourquet, “Ab-Initio Struc-

ture Determination of LiSbWO6 by X-Ray Powder Dif-

fraction,” Materials Research Bulletin, Vol. 23, No. 3,

1988, pp. 447-452. doi:10.1016/0025-5408(88)90019-0

[22] J. Rodriguez-Carvajal, “Fullprof, version 5.3, LLB, CEA-

CNRS,” 2012.

[23] B. Saint, Bruker AXS Inc., Madison, 2009.

[24] B. Apex, Bruker AXS Inc., Madison, 2010.

[25] G. M. Sheldrick, “A Short History of SHELX,” Acta

Crystallographica, Vol. A64, No. 1, 2008, pp. 112-122.

doi:10.1107/S0108767307043930

[26] I. Ucar, A. Bulut, O. Z. Yesilel and O. Buyukgungor,

“Picolinamidium Squarate and Di-p-Toluidinium Squa-

rate Dehydrate,” Acta Crystallographica, Vol. C60, No. 8,

2004, pp. o585-o588. doi:10.1107/S0108270104013964

[27] A. Nielsen, C. J. McKenzie and A. D. Bond, “2-Carba-

mylpyridinium Tetrachloridoferrate(III),” Acta Crystal-

G. E. DELGADO ET AL.

lographica, Vol. E65, No. 11, 2009, p. m1359.

doi:10.1107/S1600536809040148

[28] K. Gotoh, H. Nagoshi and H. Ishida, “Hydrogen-Bonded

Structures of the Isomeric 2-, 3- and 4-Carbamoylpyrid-

inium Hydrogen Chloranilates,” Acta Crystallographica,

Vol. C65, No. 6, 2009, pp. o273-o277.

doi:10.1107/S010827010901525X

[29] S. Ghosh, P. P. Bag and C. M. Reddy, “Co-Crystals of

Sulfamethazine with Some Carboxylic Acids and Amides:

Co-Former Assisted Tautomerism in an Active Pharma-

ceutical Ingredient and Hydrogen Bond Competition

Study,” Crystal Growth & Design, Vol. 11, No. 8, 2011,

pp. 3489-3503. doi:10.1021/cg200334m

[30] M. C. Etter, “Encoding and Decoding Hydrogen-Bond

Patterns of Organic Compounds,” Account of Chemical

Research, Vol. 23, No. 4, 1990, pp. 120-126.

doi:10.1021/ar00172a005

[31] M. C. Etter, J. C. MacDonald and J. Bernstein, “Graph-

Set Analysis of Hydrogen-Bond Patterns in Organic Crys-

tals,” Acta crystallographica, Vol. B46, No. 2, 1990, pp.

256-262. doi:10.1107/S0108768189012929