Three 2-(methysulfanyl)nicotinamides

organic compounds

Acta Crystallographica Section C

Crystal Structure

Communications

N-alkyl-2-(methylsulfanyl)nicotinamide derivatives, namely

N-cyclohexyl-2-(methylsulfanyl)nicotinamide, (I), N-isopro-

pyl-2-(methylsulfanyl)nicotinamide, (II), and N-(2-hydroxy-

ethyl)-2-(methylsulfanyl)nicotinamide dihydrate, (III) (see

Scheme below). The Scheme also gives details of four related

compounds, (IV)–(VII), and gives details of the dihedral

angles (ꢀ) between the amide group and the heterocyclic ring,

as well as highlighting their conformation with respect to each

other. Compounds (I)–(III) have been synthesized for an anti-

TB activity study, the results of which will be published else-

where.

ISSN 0108-2701

Three 2-(methysulfanyl)nicotinamides

Ligia R. Gomes,^aJohn Nicolson Low,^b* James L.

Wardell,^b,cAlessandra C. Pinheiro,^dThais C. N. de

Mendonc¸a^dand Marcus V. N. de Souza^d

a

´

ˆ

REQUIMTE, Departamento de Quımica e Bioquımica, Faculdade de Ciencias da

Universidade do Porto, Rua do Campo Alegre, 687, P-4169-007 Porto, Portugal,

^bDepartment of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen

c

´

AB24 3UE, Scotland, Centro de Desenvolvimento Tecnologico em Saude (CDTS),

Funda¸cao Oswaldo Cruz (FIOCRUZ), Casa Amarela, Campus de Manguinhos, Av.

˜

d

´

Brasil 4365, 21040-900 Rio de Janeiro, RJ, Brazil, and Instituto de Tecnologıa em

´

Farmacos–Farmangunhos, FioCruz–Funda¸cao Oswaldo Cruz, R. Sizenando

˜

Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil

Correspondence e-mail: jnlow111@gmail.com

Received 28 January 2013

Accepted 13 February 2013

Online 16 February 2013

The molecular conformations of three N-alkyl-2-(methyl-

sulfanyl)nicotinamide derivatives, namely N-cyclohexyl-2-

(methylsulfanyl)nicotinamide, C₁₃H₁₈N₂OS, (I), N-isopropyl-

2-(methylsulfanyl)nicotinamide, C₁₀H₁₄N₂OS, (II), in which

there are two molecules in the asymmetric unit which were

chosen to form a hydrogen-bonded pair, and N-(2-hydroxy-

ethyl)-2-(methylsulfanyl)nicotinamide dihydrate, C₉H₁₂N₂-

O₂Sꢀ2H₂O, (III), are compared with those of four unsubsti-

tuted N-alkylnicotinamide compounds. The substituted com-

pounds show a higher degree of torsion of the pyridine ring

with respect to the amide group than do the unsubstituted

compounds, with dihedral angles in the range 40–60^ꢁfor the

former and 20–35^ꢁfor the latter. In (I) and (II), the

supramolecular structure is deﬁned by amide-N to carbonyl-

O chains. In (III), the nicotinamide molecules are linked by

hydrogen bonds to two water molecules resulting in two linked

chains of rings which form the three-dimensional network.

Comment

In (I) (Fig. 1), the cyclohexyl ring adopts a chair confor-

mation. In (II) (Fig. 2), there are two molecules (A and B) in

the asymmetric unit which were chosen to form a hydrogen-

bonded pair. The results of a quaternion ﬁt of the non-H

atoms with MOLFIT in PLATON (Mackay, 1984; Spek, 2009)

indicate that molecule B inverts on to A, with a ﬁt rotation

angle of ꢂ166.88^ꢁ, and gives r.m.s. deviations of 0.142

Tuberculosis (TB) is the second greatest contributor among

infectious diseases to adult mortality, causing approximately

1.4 million deaths worldwide in 2010 (WHO, 2010). While

heteroaromatic amides, such as nicotinamide (pyridine-3-

carboxamide) and pyrazinamide (pyrazine-2-carboxamide), as

well as heteroaromatic thioamides, such as thioisonicotin-

amide (pyridine-4-carbothioamide), are well established anti-

TB agents, there is a need for new drugs in particular to

combat the emergence of strains resistant to current treat-

ments (de Souza, 2006, 2012; Gonc¸alves et al., 2012). In

continuation of our studies of amidopyridines and related

compounds (de Souza et al., 2005; Cufﬁni et al., 2006; Wardell

et al., 2007a,b, 2008), we now report the structures of the three

˚

(unweighted) and 0.180 A (weighted) for 14 atoms. Nicoti-

namide (III) (Fig. 3) crystallizes with two water molecules in

the asymmetric unit.

The steric hindrance imposed by the methylsulfanyl

substituent at the 2-position of the pyridine ring is reﬂected, as

expected, by a relatively high torsion for this ring with respect

to the amide group. Considering that methylsulfanyl is a soft

Acta Cryst. (2013). C69, 293–298

doi:10.1107/S0108270113004344

# 2013 International Union of Crystallography 293

organic compounds

Figure 1

The molecular structure of (I), showing the atom-numbering scheme.

Displacement ellipsoids are drawn at the 30% probability level.

Figure 3

The molecular structure of (III), showing the atom-numbering scheme.

Displacement ellipsoids are drawn at the 30% probability level. The

dashed lines indicate hydrogen bonds.

acceptor, it is reasonable to assume that conformational

changes imposed by the group will be similar in solid and in

aqueous environments.

The dihedral angles in compounds (I)–(III) between the

mean plane of the heterocyclic ring and that of the amide

group (deﬁned by atoms C1, O1 and N2) can be compared

with those of similar compounds without the methylsulfanyl

substituent on C2 using data obtained from the Cambridge

Structural Database (CSD, Version 5.34; Allen, 2002). Rele-

vant compounds are N-cyclohexylnicotinamide, (IV) (Li,

2010), which is the nonsubstituted derivative of (I), and

N-ethylnicotinamide, (V) (Srikrishnan & Parthasarathy, 1990),

and (S)-N-(ꢁ-methylbenzyl)nicotinamide, (VI) (Little &

Morimoto, 1981), which are similar to (II), as well as N-(pyri-

din-3-ylcarbonyl)glycine, (VII) (Krishnaswamy et al., 1987).

Such comparisons show that the methylsulfanyl group affects

the degree of twist of the pyridine ring and thus the relative

position of the heteroatom with respect to the amide group.

These are conformational aspects that may affect the docking

to the receptor and thus the pharmacological activity of the

substances described here. The values for the dihedral angles

between the planes of the amide group and the pyridine rings

are given in the Scheme. The dihedral angles, taken in

conjunction with the values for the torsion angles about the

C1—C11 bond in Tables 1 and 2, clearly indicate that the

presence of the methylsulfanyl group results in changes in the

orientation of the heterocyclic ring with respect to the amide

group. The dihedral angles for the unsubstituted compounds

are in the range 20–35^ꢁ, which have smaller angular values

than the range of 40–60^ꢁfor compounds with the methyl-

Figure 4

Part of the crystal structure of (I), showing the hydrogen-bonded chain

Figure 2

The molecular structure of (II), showing the atom-numbering scheme.

Displacement ellipsoids are drawn at the 30% probability level. The

dashed bond shows the hydrogen bond linking the two molecules in the

asymmetric unit.

which runs parallel to the c axis. Atoms labelled with an asterisk (*) and

1

hash (#) are at the symmetry positions (ꢂx + , y, z + ) and (ꢂx + , y,

2

1

z ꢂ ), respectively. H atoms not involved in the hydrogen bonding have

2

been omitted.

ꢃ

294 Gomes et al. C₁₃H₁₈N₂OS, C₁₀H₁₄N₂OS and C₉H₁₂N₂O₂Sꢀ2H₂O

Acta Cryst. (2013). C69, 293–298

organic compounds

Figure 7

Part of the crystal structure of (III), showing the ladder structure formed

by the linking of two centrosymmetric rings. This ladder runs parallel to

the a axis. Atoms labelled with an asterisk (*), hash (#), dollar sign ($),

ampersand (&) and ‘at’ symbol (@) are at the symmetry positions (ꢂx + 1,

ꢂy + 1, ꢂz + 1), (ꢂx, ꢂy + 1, ꢂz + 1), (x + 1, y, z), (ꢂx + 2, ꢂy + 1, ꢂz + 1)

and (x ꢂ 1, y, z), respectively. H atoms not involved in hydrogen bonding

have been omitted.

Figure 5

Part of the crystal structure of (I), showing the hydrogen-bonded chain

formed by the C—Hꢀ ꢀ ꢀꢂ interaction. Atoms labelled with an asterisk (*)

1

and hash (#) are at the symmetry positions (ꢂx + 1, ꢂy + 1, z + ) and

2

1

(ꢂx + 1, ꢂy + 1, z ꢂ ), respectively. H atoms not involved in hydrogen

2

bonding have been omitted.

compounds (I)–(III) around the C1—C11 bond (Table 1)

indicate that in order for the methylsulfanyl group to avoid the

proximity of the amide N—H group, a clockwise rotation

takes place such that the pyridine heteroatom sits in a cis

position with respect to the carbonyl O atom. This contrasts

sulfanyl substituent. The presence of a methylsulfanyl susti-

tuent at the 2-position also conditions the direction of rotation

of the ring. The magnitudes of the torsion angles for

Figure 8

Figure 6

Part of the crystal structure of (III), showing the hydroxy–water

hydrogen-bonded chain which runs parallel to the b axis. Atoms labelled

with an asterisk (*), hash (#) and dollar sign ($) are at the symmetry

Part of the crystal structure of (II), showing the hydrogen-bonded chain

which runs parallel to the b axis. Atoms labelled with an asterisk (*) and

hash (#) are at the symmetry positions (x, y + 1, z) and (x, y ꢂ 1, z),

respectively. H atoms not involved in hydrogen bonding have been

omitted.

1

positions (ꢂx + ₂³, y + ₂¹, ꢂz + ₂¹), (ꢂx + ₂³, y ꢂ , ꢂz + ¹₂) and (x, y + 1, z),

2

respectively. H atoms not involved in hydrogen bonding have been

omitted.

ꢃ

Acta Cryst. (2013). C69, 293–298

Gomes et al.

C₁₃H₁₈N₂OS, C₁₀H₁₄N₂OS and C₉H₁₂N₂O₂Sꢀ2H₂O 295

organic compounds

intermolecular hydrogen bonding. One common supra-

molecular structure found in compounds with amide groups is

the formation of C4 chains (Bernstein et al., 1995) via inter-

molecular N—Hꢀ ꢀ ꢀO C—NHꢀ ꢀ ꢀ hydrogen bonds. Another

common supramolecular structure, mentioned below, involves

the formation of intermolecular amide–pyridine N—Hꢀ ꢀ ꢀN

hydrogen bonds. While these supramolecular structures are

common, they may not occur in the presence of other strong

acceptors, e.g. the water molecules in (III). All the other

structures discussed above contain these C4 chains.

In (I), molecules are linked by N—Hꢀ ꢀ ꢀO hydrogen bonds

to form C(4) chains, generated by the glide-plane axis at x = ₄¹

and with translations parallel to the c axis (Fig. 4 and Table 3).

C16—H16ꢀ ꢀ ꢀCg1ⁱⁱinteractions (symmetry code as in Table 3;

Cg1 is the centroid of the pyridine ring) link these chains into a

two-dimensional sheet (Fig. 5). There are no other inter-

molecular interactions.

Figure 9

In (II), molecules A and B are linked by N—Hꢀ ꢀ ꢀO

hydrogen bonds within the selected asymmetric unit (Table 4).

These pairs are then linked to further pairs of molecules by

unit-cell translation along the b axis to form a C₂²(8) chain

(Fig. 6). There are no other intermolecular interactions.

In (III), the asymmetric unit was selected so that the N—H

and O—H donors formed hydrogen bonds with the water

molecules via N2—H2ꢀ ꢀ ꢀO2 and O23—H23ꢀ ꢀ ꢀO3 hydrogen

bonds within that unit (Table 5). Having so many donors and

acceptors available leads to a complex supramolecular struc-

ture which is best described by considering the several

substructures.

Part of the crystal structure of (III), showing the hydroxy–water

hydrogen-bonded chain which runs parallel to the a axis. Atoms labelled

with an asterisk (*), hash (#), dollar sign ($) and ampersand (&) are at the

symmetry positions (ꢂx + ¹₂, y + ₂¹, ꢂz + ₂¹), (ꢂx + ³₂, y + ₂¹, ꢂz + ¹₂), (x + 1, y,

z) and (x ꢂ 1, y, z), respectively. The pendant molecules at (x, y, z), (x + 1,

y, z) and (x ꢂ 1, y, z) are not involved in the chain. H atoms not involved

in hydrogen bonding have been omitted.

with the situation in compounds with unsubstituted 2-posi-

tions, in which the amide O atom is trans with respect to atom

C2 of the pyridine ring, as a result of the anticlockwise rota-

tion of the pyridine ring. These differences are highlighted in

the Scheme.

The S atom of the methylsulfanyl group is a very weak

electron acceptor and is not expected to enter into an intra-

molecular interaction with the amino H atom of the amide

group. Such intramolecular interactions can be observed with

strong electron-acceptor substituents at the 2-position of the

pyridine ring. In N-(2,4-diﬂuorophenyl)-2-[3-(triﬂuorophenyl)-

phenoxy]pyridine-3-carboxamide (CSD refcode; ZIKXEW;

In (III), nicotinamide molecules and hydrate atom O2 form

two centrosymmetric R²₂(16) rings (Bernstein et al., 1995), one

centred on the centre of symmetry at (¹₂, ₂¹, ₂¹) and the other at

iii

1

2

1

2

(0, , ). In the ﬁrst of these, the O2—H2Aꢀ ꢀ ꢀN11 hydrogen

bond links the asymmetric unit and its centrosymmetric

counterpart at (ꢂx + 1, ꢂy + 1, ꢂz + 1) to form the ring. In the

second, the water molecules at (ꢂx + 1, ꢂy + 1, ꢂz + 1) and

(x ꢂ 1, y, z) act as hydrogen-bond donors via H2A to atom

N11 at (x, y, z) and (ꢂx + 1, ꢂy + 1, ꢂz + 1), respectively, and

via H2B to atom O1 at (ꢂx + 1, ꢂy + 1, ꢂz + 1) and (x, y, z),

respectively, to form the ring. These rings alternate within a

ladder structure which runs parallel to the a axis (Fig. 7).

There is a ꢂ–ꢂ interaction between the pyridine rings in the

ﬁrst of these rings, in which the centroid–centroid distance

between these pyridine rings which lie across the centre of

`

Pepe et al., 1995), there is an intramolecular hydrogen bond

between the amide N atom and the phenoxy O atom [N—H =

˚

0.93 (4) A, Hꢀ ꢀ ꢀO = 1.76 (4) A, Nꢀ ꢀ ꢀO = 2.649 (4) A and N—

Hꢀ ꢀ ꢀO = 160 (3)^ꢁ]; the dihedral angle between the mean

planes of the pyridine ring and the amide group is 4.6 (4)^ꢁ.

The main factor affecting the conformation of molecules

containing an amide group is the presence of intra- and

1

2

1

symmetry at (¹₂,

, ₂) is 3.5839 (16) A, the perpendicular

˚

distance between the rings is 3.3083 (5) A and the slippage is

˚

1.378 A, so supplementing this substructure. Water molecule

O3 is hydrogen bonded to atom O23 via atom H23 in the

asymmetric unit, as mentioned above. The action of the screw

1

axis at (³₄, y, ) produces a zigzag C₂²(4) chain, which runs

4

parallel to the b axis. Atom O3 acts as a donor via H3A to

1

3

1

atom O23 at (ꢂx + , y + , ꢂz + ) and this links via H23 to

2

atom O3 in the same asymmetric residue unit, so forming the

chain (Fig. 8). This water molecule also acts as a hydrogen-

bond donor to atoms O1 and O23. C₂²(9) chains are thus

produced along the a axis linking molecules at (ꢂx + ¹₂, y + ₂¹,

ꢂz + ¹₂), (ꢂx + ₂³, y + ¹₂, ꢂz + ₂¹) etc. via water molecules at (x, y,

Figure 10

A stereoview showing the structure formed by the combination of the two

hydroxy–water hydrogen-bonded chains in (III). This lies in the ab plane.

ꢃ

296 Gomes et al. C₁₃H₁₈N₂OS, C₁₀H₁₄N₂OS and C₉H₁₂N₂O₂Sꢀ2H₂O

Acta Cryst. (2013). C69, 293–298

organic compounds

Table 1

Selected torsion angles (^ꢁ).

The angles are the equivalent torsion angles for each molecule. In (II), the

corresponding atom labels for the two independent molecules end in A and B.

(I)

(IIA)

(IIB)

(III)

O1—C1—C13—C14

N2—C1—C13—C14

O1—C1—C13—C12

N2—C1—C13—C12

ꢂ139.12 (13)

138.7 (6)

39.88 (17) ꢂ40.7 (8)

ꢂ128.7 (7)

50.7 (8)

47.7 (8)

ꢂ132.9 (6)

ꢂ120.22 (14)

59.14 (16)

57.58 (17)

ꢂ123.06 (13)

38.15 (17) ꢂ40.9 (8)

ꢂ142.85 (11)

139.7 (6)

Table 2

Selected torsion angles (^ꢁ) for (IV), (V), (VI) and (VII).

The angles are the equivalent torsion angles for each molecule as for the

current compounds.

(IV)

22.27 (19)

ꢂ157.12 (12)

ꢂ156.49 (13)

ꢂ142.85 (18)

(V)

19.7 (2)

ꢂ158.21 (16)

ꢂ158.93 (18)

23.2 (2)

(VI)

(VII)

O1—C1—C13—C14

N2—C1—C13—C14

O1—C1—C13—C12

N2—C1—C13—C12

ꢂ30.87

149.63

146.37

ꢂ36.12

ꢂ148.37 (18)

29.5 (3)

26.6 (3)

ꢂ155.55 (18)

Figure 11

A stereoview of the packing for (III).

z) and at unit-cell translations along the a axis (Fig. 9). These

two interactions combine to form a sheet of R⁶₆(20) rings

(Fig. 10). A packing diagram involving all these substructures

is shown in Fig. 11. All potential strong hydrogen-bond donors

and acceptors are utilized in the building of the supra-

molecular structure.

Data collection

Rigaku Saturn724+ (2x2 bin mode)

diffractometer

Absorption correction: multi-scan

(CrystalClear-SM Expert;

Rigaku, 2011)

11531 measured reﬂections

2731 independent reﬂections

2657 reﬂections with I > 2ꢄ(I)

R_int= 0.026

T_min= 0.942, T_max= 0.991

Reﬁnement

R[F²> 2ꢄ(F²)] = 0.024

wR(F²) = 0.064

S = 1.06

2731 reﬂections

156 parameters

1 restraint

H-atom paramete_ꢂrs₃constrained

Experimental

˚

Áꢅ_max= 0.25 e A

ꢂ3

˚

The following is a general procedure for the synthesis of N-substi-

tuted 2-(methylsulfanyl)nicotinamides. A stirred solution of methyl

2-(methylsulfanyl)nicotinate (1 mmol), prepared from 2-mercapto-

nicotinic acid, methyl iodide and K₂CO₃, and an amine (20 mmol)

was reﬂuxed for 24 h. The reaction was concentrated under reduced

pressure and the residue was diluted with ethyl acetate, washed with

brine, dried over Na₂SO₄, ﬁltered and evaporated. The crude product

was puriﬁed by column chromatography on silica gel (0–50% ethyl

acetate in hexane) affording the N-substituted 2-(methylsulfanyl)-

nicotinamide derivatives in 60–88% yield. For N-cyclohexyl-2-

(methylsulfanyl)nicotinamide, (I) (yield: 60%), the crystals used in

the structure determination were grown from an ethanol solution. For

N-isopropyl-2-(methylsulfanyl)nicotinamide (II) (yield: 65%), the

crystals used in the structure determination were grown from a

methanol solution. For N-(2-hydroxyethyl)-2-(methylsulfanyl)nico-

tinamide, (III) (yield: 88%), the crystals used in the structure deter-

mination were grown from a moist ethyl acetate solution.

Áꢅ_min= ꢂ0.15 e A

Absolute structure: Flack (1983),

1133 Friedel pairs

Flack parameter: 0.06 (5)

Compound (II)

Crystal data

3

˚

V = 2307 (8) A

C₁₀H₁₄N₂OS

M_r= 210.29

Monoclinic, P2₁=c

Z = 8

Synchrotron radiation

˚

a = 11.42 (2) A

˚

ꢇ = 0.68890 A

b = 8.580 (19) A

˚

c = 23.61 (5) A

ꢆ = 94.15 (3)^ꢁ

ꢃ = 0.25 mm^ꢂ1

T = 100 K

˚

0.10 ꢄ 0.03 ꢄ 0.01 mm

Data collection

CrystalLogic diffractometer

Absorption correction: multi-scan

(CrystalClear-SM Expert;

Rigaku, 2011)

10806 measured reﬂections

4493 independent reﬂections

2445 reﬂections with I > 2ꢄ(I)

R_int= 0.150

Compound (I)

T_min= 0.975, T_max= 0.998

Crystal data

3

˚

C₁₃H₁₈N₂OS

M_r= 250.35

Orthorhombic, Pca2₁

V = 1302.97 (17) A

Z = 4

Mo Kꢁ radiation

ꢃ = 0.24 mm^ꢂ1

T = 100 K

Reﬁnement

R[F²> 2ꢄ(F²)] = 0.119

wR(F²) = 0.366

S = 1.06

259 parameters

H-atom paramete_ꢂrs₃constrained

˚

a = 11.5273 (9) A

˚

b = 13.4634 (10) A

˚

c = 8.3956 (6) A

˚

Áꢅ_max= 0.67 e A

ꢂ3

˚

0.26 ꢄ 0.19 ꢄ 0.04 mm

4493 reﬂections

Áꢅ_min= ꢂ0.67 e A

ꢃ

Acta Cryst. (2013). C69, 293–298

Gomes et al.

C₁₃H₁₈N₂OS, C₁₀H₁₄N₂OS and C₉H₁₂N₂O₂Sꢀ2H₂O 297

organic compounds

˚

methyl C—H = 0.98 A, with U_iso(H) = 1.5U_eq(C). In (III), H atoms

˚

were treated as riding atoms, with aromatic C—H = 0.95 A and

Table 3

Hydrogen-bond geometry (A, ) for (I).

ꢁ

˚

U_iso(H) = 1.2U_eq(C), and methyl C—H = 0.98 A and U_iso(H) =

Cg1 is the centroid of the pyridine ring.

1.5U_eq(C). The positions of the H atoms attached to N, hydroxy O

and the water O atoms were located in difference maps and allowed

to ride at these positions, with U_iso(H) = 1.2U_eq(N) and 1.5U_eq(O).

The positions of the H atoms attached to N atoms, methyl groups,

hydroxy groups and water molecules were checked in difference

maps during and after the reﬁnement was complete.

D—Hꢀ ꢀ ꢀA

D—H

Hꢀ ꢀ ꢀA

Dꢀ ꢀ ꢀA

D—Hꢀ ꢀ ꢀA

N2—H2ꢀ ꢀ ꢀO1ⁱ

0.88

0.95

2.01

2.97

2.8399 (15)

3.7489 (18)

157

141

C16—H16ꢀ ꢀ ꢀCg1ⁱⁱ

1

2

1

2

1

2

Symmetry codes: (i) ꢂx þ ; y; z þ ; (ii) ꢂx þ 1; ꢂy þ 1; z þ .

The crystals of (II) were very small (0.10 ꢄ 0.03 ꢄ 0.01 mm) and

even though data were collected by synchrotron radiation it was not

possible to collect a complete observable data set.

Table 4

Hydrogen-bond geometry (A, ) for (II).

ꢁ

˚

For all compounds, data collection: CrystalClear-SM Expert

(Rigaku, 2011); cell reﬁnement: CrystalClear-SM Expert; data

reduction: CrystalClear-SM Expert; program(s) used to solve struc-

ture: SHELXS97 (Sheldrick, 2008); program(s) used to reﬁne struc-

ture: OSCAIL (McArdle et al., 2004) and SHELXL97 (Sheldrick,

2008); molecular graphics: PLATON (Spek, 2009); software used to

prepare material for publication: OSCAIL and SHELXL97.

D—Hꢀ ꢀ ꢀA

D—H

Hꢀ ꢀ ꢀA

Dꢀ ꢀ ꢀA

D—Hꢀ ꢀ ꢀA

N2A—H2Aꢀ ꢀ ꢀO1B

0.88

2.02

2.03

2.862 (9)

2.869 (9)

160

159

N2B—H2Bꢀ ꢀ ꢀO1Aⁱ

Symmetry code: (i) x; y þ 1; z.

Table 5

Hydrogen-bond geometry (A, ) for (III).

ꢁ

˚

Supplementary data for this paper are available from the IUCr electronic

archives (Reference: SK3475). Services for accessing these data are

described at the back of the journal.

D—Hꢀ ꢀ ꢀA

D—H

Hꢀ ꢀ ꢀA

Dꢀ ꢀ ꢀA

D—Hꢀ ꢀ ꢀA

N2—H2ꢀ ꢀ ꢀO2

0.98

0.84

0.80

0.89

0.83

0.95

0.99

1.83

1.85

2.00

1.84

2.04

2.37

2.48

2.8096 (16)

2.6906 (17)

2.7966 (15)

2.7200 (15)

2.8449 (17)

3.3122 (19)

2.8208 (17)

176

177

178

170

164

174

100

O23—H23ꢀ ꢀ ꢀO3

O3—H3Bꢀ ꢀ ꢀO1ⁱ

O3—H3Aꢀ ꢀ ꢀO23ⁱⁱ

O2—H2Aꢀ ꢀ ꢀN11ⁱⁱⁱ

C14—H14ꢀ ꢀ ꢀO3

C21—H21Aꢀ ꢀ ꢀO1

References

Allen, F . H . (2002). Acta Cryst. B 58 , 380–388.

Bernstein, J., Davis, R. E., Shimoni, I. & Chang, N.-L. (1995). Angew. Chem.

Int. Ed. Engl. 34 , 1555–1573.

Cufﬁni, S., Glidewell, C., Low, J. N., de Oliveira, A. G., de Souza, M. V . N .,

V a sconcelos, T. R. A., Wardell, S. M. S. V . & W a rdell, J. L. (2006). Acta Cryst.

B 62 , 651–665.

1

2

1

2

1

2

3

2

1

2

1

2

Symmetry codes: (i) ꢂx þ ; y þ ; ꢂz þ ; (ii) ꢂx þ ; y þ ; ꢂz þ ; (iii) ꢂx þ 1; ꢂy þ 1,

ꢂz þ 1.

Flack, H. D. (1983). Acta Cryst. A 39 , 876–881.

Compound (III)

Gon c ¸alves, R. S. B., Kaiser, C. R., Louren c ¸o, M. C. S., Bezerra, F . A . F . M ., de

Souza, M. N., Wardell, J. L., Wardell, S. M. S. V ., Henriques, M., das, G. M. de

O. & Costa, T. (2012). Bioorg. Med. Chem. 20 , 243–248.

Krishnaswamy, S., Pattabhi, V . & G uru Row, T. N. (1987). Acta Cryst. C 43 , 728–

729.

Li, N. (2010). Acta Cryst. E 66 , o1759.

Little, R. G. & Morimoto, C. (1981). Acta Cryst. B 37 , 1637–1640.

Mackay, A. L. (1984). Acta Cryst. A 40 , 165–166.

McArdle, P ., Gilligan, K., Cunningham, D., Dark, R. & Mahon, M. (2004).

CrystEngComm , 6 , 303–309.

`

Pepe, G., Pfefer, G., Boistelle, R. & Marchal, P . (1995). Acta Cryst. C 51 , 2671–

2672.

Rigaku (2011). CrystalClear-SM Expert . Rigaku Corporation, T o kyo, Japan.

Sheldrick, G. M. (2008). Acta Cryst. A 64 , 112–122.

Souza, M. V . N. d e (2006). Recent Pat. Antiinfect. Drug Discov. 1 , 33–44.

Souza, M. V . N. d e (2012). Mycobact. Diseases , 2 , e107. doi:10.4172/2161-

1068.1000e107.

Souza, M. V . N. d e, Vasconcelos, T. R. A., Wardell, S. M. S. V ., Wardell, J. L.,

Low, J. N. & Glidewell, C. (2005). Acta Cryst. C 61 , o204–o208.

Spek, A. L. (2009). Acta Cryst. D 65 , 148–155.

Crystal data

3

˚

C₉H₁₂N₂O₂Sꢀ2H₂O

V = 1173.3 (7) A

Z = 4

M_r= 248.30

Monoclinic, P2₁=n

Mo Kꢁ radiation

ꢃ = 0.28 mm^ꢂ1

T = 100 K

0.26 ꢄ 0.12 ꢄ 0.05 mm

˚

a = 7.194 (2) A

˚

b = 7.285 (3) A

˚

c = 22.388 (8) A

ꢆ = 90.341 (5)^ꢁ

Data collection

Rigaku Saturn724+ (2x2 bin mode)

diffractometer

Absorption correction: multi-scan

(CrystalClear-SM Expert;

Rigaku, 2011)

6865 measured reﬂections

2063 independent reﬂections

1977 reﬂections with I > 2ꢄ(I)

R_int= 0.016

T_min= 0.931, T_max= 0.986

Srikrishnan, T. & Parthasarathy, R. (1990). Acta Cryst. C 46 , 1723–1725.

Wardell, S. M. S. V ., de Souza, M. V . N ., V a sconcelos, T. R. A., Ferreira,

M. L., Wardell, J. L., Low, J. N. & Glidewell, C. (2008). Acta Cryst. B 64 , 84–

100.

Wardell, S. M. S. V ., de Souza, M. V . N ., Wardell, J. L., Low, J. N. & Glidewell,

C. (2007 a ). Acta Cryst. B 63 , 879–895.

Wardell, S. M. S. V ., de Souza, M. V . N ., Wardell, J. L., Low, J. N. & Glidewell,

C. (2007 b ). Acta Cryst. B 63 , 101–110.

WHO (2010). Global Tuberculosis Control . Report. Geneva: World Health

Organization.

Reﬁnement

R[F²> 2ꢄ(F²)] = 0.027

wR(F²) = 0.071

S = 1.07

146 parameters

H-atom paramete_ꢂrs₃constrained

˚

Áꢅ_max= 0.25 e A

ꢂ3

˚

2063 reﬂections

Áꢅ_min= ꢂ0.24 e A

In (I) and (II), H atoms were treated as riding atoms, with aromatic

˚

C—H = 0.95 A and N—H = 0.88 A, with U_iso(H) = 1.2U_eq(C,N), and

˚

ꢃ

298 Gomes et al. C₁₃H₁₈N₂OS, C₁₀H₁₄N₂OS and C₉H₁₂N₂O₂Sꢀ2H₂O

Acta Cryst. (2013). C69, 293–298

supplementary materials

Acta Cryst. (2013). C69, 293-298 [doi:10.1107/S0108270113004344]

Three 2-(methysulfanyl)nicotinamides

Ligia R. Gomes, John Nicolson Low, James L. Wardell, Alessandra C. Pinheiro, Thais C. N. de

Mendonça and Marcus V. N. de Souza

(I) N-Cyclohexyl-2-(methylsulfanyl)nicotinamide

Crystal data

C₁₃H₁₈N₂OS

M_r= 250.35

F(000) = 536

D_x= 1.276 Mg m⁻³

Mo Kα radiation, λ = 0.71075 Å

Cell parameters from 11307 reflections

θ = 3.0–27.6°

Orthorhombic, Pca2₁

Hall symbol: P 2c -2ac

a = 11.5273 (9) Å

b = 13.4634 (10) Å

c = 8.3956 (6) Å

V = 1302.97 (17) Å³

Z = 4

µ = 0.24 mm⁻¹

T = 100 K

Plate, colourless

0.26 × 0.19 × 0.04 mm

Data collection

Rigaku Saturn724+ (2x2 bin mode)

diffractometer

Radiation source: Rotating Anode

Confocal monochromator

Detector resolution: 28.5714 pixels mm^-1

profile data from ω–scans

11531 measured reflections

2731 independent reflections

2657 reflections with I > 2σ(I)

R_int= 0.026

θ_max= 27.5°, θ_min= 3.0°

h = −14→14

k = −17→16

l = −10→9

Absorption correction: multi-scan

(CrystalClear-SM Expert; Rigaku, 2011)

T

_min= 0.942, T_max= 0.991

Refinement

Refinement on F²

Least-squares matrix: full

R[F²> 2σ(F²)] = 0.024

wR(F²) = 0.064

Secondary atom site location: difference Fourier

map

Hydrogen site location: inferred from

neighbouring sites

S = 1.06

2731 reflections

156 parameters

1 restraint

Primary atom site location: structure-invariant

direct methods

H-atom parameters constrained

w = 1/[σ²(F_o²) + (0.0369P)²+ 0.1954P]

where P = (F_o²+ 2F_c²)/3

(Δ/σ)_max= 0.001

Δρ_max= 0.25 e Å⁻³

Δρ_min= −0.15 e Å⁻³

Absolute structure: Flack, (1983)

Flack parameter: 0.06 (5)

Acta Cryst. (2013). C69, 293-298

sup-1

supplementary materials

Special details

Experimental. N-Cyclohexyl-2-(methylsulfanyl)nicotinamide (I). NMR¹H (400MHz, DMSO-d₆) δ (ppm): 8.50 (1H, dd;

J = 4.8 and J = 1.7, H6), 8.27 (1H, d, J = 7.7 Hz, NH), 7.68 (1H, dd, J = 7.5 and J = 1.7 Hz, H4), 7.16 (1H, dd, J = 7.5 and

J = 4.8Hz, H5), 3.70 (1H, m; CHNH), 2.43 (3H, s; (CH₃)S), 1.8-1.2 (10H, m, Cy).

NMR ¹³C (100MHz, DMSO-d₆) δ (ppm): 165.2,157.2, 149.6, 134.8, 130.6, 118.6, 48.1, 32.2, 25.2, 24.6, 12.9. IR (cm^-1;

KBr): 3231 (NH), 1643 (CON) MS/ESI: [M+Na]: 273.1

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full

covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and

torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry.

An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F²against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F²,

conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F²> σ(F²) is used

only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F²

are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²)

x

y

z

U_iso*/U_eq

S12

0.57915 (2)

0.35932 (8)

0.21218 (8)

0.1828

0.73272 (2)

0.73433 (7)

0.75002 (7)

0.7291

0.50452 (5)

0.35091 (12)

0.52819 (14)

0.6189

0.01785 (8)

0.0187 (2)

0.0164 (2)

0.020*

O1

N2

H2

N11

0.55072 (9)

0.31404 (10)

0.49487 (10)

0.37295 (10)

0.31125 (11)

0.2292

0.58148 (10)

0.71397 (9)

0.64461 (9)

0.64360 (9)

0.57267 (9)

0.5698

0.70269 (16)

0.47992 (16)

0.60905 (16)

0.59140 (15)

0.67571 (17)

0.6669

0.0249 (3)

0.0144 (2)

0.0162 (3)

0.0152 (2)

0.0200 (3)

0.024*

C1

C12

C13

C14

H14

C15

0.36892 (13)

0.3280

0.50619 (11)

0.4570

0.7725 (2)

0.8310

0.0274 (3)

0.033*

H15

C16

0.48803 (14)

0.5281

0.51356 (12)

0.4677

0.7814 (2)

0.8474

0.0314 (4)

0.038*

H16

C121

H12A

H12B

H12C

C21

0.71530 (12)

0.7017

0.72066 (11)

0.7247

0.6085 (2)

0.7235

0.0292 (3)

0.044*

0.7676

0.7743

0.5757

0.044*

0.7505

0.6564

0.5827

0.044*

0.14793 (10)

0.1579

0.82314 (9)

0.8071

0.43501 (16)

0.3195

0.0149 (2)

0.018*

H21

C22

0.19572 (10)

0.1877

0.92726 (9)

0.9440

0.46497 (18)

0.5793

0.0198 (3)

0.024*

H22A

H22B

C23

0.2792

0.9290

0.4376

0.024*

0.13070 (11)

0.1615

1.00374 (10)

1.0709

0.36499 (19)

0.3876

0.0216 (3)

0.026*

H23A

H23B

C24

0.1429

0.9896

0.2505

0.026*

0.00155 (11)

−0.0400

1.00077 (10)

1.0478

0.40255 (17)

0.3321

0.0187 (3)

0.022*

H24A

H24B

C25

−0.0112

1.0219

0.5141

0.022*

−0.04705 (10)

−0.0435

0.89657 (10)

0.8793

0.37903 (18)

0.2645

0.0203 (3)

0.024*

H25A

H25B

−0.1296

0.8958

0.4117

0.024*

Acta Cryst. (2013). C69, 293-298

sup-2

supplementary materials

C26

0.01919 (10)

0.0078

0.81846 (9)

0.8304

0.47470 (17)

0.5900

0.0190 (3)

0.023*

H26A

H26B

−0.0112

0.7515

0.4493

0.023*

Atomic displacement parameters (Å²)

U¹¹

U²²

U³³

U¹²

U¹³

U²³

S12

O1

0.01405 (13)

0.0153 (4)

0.0152 (5)

0.0199 (5)

0.0141 (5)

0.0163 (6)

0.0159 (5)

0.0194 (6)

0.0280 (7)

0.0279 (8)

0.0161 (6)

0.0129 (5)

0.0118 (5)

0.0143 (6)

0.0137 (5)

0.0121 (5)

0.01819 (14)

0.0281 (5)

0.0206 (5)

0.0276 (6)

0.0168 (5)

0.0163 (6)

0.0158 (6)

0.0203 (6)

0.0225 (7)

0.0319 (9)

0.0332 (8)

0.0185 (6)

0.0209 (6)

0.0198 (6)

0.0214 (6)

0.0244 (6)

0.0206 (6)

0.02131 (17)

0.0128 (5)

0.0133 (6)

0.0272 (7)

0.0122 (7)

0.0161 (6)

0.0140 (7)

0.0203 (7)

0.0316 (9)

0.0344 (9)

0.0383 (10)

0.0131 (6)

0.0267 (8)

0.0306 (8)

0.0210 (7)

0.0243 (7)

0.0244 (8)

−0.00011 (9)

0.0022 (3)

0.0026 (3)

0.0055 (4)

−0.0016 (4)

0.0019 (4)

0.0018 (4)

0.0004 (5)

0.0016 (5)

0.0081 (6)

−0.0020 (5)

0.0018 (4)

−0.0002 (4)

0.0001 (5)

0.0039 (4)

0.0009 (5)

−0.0012 (4)

0.00024 (15)

0.0006 (4)

0.0016 (4)

−0.0005 (5)

−0.0013 (4)

0.0018 (5)

−0.0005 (5)

0.0026 (5)

0.0072 (6)

0.0007 (6)

−0.0055 (6)

0.0002 (4)

−0.0020 (5)

0.0028 (5)

0.0018 (5)

−0.0023 (5)

0.0004 (5)

0.00287 (15)

0.0030 (4)

0.0032 (4)

0.0090 (5)

−0.0010 (5)

−0.0005 (5)

−0.0023 (5)

0.0006 (6)

0.0120 (6)

0.0189 (7)

0.0065 (7)

−0.0001 (5)

−0.0010 (5)

0.0021 (6)

0.0001 (5)

0.0002 (5)

0.0024 (5)

N2

N11

C1

C12

C13

C14

C15

C16

C121

C21

C22

C23

C24

C25

C26

Geometric parameters (Å, º)

S12—C12

S12—C121

O1—C1

1.7668 (13)

C121—H12C

0.9800

1.8030 (15)

1.2332 (16)

1.3336 (15)

1.4593 (16)

0.8800

C21—C26

C21—C22

1.5222 (15)

1.5271 (17)

1.0000

N2—C1

C21—H21

C22—C23

N2—C21

1.5253 (18)

0.9900

N2—H2

C22—H22A

C22—H22B

C23—C24

N11—C12

N11—C16

C1—C13

1.3247 (17)

1.340 (2)

1.4949 (17)

1.4132 (16)

1.3853 (18)

1.379 (2)

0.9500

0.9900

1.5223 (17)

0.9900

C23—H23A

C23—H23B

C24—C25

C12—C13

C13—C14

C14—C15

C14—H14

C15—C16

C15—H15

C16—H16

C121—H12A

C121—H12B

0.9900

1.5234 (19)

0.9900

C24—H24A

C24—H24B

C25—C26

0.9900

1.379 (2)

0.9500

1.5278 (18)

0.9900

C25—H25A

C25—H25B

C26—H26A

C26—H26B

0.9500

0.9900

0.9800

0.9900

0.9800

0.9900

C12—S12—C121

C1—N2—C21

C1—N2—H2

100.24 (7)

121.97 (11)

119.0

C26—C21—H21

C22—C21—H21

C23—C22—C21

C23—C22—H22A

108.4

110.60 (10)

109.5

C21—N2—H2

119.0

Acta Cryst. (2013). C69, 293-298

sup-3

supplementary materials

C12—N11—C16

O1—C1—N2

117.93 (12)

123.96 (12)

119.91 (11)

116.13 (11)

122.64 (11)

117.28 (9)

120.08 (9)

117.62 (11)

121.57 (11)

120.75 (11)

120.05 (12)

120.0

C21—C22—H22A

C23—C22—H22B

C21—C22—H22B

109.5

O1—C1—C13

N2—C1—C13

H22A—C22—H22B

C24—C23—C22

108.1

N11—C12—C13

N11—C12—S12

C13—C12—S12

C14—C13—C12

C14—C13—C1

C12—C13—C1

C15—C14—C13

C15—C14—H14

C13—C14—H14

C16—C15—C14

C16—C15—H15

C14—C15—H15

N11—C16—C15

N11—C16—H16

C15—C16—H16

S12—C121—H12A

S12—C121—H12B

H12A—C121—H12B

S12—C121—H12C

H12A—C121—H12C

H12B—C121—H12C

N2—C21—C26

N2—C21—C22

C26—C21—C22

N2—C21—H21

110.41 (11)

109.6

C24—C23—H23A

C22—C23—H23A

C24—C23—H23B

C22—C23—H23B

H23A—C23—H23B

C23—C24—C25

109.6

108.1

110.92 (10)

109.5

C23—C24—H24A

C25—C24—H24A

C23—C24—H24B

C25—C24—H24B

H24A—C24—H24B

C24—C25—C26

120.0

109.5

117.72 (13)

121.1

109.5

121.1

108.0

124.03 (13)

118.0

112.45 (11)

109.1

C24—C25—H25A

C26—C25—H25A

C24—C25—H25B

C26—C25—H25B

H25A—C25—H25B

C21—C26—C25

118.0

109.1

109.5

109.1

109.5

109.1

109.5

107.8

109.5

110.10 (10)

109.6

109.5

C21—C26—H26A

C25—C26—H26A

C21—C26—H26B

C25—C26—H26B

H26A—C26—H26B

109.5

109.6

110.46 (10)

110.36 (10)

110.71 (10)

108.4

109.6

108.2

C21—N2—C1—O1

−4.14 (18)

176.90 (10)

0.9 (2)

C1—C13—C14—C15

C13—C14—C15—C16

C12—N11—C16—C15

C14—C15—C16—N11

C1—N2—C21—C26

C1—N2—C21—C22

N2—C21—C22—C23

C26—C21—C22—C23

C21—C22—C23—C24

C22—C23—C24—C25

C23—C24—C25—C26

N2—C21—C26—C25

C22—C21—C26—C25

C24—C25—C26—C21

177.27 (13)

0.1 (2)

C21—N2—C1—C13

C16—N11—C12—C13

C16—N11—C12—S12

C121—S12—C12—N11

C121—S12—C12—C13

N11—C12—C13—C14

S12—C12—C13—C14

N11—C12—C13—C1

S12—C12—C13—C1

O1—C1—C13—C14

N2—C1—C13—C14

O1—C1—C13—C12

N2—C1—C13—C12

C12—C13—C14—C15

−0.9 (3)

−179.30 (12)

−13.77 (13)

166.03 (11)

−0.45 (19)

179.76 (10)

−177.82 (12)

2.39 (16)

0.4 (3)

155.76 (11)

−81.49 (14)

178.71 (10)

−58.69 (14)

57.95 (15)

−55.64 (15)

54.76 (16)

178.91 (11)

56.37 (14)

−54.86 (15)

−139.12 (13)

39.88 (17)

38.15 (17)

−142.85 (11)

−0.08 (19)

Acta Cryst. (2013). C69, 293-298

sup-4

supplementary materials

Hydrogen-bond geometry (Å, º)

Cg1 is the centroid of the pyridine ring.

D—H···A

D—H

H···A

D···A

D—H···A

N2—H2···O1ⁱ

C16—H16···Cg1ⁱⁱ

0.88

0.95

2.01

2.97

2.8399 (15)

3.7489 (18)

157

141

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

(II) N-Isopropyl-2-(methylsulfanyl)nicotinamide

Crystal data

C₁₀H₁₄N₂OS

M_r= 210.29

F(000) = 896

D_x= 1.211 Mg m⁻³

Monoclinic, P2₁/c

Hall symbol: -P 2ybc

a = 11.42 (2) Å

b = 8.580 (19) Å

c = 23.61 (5) Å

β = 94.15 (3)°

V = 2307 (8) Å³

Z = 8

Synchrotron radiation, λ = 0.68890 Å

Cell parameters from 3067 reflections

θ = 1.7–26.9°

µ = 0.25 mm⁻¹

T = 100 K

Plate, colourless

0.10 × 0.03 × 0.01 mm

Data collection

CrystalLogic

T_min= 0.975, T_max= 0.998

diffractometer

Radiation source: synchrotron, DLS beamline

I19

Double crystal silicon monochromator

Detector resolution: 28.5714 pixels mm^-1

profile data from ω–scans

Absorption correction: multi-scan

(CrystalClear-SM Expert; Rigaku, 2011)

10806 measured reflections

4493 independent reflections

2445 reflections with I > 2σ(I)

R_int= 0.150

θ

_max= 26.4°, θ_min= 1.7°

h = −14→7

k = −9→11

l = −30→24

Refinement

Refinement on F²

Least-squares matrix: full

R[F²> 2σ(F²)] = 0.119

wR(F²) = 0.366

Secondary atom site location: difference Fourier

map

Hydrogen site location: inferred from

neighbouring sites

S = 1.06

4493 reflections

259 parameters

0 restraints

Primary atom site location: structure-invariant

direct methods

H-atom parameters constrained

w = 1/[σ²(F_o²) + (0.1896P)²+ 2.8333P]

where P = (F_o²+ 2F_c²)/3

(Δ/σ)_max< 0.001

Δρ_max= 0.67 e Å⁻³

Δρ_min= −0.67 e Å⁻³

Special details

Experimental. N-iso-Propyl-2-(methylsulfanyl)nicotinamide (II). NMR ¹H (400MHz, DMSO-d₆) δ (ppm): 8.51 (1H, dd;

J = 4.8 and J = 1.7 Hz, H6), 8.28 (1H, d, J = 7.5Hz, NH), 7.70 (1H, dd; J = 7.5 and J = 1.7 Hz, H4), 7.16 (1H, dd, J = 7.5

and J = 4.8 Hz, H5), 4.02 (1H, dq, J = 7.5 and J = 6.5 Hz, CH), 2.43 (3H, s, (CH3)S), 1.14 (6H, d, J= 6.5 Hz, (CH3)2C).

(ppm): 165.2, 157.3, 149.6, 134.8, 130.5, 118.5, 40.9, 22.1, 12.9. IR (cm^-1; KBr): 3234 (NH), 1628 (CON) MS/ESI: [M-

H]: 209.2

Acta Cryst. (2013). C69, 293-298

sup-5