Polymorphism in Secondary Benzene Sulfonamides

5/28/2018 Polymorphism in Secondary Benzene Sulfonamides

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pubs.acs.org/crystal Published on Web 08/25/2010 r 2010 American Chemical Society

DOI: 10.1021/cg100845f

2010, Vol. 10

45504564

Polymorphism in Secondary Benzene Sulfonamides

Palash Sanphui, Bipul Sarma, and Ashwini Nangia*

School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli,Central University P.O., Hyderabad 500046, India

Received June 25, 2010; Revised Manuscript Received August 3, 2010

ABSTRACT: Therole of about 20different solvents in thecrystallization of polymorphs for13 N-phenyl benzene sulfonamideswas studied. Five compounds (1, 2, 3, 7, and 11) are dimorphic, and one is trimorphic (6). All the crystalline solids werecharacterized by powder and single crystal X-ray diffraction, thermal analysis, hot stage microscopy, and IR and Ramanspectroscopy. The phase transition from a metastable form to the stable form was examined visually for two compounds (1,11)on a HSM and confirmed by differential scanning calorimetry and X-ray diffraction. The N-H 3 3 3 O hydrogen bond catemer(chain) anddimer (cyclic) motifs of thesulfonamide group were analyzed as themain difference between polymorphs of1, 3,and6. WeakerC-H 3 3 3 O interactions differentiate the molecular packing of other polymorphic systems. Accordingly, these crystalstructures are referred to as synthon polymorphs. The occurrence of N-H 3 3 3 O catemer and dimer synthon in secondarysulfonamides is compared with crystal structures in the Cambridge database. The nearly equal probability of the dimer andcatemer motifs for secondary sulfonamides (19%) is attributed to the possibility of making the catemer synthon via both anti

and syn oxygen atoms of the SO2NH group, with the former acceptor being preferred in two-thirds of the cases.

Introduction

Sulfonamides continue to attract the attention of structuraland pharmaceutical chemists because of their druglike pro-perties.1 A thorough screening for all possible polymorphs isconsidered an essential step in the pharmaceutical industry toselect the best drug formulation.2 Gelbrich, Hursthouse, andThrelfall3 reported a comparative study of molecular packingand hydrogen bonding in one hundred phenylbenzene sulfon-amides having the para-para substitution on the the N-Phand Ph-SO2 moieties. They classified the 133 crystal struc-tures into 56 different structure types. We have synthesized 13N-phenyl benzenesulfonamides of ortho-meta-para substi-tution. The formation of different N-H 3 3 3 O hydrogen bondsynthons4 between the sulfonamide group, namely dimer andcatemer, is the main focus of this study. Changes in molecularconformation and weak intermolecular interactions such asC-H 3 3 3 O, C-H 3 3 3 ,-stacking, etc. afforded differentcrystalline polymorphs. The role of the crystallization solvent(polar vs nonpolar) to give one or another polymorph, ormixtures in some cases, is discussed.

Results and Discussion

N-Phenyl benzenesulfonamides were prepared by the con-

densation of the substituted benzenesulfonyl chloride withtheappropriate aniline (Scheme 1). After confirming the com-pound homogeneity and purity by 1H NMR and FT-IR, theywere crystallized from about 20 different solvents (Table 1).Six of the13 compoundsstudied arepolymorphic.These solventscreens give an idea of the solvent effect on the polymorphicoutcome (or absence of polymorphism) in crystallizationexperiments. In general, a variety of experimental methodsare practiced to crystallize new polymorphs, for example,solvent/antisolvent evaporation, slurry crystallization, melting,

sublimation, additives, cocrystal formers, polymer-inducedheteronucleation, etc.5 We used common laboratory solventsfor the crystallization of polymorphs along with melting andsublimation techniques. However, the solvent-free method

did not afford a new crystalline form because these com-pounds did not sublime and melting afforded the stablemodification of solution crystallization. N-H 3 3 3 O dimerand catemer between the sulfonamide group are possible

hydrogen bond motifs in these crystal structures (Figure 1).Structural Analysis.Molecule1 crystallized as two differ-

ent polymorphs, forms I and II, by slow evaporation ofmethanol andp-xylene, respectively. The first form matches

with the crystal structure reported recently by Gowda et al.6

The crystal structure of form I (in the P21/n space group,Table 2) has one-dimensional tapes of molecules connectedvia a catemeric N-H 3 3 3 O hydrogen bond (N1-H1 3 3 3 O1,2.21 A , 162.5) along [100] (Figure 2). These tapes are

connected via C-H 3 3 3 interaction cross-links to form asheet parallel to the (001) plane. C-H 3 3 3 O interaction(C5-H5 3 3 3 O2, 2.48 A

, 126.2, Table 3) between theseparallel sheets sustains the overall packing. The sulfonamide

dimer (N1-H1 3 3 3 O1, 2.00A , 170.2) is present inthe crystal

structure of form II (Figure 3). Close packing of the dimericunits in the P2

1/c crystal system completes the molecular

arrangement. The basic difference between these two poly-

morphs comes from the catemer and dimer motif ofN-H 3 3 3 O hydrogen bonds of the sulfonamide group.

Molecule2 is also dimorphic. Form I crystallized in theP21/cspace group whereas form II is in the P1 space group.The sulfonamide dimer synthon is present in both poly-morphs, with the difference being the C-H 3 3 3 O interactionleading to differentpacking arrangements. In form I, the SO2oxygen acceptor that is not involved in the sulfonamidehomodimer makes a C-H 3 3 3 O chelate motif

7 (Figure 4a).In form II, the sulfonamide dimer units extend through aC-H 3 3 3 O interaction along [001] (C11-H11 3 3 3 O2 2.68 A

,150.8) (Figure4b). Thedifference between these twopolymorphs

*To whom correspondence should be addressed. E-mail: [email protected].


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Article Crystal Growth & Design, Vol. 10, No. 10, 2010 4551

can be understood by their C-H 3 3 3 O interactions. Theymay be classified as synthon polymorphs at the secondarylevel, because the strong hydrogen bonding is the same butthere are differences at the weak interactions level.8 Thegraph set notation9 of the hydrogen bond motifs for theN-H 3 3 3 O dimer, N-H 3 3 3 O catemer, C-H 3 3 3 O chelate,and C-H 3 3 3 O dimer are R2

2(8), C(4), R21(6), and R2

2(16).Changes in molecular conformation are listed as torsionangles in Table 4.

For molecule 3, polymorph I contains the sulfonamideN-H 3 3 3 O dimer units, which are connected via type II

Cl 3 3 3 Cl10

(Cl1-Cl2: 3.44 A , 113.5 and 164.7) andC-H 3 3 3 O interactions (Figure 5a). In form II, catemerN-H 3 3 3 O chains are connected through C-H 3 3 3 O inter-actions (Figure 5b). Thus, sulfonamide dimer and catemerare the main difference between these two polymorphs. Thisset as well as molecule 1 structures differing in the strongN-H 3 3 3 O motifs are primary synthon polymorphs.

4c,11

Molecules4and5have the sulfonamide N-H 3 3 3 O dimeras the common synthon (Figure 6). Both structures exhibitsimilar kinds of molecular arrangements and graph setsR2

2(8) and R22(16) along [010]. In structure 4, -interaction

(3.47 A ), whereas in structure 5 - (3.47 A ) and Cl 3 3 3interactions (3.53 A ), contributes to the weaker interactionsin the crystalline lattice.

Table1.

ListofCrystallizationSolventsforPolymorphScreeningandtheHydrogenBondMotifinEachCase

polymorph

crystallizationmeltmethanol

n-propanol

acetone

dichloro-

methane

tetra-

hydrofuran

nitro-

methaned

ioxane

dimethyl

sulfoxide

ethyl

acetate

aceto-

nitrile

chloro-

benzenebenzene

hexane-

EtOAc

p-xylene

trifluoro-

toluene

mesitylene

chloro-

form

diethyl-

ether

hexane

molecule1

Ib

Ib

Ib

Ib

Ib

IIa

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

IIa

Ib

Ib

Ib

Ib

Ib

molecule2

Ia

Ia,

IIa

Ia

Ia

Ia

IIa

Ia

Ia

Ia

Ia

Ia

IIa

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

molecule3

Ia

IIb

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

molecule6

Ib

IIb

IIb

IIb

IIb

IIb

IIb

IIb

IIb

IIb

IIb

Ib

Ib

IIb

Ib

Ib

Ib

IIb

IIb

IIIa

molecule7

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

Ib

IIb

Ib

Ib

Ib

Ib

Ib

molecule11

IIa

IIa

IIa

Ia

Ia

Ia

Ia

IIa

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

Ia

a

Sulfonamidedimer.

b

Sulfonamidecatemer.

Scheme 1. (a)Synthetic Procedure for the Preparation ofSecondary Sulfonamides 1-13.(b)A Single CPh-S-N-CPh

Torsion Angle Defines Much of the Shape ofN-PhenylBenzenesulfonamide Molecules


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4552 Crystal Growth & Design, Vol. 10, No. 10, 2010 Sanphui et al.

Molecule6is trimorphic in the monoclinic crystal system.

Forms I and II have a catemer N-H 3 3 3 O chain (Figure 7a,b)

that is connected by C-H 3 3 3 O interaction. However, form

III hasthe sulfonamide dimer motif (Figure 7c)together with

a-stacking interaction. The molecular packing of form III

is similar to that of12 and 13, which are discussed later in

the paper.Molecule7 is dimorphic. Form I crystallized in the P21/c

space group with two molecules in the asymmetric unit.Sulfonamide N-H 3 3 3 O catemer forms a helical structure

along [010] (Figure 8a). A difference between the catemer

motif in this crystal structure compared to previous ones is

that the syn O of sulfonamide is the acceptor here compared

to themore commonanti O in previous structures. Form II in

the P21/n space group also has two symmetry-independent

molecules. One molecule makes a catemer via anti O along

[010], and the second molecule fills the voids betweenb-translated molecules connected by N-H 3 3 3 O and C-

Cl 3 3 3 O (3.19 A ) interactions (Figure 8b).

Molecule8 has similar molecular packing to form II of7

with two symmetry-independent molecules in the P21/n

space group (Figure 9). One molecule (ball and stick model)

makes an N-H 3 3 3 O catemer along [010] using the anti O

Figure 1. Dimer and catemer hydrogen bond synthons of thesulfonamide group. The chain motif formed with anti and syn O

acceptor atoms.

Table 2. Crystallographic Parameters of Structures 1-13

compound 1 2 3 4

polymorph form I form II form I form II form I form II

empirical formula C14H15NO2S C14H15NO2S C15H17NO2S C15H17NO2S C13H11Cl2NO2S C13H11Cl2NO2S C14H14ClNO2Sformula weight 261.33 261.33 275.36 275.36 316.19 316.19 295.77crystal system monoclinic monoclinic monoclinic triclinic monoclinic monoclinic monoclinicspace group P21/n P21/c P21/c P1 P21/n P21 P21/na(A ) 5.2133(16) 7.6844(6) 8.2222(8) 7.954(3) 9.495(5) 4.9650(8) 8.290(3)b(A ) 17.989(5) 23.9322(17) 8.1697(8) 8.367(3) 12.260(6) 17.550(3) 12.476(5)c(A ) 14.052(4) 8.0899(6) 21.715(2) 12.305(5) 12.154(6) 8.1488(13) 13.885(5)R(deg) 90 90 90 81.347(5) 90 90 90(deg) 91.659(5) 115.0690(10) 95.0480(10) 87.854(6) 97.162(7) 102.245(3) 98.192(6)

(deg) 90 90 90 64.361(6) 90 90 90V(A 3) 1317.3(7) 1347.62(17) 1453.0(2) 729.5(5) 1403.7(12) 693.88(19) 1421.5(9)Dcalcd(g cm

-3) 1.318 1.288 1.259 1.254 1.496 1.513 1.382(mm-1) 0.239 0.234 0.220 0.219 0.607 0.614 0.412range 1.84 to 26.14 1.70 to 26.01 2.49 to 25.91 2.73 to 25.88 2.37 to 26.15 2.32 to 19.06 2.20 to 25.99Z 4 4 4 2 4 2 4rangeh -6 to 6 -9 to 9 -10 to 10 -9 to 9 -11 to 11 -6 to 6 -10 to 10rangek -22 to 22 -29 to 29 -10 to 10 -10 to 10 -15 to 15 -21 to 21 -15 to 15rangel -17 to 22 -9 to 9 -26 to 26 -15 to 14 -14 to 15 -10 to 9 -14 to 17reflections collected 13267 13863 14612 7467 13065 7110 10926observed reflections 2295 2245 2342 2485 2463 2175 2185total reflections 2626 2641 2870 2835 2809 2703 2836R1[I> 2(I)] 0.0738 0.0424 0.0478 0.0434 0.0358 0.0544 0.0663wR2(all) 0.1829 0.1160 0.1329 0.1224 0.1054 0.1015 0.1513goodness-of-fit 1.181 1.039 1.029 1.055 1.056 1.057 1.079T(K) 298 298 298 298 298 298 298

compound 5 6 7polymorph form I form II form III form I form II

empirical formula C13H11Cl2NO2S C12H9Cl2NO2S C12H9Cl2NO2S C12H9Cl2NO2S C13H12ClNO2S C13H12ClNO2Sformula weight 316.19 302.16 302.16 302.16 281.75 281.75crystal system monoclinic monoclinic monoclinic monoclinic monoclinic monoclinicspace group P21/n P21/n P21/n P21/c P21/c P21/na(A ) 8.2137(8) 5.0633(11) 5.0326(6) 9.4444(10) 19.9753(18) 11.083(2)b(A ) 12.4688(12) 17.083(4) 14.4315(13) 12.2349(12) 6.1903(5) 10.184(2)c(A ) 14.0076(14) 15.300(3) 18.120(2) 12.3344(12) 22.208(2) 24.045(5)R(deg) 90 90 90 90 90 90(deg) 101.5720(10) 90.485(3) 99.251(10) 111.4710(10) 97.165(2) 102.907(3)(deg) 90 90 90 90 90 90V(A 3) 1405.4(2) 1323.3(5) 1298.9(2) 1326.3(2) 2645.2(9) 2724.6(4)Dcalcd(g cm

-3) 1.494 1.517 1.545 1.513 1.415 1.374(mm-1) 0.606 0.640 0.652 0.638 0.439 0.426range 2.21-26.08 2.38-26.00 3.04-26.37 2.32-25.14 2.18-24.59 3.42-20.13


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while thesecond molecule (capped stick model) fills thevoidsbetween screw axis related molecules by connecting via aN-H 3 3 3 O hydrogen bond to the second sulfonyl oxygenacceptor. The difference comes from the exchange of the Clatom by a methyl group. Molecule 9 has a catemer chainalong [010] using the syn O but now with only one moleculein the crystal structure in the Pbcaspace group (Figure 10).Molecule10 has the sulfonamide dimer synthon along with-stacking of aromatic rings at 3.49 A (Figure 11).

The only difference in crystal structures 7-10 is theexchange of methyl with a chloro group. A change in thestrong N-H 3 3 3 O synthon from dimer to catemer by this

interchange is somewhat surprising because normally suchisosteric Me/Cl substitution (20, 24 A 3 volume) is expected togive identical crystal structures.12

Molecule 11 crystallized in two different forms. Bothforms I and II have the sulfonamide dimer of N-H 3 3 3 Ohydrogen bonds. These dimeric units extend in the planeparallel to (202) via C-H 3 3 3 O interaction involving the freeO of the sulfonamide group and a ring hydrogen donor. Thebasic difference between the two forms is the type of C-H 3 3 3 O interaction between the dimer units. A ring hydrogenis involved in form I whereas a methyl group donor makesthe C-H 3 3 3 O interaction in form II (Figure 12). They are

Table 2. Continued

compound 5 6 7

polymorph form I form II form III form I form II

Z 4 4 4 4 8 8rangeh -10 to 10 -6 to 6 -6 to 6 -11 to 11 -13 to 13 -23 to 23rangek -15 to 15 -21 to 21 -18 to 18 -14 to 14 -12 to 12 -7 to 7rangel -17 to 17 -18 to 18 -22 to 22 -14 to 14 -29 to 29 -26 to 26reflections collected 14048 13467 5880 11728 26763 24906observed reflections 2716 2269 2657 2138 3610 3153

total reflections 2777 2596 1684 2366 5236 4803R1[I> 2(I)] 0.0627 0.0416 0.0399 0.0447 0.0502 0.0647wR2(all) 0.1385 0.1013 0.0931 0.1141 0.1335 0.1492goodness-of-fit 1.336 1.082 0.924 1.074 1.023 1.060T(K) 298 298 298 298 298 298

compound 8 9 10 11 12 13

polymorph form I form II

empirical formula C14H15NO2S C12H9Cl2NO2S C13H12ClNO2S C13H12FNO2S C13H12FNO2S C14H14FNO2S C14H14ClNO2Sformula weight 261.33 302.16 281.75 265.30 265.30 279.32 295.77crystal system monoclinic orthorhombic monoclinic monoclinic monoclinic triclinic triclinicspace group P21/n Pbca P21/c P21/n P21/c P1 P1a(A ) 11.1556(8) 15.6409(15) 10.400(5) 8.716(6) 9.485(5) 8.518(6) 8.566(2)b(A ) 10.1380(7) 7.4161(7) 10.989(4) 9.834(7) 13.752(8) 9.045(7) 9.226(2)c(A ) 24.1724(17) 23.015(2) 11.639(5) 15.410(11) 9.822(6) 9.189(7) 9.307(3)R(deg) 90 90 90 90 90 87.020(9) 84.940(3)

(deg) 103.0230(10) 90 98.942(7) 100.176(12) 90.881(10) 77.933(11) 75.128(4)(deg) 90 90 90 90 90 76.759(11) 79.458(4)V(A 3) 2663.5(3) 2669.6(4) 1314.1(10) 1300.1(16) 1281.0(13) 674.0(9) 698.2(3)Dcalcd(g cm

-3) 1.303 1.504 1.424 1.355 1.376 1.376 1.407(mm-1) 0.236 0.634 0.442 0.254 0.258 0.249 0.419range 2.25-26.01 2.60-25.57 2.56-25.96 2.47-23.14 2.55-20.39 2.27-26.14 2.25-25.81Z 8 8 4 4 4 2 2rangeh -13 to 13 -18 to 18 -12 to 12 -10 to 9 -11 to 11 -10 to 10 -10 to 10rangek -12 to 12 -8 to 8 -13 to 13 -11 to 11 -16 to 16 -11 to 11 -11 to 11rangel -29 to 29 -27 to 27 -14 to 14 -19 to 18 -11 to 11 -11 to 11 -11 to 11reflections collected 25971 23822 12619 10579 12074 6858 7044observed reflections 4529 1706 2418 1676 1856 2282 2381total reflections 5251 2360 2561 2511 2259 2657 2660R1[I> 2(I)] 0.0471 0.0528 0.0671 0.0636 0.0455 0.0515 0.0395wR2(all) 0.1285 0.1371 0.1450 0.1503 0.1195 0.1395 0.1079goodness-of-fit 1.062 1.008 1.275 1.054 1.071 1.059 1.043T(K) 298 298 298 298 298 298 298

Figure 2. (a) Catemeric N-H 3 3 3 O hydrogen bond along [100] in form I of1. (b) Herringbone motif C-H 3 3 3 interaction connecting the

linear tapes.


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Table 3. Hydrogen Bonds in Crystal Structures(Neutron-Normalized Distance)

crystal form interaction H 3 3 3 A/A D 3 3 3 A/A

D-H 3 3 3 A/deg symmetry code

1_form I N1-H1 3 3 3 O1 2.21 3.188(3) 162.5 -1 x,y,zC5-H5 3 3 3 O2 2.48 3.236(5) 126.2

1/2 x,3/2 - y,

1/2 zC13-H13A 3 3 3 N1 2.41 2.906 (5) 106.4 intramolecular

1_form II N1-H1 3 3 3 O1 2.00 3.004(2) 170.2 2 - x, 1 - y, 1 - zC6-H6 3 3 3 O2 2.52 2.916(3) 127.3 intramolecularC14-H14A 3 3 3 O2 2.46 3.129(3) 118.6 1 x,y,z

2_form I N1-H1 3 3 3 O1 1.96 2.945(2) 165.8 1 - x, -y, -z

C10-H10 3 3 3 O2 2.63 3.489(2) 153.7 1 - x,1

/2 y,1

/2 - zC15-H15 3 3 3 O2 2.69 3.466(2) 138.3 1 - x,

1/2 y,1/2 - z

2_form II N1-H1 3 3 3 O1 1.98 2.963(2) 161.9 -x, 1 - y, 1 - zC7-H7B 3 3 3 O2 2.32 3.349(3) 157.7 -

1/2 x,1/2 - y,

1/2 zC11-H11 3 3 3 O2 2.68 3.524(3) 150.8 1 - x, -y, -z

3_form I N1-H1 3 3 3 O1 1.99 2.963(2) 161.9 -x, 1 - y, -zC7-H7B 3 3 3 O2 2.32 3.349(3) 157.7 -

1/2 x,1/2 - y,

1/2 z

3_form II N1-H1 3 3 3 O2 1.95 2.955(5) 173.9 1 x,y,zC2-H2 3 3 3 O1 2.52 2.913(6) 100.4 intramolecularC6-H6 3 3 3 Cl1 2.60 3.682(5) 177.3 -1 x,y,z

4 N1-H1 3 3 3 O2 1.99 2.975(4) 165.2 2 - x, 2 - y, 1 - zC4-H4 3 3 3 O1 2.44 3.401(4) 147.5 -1 x,y,zC6-H6 3 3 3 O1 2.49 2.885(4) 100.1 intramolecularC13-H13A 3 3 3 O1 2.54 3.128(6) 113.3 intramolecular

5 N1-H1 3 3 3 O1 2.02 2.968(4) 155.5 2 - x, 1 - y, 1 - zC2-H2 3 3 3 O2 2.47 2.873(4) 100.7 intramolecular

C4-H4 3 3 3 O2 2.42 3.353(5) 144.1 -1 x,y,z6_form I N1-H1 3 3 3 O2 2.05 3.026(3) 162.5 1 x,y,z

C5-H5 3 3 3 O1 2.27 3.253(4) 148.9 -1/2 x,

1/2 - y, -1/2 z

C6-H6 3 3 3 Cl2 2.62 3.682(3) 167.6 -1 x,y,z

6_form II N1-H1 3 3 3 O1 2.04 3.039(6) 169.7 -1 x,y,zC6-H6 3 3 3 Cl1 2.61 3.693(8) 174.8 1 x,y,zC9-H9 3 3 3 O2 2.34 3.305(8) 174.2 -

1/2 x,1/2 - y, -

1/2 z

6_form III N1-H1 3 3 3 Cl2 2.81 3.022(2) 100 intramolecularN1-H1 3 3 3 O1 2.22 2.914(3) 158 1 - x, 1 - y,zC2-H2 3 3 3 O2 2.56 2.920(4) 103.2 intramolecular

7_form I N1-H1 3 3 3 O4 1.92 2.924(4) 177.3 x, 1 y, -1 zN2-H2A 3 3 3 O2 1.91 2.921(4) 176.6 x, 1 y,zC12-H12 3 3 3 O1 2.41 3.476(5) 166.9 x, 1 y,zC19-H19 3 3 3 O3 2.56 3.123(3) 111.57 intramolecular

7_form II N1-H1 3 3 3 O1 2.12 3.091(4) 159.8 1/2 - x, -

1/2 y,1/2 - z

N2-H2A 3 3 3 O2 1.97 2.980(3) 178.9 1/2 - x,

1/2 y,1/2 - z

C2-

H2 3 3 3 O1 2.45 3.405(4) 145.8

1

/2-

x,-

1

/2

y,

1

/2-

zC6-H6 3 3 3 O1 2.45 2.868(3) 101.4 intramolecularC12-H12 3 3 3 O1 2.37 3.059(4) 119.7 intramolecularC19-H19 3 3 3 O3 2.44 2.869(4) 101.64 intramolecularC21-H21 3 3 3 O3 2.44 3.086(4) 117.0 intramolecularC22-H22 3 3 3 O3 2.39 3.450(4) 166.9 1 - x, -y, -z

8 N1-H1 3 3 3 O4 1.98 2.980(2) 170.0 3/2 - x,

1/2 y,1/2 - z

N2-H2A 3 3 3 O3 2.07 3.040(2) 160.9 3/2 - x, -

1/2 y,1/2 - z

C6-H6 3 3 3 O2 2.45 2.873(3) 101.4 intramolecularC12-H12 3 3 3 O2 2.38 3.442(3) 167.4 2 - x, 1 - y, -zC13-H13 3 3 3 O2 2.43 3.087(3) 117.7 intramolecularC16-H16 3 3 3 O3 2.46 3.416(3) 147.1

3/2 - x, -1/2 y,

1/2 - zC20-H20 3 3 3 O3 2.46 2.870(3) 100.9 intramolecularC21-H21C 3 3 3 O1 2.27 3.304(4) 158.7 x, -1 y,zC23-H23 3 3 3 O3 2.36 3.050(3) 119.6 intramolecular

9 N1-H1 3 3 3 O2 2.08 2.996(3) 149.2 3/2 - x, -1/2 y,z

C6-H6 3 3 3 O2 2.49 2.891(4) 100.3 intramolecular

C9-H9 3 3 3 O1 2.48 3.286(4) 130.2 x, -1 y,zC11-H11 3 3 3 Cl1 2.66 3.681(3) 156.2

1/2 - x, -1/2 y,

1/2 - zC12-H12 3 3 3 O1 247 3.004(4) 108.7 intramolecular

10 N1-H1 3 3 3 O1 1.98 2.972(4) 166.8 2 - x, 2 - y, 1 - zC12-H12 3 3 3 O2 2.39 3.063(4) 118.6 intramolecular

11_form I N1-H1 3 3 3 O1 1.97 2.980(4) 173.9 2 - x, 1 - y, 1 - zC3-H3 3 3 3 O2 2.44 3.526(4) 176.7 -

1/2 x,1/2 - y, -

1/2 zC6-H6 3 3 3 O2 2.49 2.903(4) 101.0 intramolecularC9-H9 3 3 3 O2 2.39 3.090(5) 121.0 intramolecular

11_form II N1-H1 3 3 3 O2 1.91 2.912(3) 173.6 -x, 1 - y, -zC9-H9 3 3 3 O1 2.30 3.036(3) 123.1 intramolecularC12-H12 3 3 3 O2 2.44 3.491(4) 162.0 -x, -

1/2 y,1/2 - z

12 N1-H1 3 3 3 O1 1.90 2.906(4) 171.1 1 - x, 1 - y, -zC9-H9 3 3 3 O2 2.33 3.034(4) 121.3 intramolecular

13 N1-H1 3 3 3 O2 1.90 2.910(2) 175.4 2 - x, -y, -zC13-H13 3 3 3 O1 2.32 3.032(3) 121.3 intramolecular


6


synthon polymorphs at the secondary level; the N-H 3 3 3 Ohydrogen bond is the same, but the C-H 3 3 3 O interaction isdifferent.

Molecules12and13 were prepared to compare the effectof halogen exchange on crystal packing. These Cl/F analo-gues have a similar molecular arrangement in the crystallattice mediated via a sulfonamide N-H 3 3 3 O dimer,3 3 3stacking, and C-H 3 3 3 F/C-H 3 3 3 Cl interaction (Figure 13).

There are minor conformational differences (Figure 14)among the sulfonamide polymorphs (selected torsion anglesare listed in Table 4). The main torsion angle which definesthe molecular shape (Scheme 1) varies from 55 to 85 in 1-13

while the variation within a polymorph set is smaller (2-5).Lattice energies for the polymorphic systems calculated inCerius2 are within 0.5-1.0 kcal mol-1 (except for 3, Table 5),and so it is difficult to identify the stable polymorph fromenergy values.

Role of Solvent in Polymorph Crystallization. Ostwaldsrule of stages13a states the least stable polymorph appearsfirst followed by more stable states and finally the thermo-dynamic modification. Solvent-mediated transformationscan proceed in three steps: (1) dissolution of the metastableform; (2) nucleation of the stable form; (3) crystal growth ofthe thermodynamic phase. Generally, slow crystallizationfrom dilute solution produces the stable form, whereas rapidcrystallization from concentrated solution generates the

metastable form(s). The solution concentration will be dif-ferent depending on the polarity of the solvent, which plays arole in supramolecular aggregation via strong and/or weakhydrogen bonds. In less polar or nonpolar solvents, intra-molecular hydrogen bonds areexpected to be strong, and theconverse is true in polar solvents.13b

Several common laboratory solvents were used to screenfor the crystallization of different polymorphic phases(Table 1). All six sulfonamide molecules that are poly-morphic afforded the stable polymorph from a more polarsolvent; for example, stable form I of molecule1was crystal-lized from MeOH but metastable form II crystallized from

p-xylene. The packing fraction (Table 6), density, and phasetransition of form II suggest that form I is the stablemodification. Similarly, polymorphs I, II, and III of mole-cule6 were crystallized fromp-xylene, MeOH, and hexane,

respectively. Their stability order is form II (most stable),form I (intermediate), and form III (least stable), as con-firmed by packing fraction, density, and heat of fusion (seeTable 9 discussed later). So molecule6also follows the sametrend that the most stable form was crystallized from a polarsolvent and the least stable from a nonpolar solvent.

Another trend regarding solvent polarity and crystalstructure is that, in general, polar or hydrogen bonding sol-vents afforded a polymorph with the catemer chain whereasnonpolar or less polar solvents gave a structure of dimermotif (dimer/catemer motifs for polymorphic structures arelisted in Table 1). There is a similar precedent in at least onesystem: in situ IR spectroscopy showed the presence oftetrolic acid dimers in CHCl3solution and O-H 3 3 3 O cate-

mer in EtOH.4c

IR and Raman Spectroscopy. FT-IR and FT-Ramanspectroscopy14 are popular analytical methods for studyingpolymorphism in pharmaceuticals. In the spectra of solid-state samples, asymmetric and symmetric N-H stretchingvibrations are observed in the range 3390-3323 cm-1 and3279-3229 cm-1, respectively, due to intermolecular hydro-gen bonding; however, these absorptions appear at higherfrequencies for dilute solution samples (3520-3400 cm-1) inthe absence of hydrogen bonding. Primary sulfonamidesshow strong N-H stretching bands at 3390-3330 cm-1,and secondary sulfonamides absorb near 3265 cm-1. Asym-metric and symmetric SdO stretching vibrations appear asstrong absorption peaks in the range 1344-1317 cm-1 and

Figure 3. (a) N-H 3 3 3 O hydrogen bond dimer in form II of 1.(b) The dimeric units are connected through a C-H 3 3 3 O hydrogenbond (2.46 A , 118.6) along [100].

Figure 4. (a) Bifurcated C-H 3 3 3 O motif connects sulfonamidedimer units along [001] in form I of 2. (b) Sulfonamide dimersextend through the C-H 3 3 3 O dimer motif in form II.

Table 4. C-S-N-C Torsion Angle(see Scheme 1)in Molecules 1-13

crystal form torsion angle

molecule1_form I 78.15molecule1_form II 78.21molecule2_form I 75.33molecule2_form II 71.26molecule3_form I 77.19molecule3_form II 83.86molecule4 68.65molecule5 70.81molecule6_form I 82.49molecule6_form II 83.56molecule6_form III 84.83molecule7_form I 66.92, 62.09molecule7_form II 64.42, 54.45molecule8 54.88, 65.35molecule9 69.40molecule10 56.05molecule11_form I 52.21molecule11_form II 57.58molecule12 61.26molecule13 59.27


7


1187-

1147 cm

-1

, respectively. Sulfonamides exhibit S-

Nstretching vibrations at 924-906 cm-1. Solid-state IR andRaman spectra (Figures 15 and 16) show differences inhydrogen bonding. For example, molecules 1 and 6 haveN-H 3 3 3 O hydrogen bonds of different strengths (due todimer/catemer synthons) in their polymorphs. The N-Hstretch is at higher frequency for form I (3304.8 cm-1)compared to form II (3255.7 cm-1), indicating a weakerN-H 3 3 3 OdS hydrogen bond in form I of1, which is con-sistent with the hydrogen bond distance (2.21 vs 2.00 A ,Table 3). Similarly, the Raman spectra of the two poly-morphs of molecule1 show higher stretching frequency fortheN-H group in form I, which suggests stronger N-H andconsequently weaker N-H 3 3 3 O hydrogen bond. Spectral

parameters for N-H stretch, N-H bend, and Sd

O sym-metric/asymmetric stretch are summarized in Table 7(IRstretching)and Table 8 (Raman shift). Such a correlationin red/blue shift of IR frequency and short/long hydrogenbond distance is absent for polymorphs of6.

Phase Transitions. Polymorphs exist only in the solid-state. Melting or dissolution destroys any distinctions be-tween them. The presence of solvent or moisture can speedup interconversion between polymorphs. Compounds1and11 show phase transition15 by differential scanning calori-metry (differential scanning calorimetry (DSC) plots areshown in Figure 17). Form II converts to form I as thetemperature is raised, and form I is the thermodynamicallystable polymorph. Form II of1 shows a small exotherm at

97.5 C and then melts at 153.1 C. The melting of form I issharp (Tonset 151.5 C, Tpeak 152.0 C). From the crystalstructure, form II has the N-H 3 3 3 O dimer and form I issustained by the catemer chain. This solid to solid transitionwas visualized on a hot stage microscope. A phase transitionof the plate shapedcrystal of form II occurs at97-98 C, andit then melts at 152-154 C, matching with the melting pointof form I. A small difference between theTonset of theoriginalsolid and that obtained after phase transformation happensdue to different contact surfaces. The transformation of formII to I was confirmed by X-ray diffraction (unit cell check).A similar behavior is shown by form II of compound 11,wherein the first endotherm appears at 80C and the meltingendotherm at 111C in DSC, which corresponds to thenewlytransformed form I. These events were visualized on HSM(Figure 18) and confirmed by X-ray diffraction. Compounds2,3,6, and 7 do not show any phase transition up to 20-30C beyond their melting temperature. The monotropic andenantiotropic behavior of polymorphs was established bycalculating the enthalpy of melting from DSC plots (Table 9)and using Burger and Rambergers16a,b heat-of-fusion rule.If the higher melting polymorph has the higher heat of

fusion, then it is a monotropic system (no phase transitionin the given temperature range); if the higher melting poly-morph has a lower heat of fusion, then it is an enantiotropicsystem (phase transition before melting). Another importantguide is the heat-of-transition rule (Grunenberg et al.16c andBurger-Ramberger16a,b): If an endothermic phase change isobserved at a particular temperature, then the two poly-morphs are enantiotropically related; if an exothermic phasetransition is observed, the two polymorphs are monotropi-cally related or the transition point is higher and they areenantiotropically related. These well-known rules to under-stand the thermodynamics of polymorphs are summarizedelsewhere.16d

CSD Analysis of Dimer/Catemer Synthons. The sulfona-

mide group is capable of making dimer andcatemer motifsofN-H 3 3 3 O hydrogen bonds. Yet, sulfonamide polymorphshave not been studied or classified according to dimer/catemersynthons. We surveyed the Cambridge Structural Database17

(version 5.31, ConQuest 1.12, May 2010) to tabulate thefrequency of dimer and catemer synthons (Figure 1) inprimary and secondary sulfonamides (Table 10). Out of1054 secondary sulfonamides, 204 contain the dimer motifand 196 have the catemer chain. Similarly, the numbers for186 primary sulfonamides are 32 and 36. The near equalprobability of dimer and catemer motifs in secondary sulfo-namides of19% came as a surprise because the situation isvery different in carboxamides and carboxylic acids. Thedimer motif is overwhelmingly favored, and the catemer is

Figure 5. (a) C-H 3 3 3 O and Cl 3 3 3 Cl type-II interactions connect sulfonamide dimers along [010] in form I of molecule3. (b) CatemericN-H 3 3 3 O H bond along [100] and C-H 3 3 3 O interactions in form II.

Figure 6. Sulfonamide dimer extends viaC-H 3 3 3 O dimer instruc-tures4(a) and5(b).


8/


very rare in acids and amides.4c,d,11a We sought a reason for theequal probability of dimer and catemer motifsin sulfonamides.1i

In carboxylic acids and amides the NH or OH hydrogencan reside syn or anti to the CdO oxygen, and of these two

orientations the syn conformation is energetically preferred.Thus, the dimer is the default motif. The fact that the dimer

Figure 7. (a and b) N-H 3 3 3 O chain and C-H 3 3 3 O cross-link in polymorphs I and II of molecule6. (c) N-H 3 3 3 O dimer in polymorph III.

Figure 8. (a) N-H 3 3 3 O helix viathe synO of symmetry-independent molecules along [010] in form I of molecule7. (b)N-H 3 3 3 O catemer viathe anti O along [010] with the second molecule making N-H 3 3 3 O and Cl 3 3 3 O interactions in form II.

Figure 9. N-H 3 3 3 O catemer viathe anti O of twocrystallographicmolecules in structure8.

Figure 10. Catemer N-H 3 3 3 O chain using the syn O along [010]with only one crystallographic molecule of9. Thisseemsto bea raresituation in sulfonamide structures.


9


motif occurs across the inversion center, the most preferredcrystallography symmetry element in crystal structures, is anadditional favorable factor. The situation is different insulfonamides because there are two O atoms here. Hence,

the question is: which of these is involved in dimer/catemerhydrogen bonding? The dimer motif can be made only withsyn O (to NH),but the catemer can formvia either syn orantiO. CSD statistics show that there is a >2:1 preference foranti O compared to syn O in the catemer N-H 3 3 3 O chain:137/59 for secondary sulfonamides and 25/11 for primarysulfonamides. In the polymorphic systems studied by us,the anti O catemer is present in molecule 1_formI, mole-cule 3_formII, molecule 6_formI, molecule 6_formII, and

Figure 14. Overlay of molecular conformations: form-I = red; form II = blue; form III = magenta for1,2, 3,6, and11. For7, form I = red,blue and form II = green, brown (two symmetry-independent molecules). There is not much variation in these molecular conformations andorientation of aromatic rings in the crystal structures.

Figure 12. (a) Dimer sulfonamide units are connected through aromatic C-H 3 3 3 O interaction in form I of11. (b) Sulfonamide dimers areconnected by the methyl C-H 3 3 3 O in form II.

Figure 11. Sulfonamidedimers are connectedvia3 3 3stacking ofCl-Ph rings (3.49 A ) in 10.

Figure 13. Sulfonamide dimer along with-stacking in structures12(a, left) and13(b, right).

Table 5. Lattice Energy(kcal mol-1)Calculated in Cerius2

(Compass Force Field)

molecule form I form II form III

1 -30.031 -30.0402 -30.973 -30.5833 -30.696 -33.2646 -30.534 -31.626 -30.4037 -30.745 -31.11911 -29.243 -29.186


1


Table 6. Density, Packing Fraction, and Melting Onset of Sulfonamide Polymorphs

sulfonamide polymorphs density (g cm-3), packing fraction (%), and melting onset (C)

form I form II form III

molecule 1 1.318, 67.3, 151.5 1.286, 65.4, 97.5a

molecule 2 1.259, 65.1, 120.8 1.243, 64.5, 124.3molecule 3 1.496, 66.8, 168.9 1.507, 67.2, 168.5molecule 6 1.517, 66.0, 155.3 1.548, 67.2, 156.5 1.513, 66.0, 155.87molecule 7 1.371, 64.3, 93.6 1.415, 66.5, 91.6molecule 11 1.355, 64.7, 111.86 1.376, 65.7, 80.27a

a Phase transition temperature.

Figure 15. IR spectra of polymorphs of molecules1(a) and6 (b).


1


Figure 16. Raman spectra of polymorphs of molecules1(a) and6 (b).

Table 7. IR Resonances(cm-1)of Sulfonamide Polymorphs

molecule N-H stretch N-H bend SdO asym/sym stretch

1form I 3304.8 1472.0 1327.6/1161.51form II 3255.7 1473.0 1329.6/1162.02form I 3261.1 1473.8 1331.2/1158.62form II 3261.2 1473.8 1331.0/1158.13form I 3249.1 1478.5 1340.8/1157.43form II 3251.5 1477.8 1339.6/1157.56form I 3271.1 1445.6 1336.8/1168.56form II 3259.4 1447.9 1341.0/1168.76form III 3240.8 1447.0 1343.0/1166.17form I 3215.5 1463.7 1334.7/1157.77form II 3215.7 1463.5 1341.9/1157.711form I 3243.3 1498.0 1333.2/1163.811form II 3245.2 1497.7 1328.8/1162.9

Table 8. Raman Resonances(cm-1)of Sulfonamide Polymorphs

molecule N-H stretch N-H bend SdO asym/sym stretch

1form I 3308.0 1584.7 1325.5/1160.81form II 3249.4 1587.0 1325.3/1150.72form I 3257.4 1593.4 1321.5/1145.42form II 3252.2 1597.4 1326.4/1145.13form I 3249.0 1575.4 1333.2/1165.23form II 3249.8 1575.2 1334.0/1154.56form I 3271.9 1583.3 1336.7/1164.66form II 3278.9 1580.5 1336.7/1163.36form III 3269.7 1582.1 1333.4/1162.67form I 3220.3 1580.8 1336.5/1157.17form II 3214.6 1581.5 1336.3/1157.211form I 3239.8 1597.5 1332.4/1154.411form II 3237.9 1597.4 1331.8/1154.2


1


molecule 7_formII, whereas syn O catemer is in molecule7_formI only. N-H 3 3 3 O hydrogen bond synthon andgraph

set notation in sulfonamides1-13is summarized in Table 11.Surprisingly, the presence of sulfonamide dimer in one

Table 9. Thermal Parameters from DSC for Sulfonamide Polymorphs

sulfonamide Tm(C), Hfus(kJ mol-1) stable polymorph relationship and rule applied


molecule1 151.5, -38.32 97.5, 1.99 form I monotropic, heat-of-transition153.1,-30.11

molecule2 120.8, -15.91 124.3, -25.79 form II monotropic, heat-of-fusionmolecule3 168.2, -115.37 167.3, -107.09 form I monotropic, heat-of-fusionmolecule6 155.3, -88.27 156.5, -99.33 155.9, -79.99 form II monotropic, heat-of-fusionmolecule7 93.6, -26.44 91.6, -18.16 form I monotropic, heat-of-fusion

molecule11 111.9, -18.61 80.3, -1.14 form I enantiotropic, heat-of-atransition111.2,-18.83

Figure 17. Differential scanning calorimetry of sulfonamides1 and11. Remaining thermograms are shown in Supporting Information.


1


polymorph and catemer in another polymorph is quite arare situation. CSD Refcodes FIBKUW01/FIBKUW0218a

(secondary sulfonamide) and SULAMD07/SULAMD0818b

(primary sulfonamide) are the only sulfonamide pairs where

the basic difference in structures is the SO2NH dimer vscatemer motif. We add three structure pairs of dimer andcatemer motif in polymorphs: molecules 1, 3, and 6. Thereason for the near equal probability of dimer and catemerN-H 3 3 3 O motifs in sulfonamides is the ease with which thecatemer chain can form using the anti O of the SO2NHgroup, a conformation that is predisposed to extend thehydrogen bond chain. There are no tangible differencesbetween the conformations of molecules (Figure 14) in

crystal structures containing dimer or catemer synthon.

Conclusion

Hydrogen bonding of the sulfonamide group as N-H 3 3 3 Odimer and catemer synthons is systematically studied inpolymorphic crystal structures. The relatively rare occurrenceof the dimer motif in one polymorph and the catemer inanother structure is shown to occur in three systems amongwith the 13 sulfonamides studied. Thefrequency of dimer andcatemer synthons is about the same for the sulfonamidegroup. The greater frequency for the catemer motif in sulfo-namides, compared to carboxamides and carboxylic acids, isattributed to the anti O participating in the infinitechain motif

twice as often as syn O. The crystallization solvent is impor-tant to obtain a particular polymorph, with polar solventsgiving the stable polymorph while nonpolar solvents affordeda metastable state.

Experimental Section

The phenyl benzenesulfonamides listed in Scheme 1 were synthe-sized by the condensation of the appropriate aniline with a substi-tuted sulfonyl chloride (1:1 molar ratio) in the presence of pyridinebase. All starting materials werepurchased fromSigma-Aldrich and/or Lancaster. Molecules1-13 were purifiedand crystallizedusingthe

Figure 18. Hot Stage microscopesnapshots of compounds1 and 11to study phase transitions.

Table 10. CSD Statistics on Sulfonamides

no. of secondary sulfonamides after removing all duplicates 1054no. of primary sulfonamides after removing all duplicates 186no. of secondary sulfonamides that are polymorphic 17 (Refcodes list is given in Supporting Information)no. of primary sulfonamides that are polymorphic 5 (Refcodes list is given in Supporting Information)primary sulfonamide having dimer/catemer synthon in polymorphs 1 (SULAMD02 and SULAMD07)secondary sulfonamide polymorphs containing dimer/catemer synthon 1 (FIBKUW01 and FIBKUW02)no. of secondary sulfonamides containing dimer motif 204 (19.3%)no. of secondary sulfonamides containing catemer motif 196 (18.6%)no. of secondary sulfonamide catemer motifs with anti O 137 (Refcodes list is given in Supporting Information)no. of secondary sulfonamide catemer motifs with syn O 59 (Refcodes list is given in Supporting Information)no. of primary sulfonamides containing dimer motif 32 (Refcodes list is given in Supporting Information)no. of primary sulfonamides containing catemer motif 36 (Refcodes list is given in Supporting Information)no. of primary sulfonamide catemer motifs with anti O 25 (Refcodes list is given in Supporting Information)no. of primary sulfonamide catemer motifs with syn O 11 (Refcodes list is given in Supporting Information)

Table 11. Summary of N-H 3 3 3 O Hydrogen Bond Synthon and Graph Set Notation in Sulfonamides 1-13

compound crystal polymorph, synthon, graph set classification


1 catemer, anti O C(4) dimer, syn O R22(8) synthon polymorphs, primary

2 dimer, syn O R22(8) dimer, syn O R2

2(8) synthon polymorphs, secondary3 dimer, syn O R2

2(8) catemer, anti O C(4) synthon polymorphs, primary4 dimer, syn O R2

2(8) no polymorph5 dimer, syn O R2

2(8) no polymorph6 catemer, anti O C(4) catemer, anti O C(4) dimer, syn O R2

2(8) synthon polymorphs, primary7 catemer, syn O C(4) catemer, anti O C(4) synthon polymorphs, secondary8 catemer, anti O C(4) no polymorph9 catemer, syn O C(4) no polymorph10 dimer, syn O R2

2(8) no polymorph11 dimer, syn O R2

2(8) dimer, syn O R22(8) synthon polymorphs, secondary

12 dimer, syn O R22(8) no polymorph

13 dimer, syn O R22(8) no polymorph


1


solvents listed in Table 1. All products were characterized by1H NMR ( ppm, J Hz) and FT-IR spectroscopy and finally bysingle crystal X-ray diffraction. The N-H asymmetric and sym-metric stretching vibrations absorb at 3390-3323 cm-1 and 3279-3229 cm-1, and the asymmetric and symmetric SO2 stretches at1344-1317 cm-1 and 1187-1147 cm-1. Sulfonamides exhibit S-Nstretching absorption at 924-906 cm-1. All polymorphic structureswere confirmed and differentiated by single crystal and powderXRD, FT-IR (KBr and ATR modes), FT-Raman, and DSC.

General Synthesis Procedure.Phenyl benzenesulfonamides were

prepared by mixing equivalent amounts of aniline (1 mmol) andbenzensulfonyl chloride (1 mmol) in 20 mL of freshly distilledacetone under inert atmosphere. Pyridine (2 mL) was added drop-wise and the reaction mixture was refluxed at 60 C for 2-3 h.Finally the product was washed with water and the colorless pro-duct was filtered. The product was purified by crystallization fromacetone.

Molecule1: Yield 78%. Mp 151-153C. IR (KBr, cm-1) 3306,2928, 1586, 1471, 1451, 1393, 1327, 1194, 1161, 1090, 899, 825, 777,762, 742, 719, 688. 1H NMR (CDCl3) 7.58 (2H, d, J= 8), 7.44(1H, t,J= 8), 7.32 (2H, t, J= 8), 6.94 (1H, t, J= 8), 6.86 (2H, d,J= 8), 5.94 (1H, s), 1.89 (6H, s).

Molecule2: Yield 76%. Mp 127-129C. IR (KBr, cm-1) 3262,3059, 2926, 1474, 1398, 1381, 1333, 1157, 1097, 910, 829, 791. 1HNMR (CDCl3) 7.51 (1H, s), 7.50 (1H, d, J= 8), 7.38-7.32 (2H,m), 7.08(1H, t, J= 8), 6.99(2H,d, J= 8), 5.88(1H,s), 2.35(3H,s),2.03 (6H, s).

Molecule3: Yield 65%. Mp 167-168C. IR (KBr, cm-1) 3252,2928, 1586, 1468, 1450, 1408, 1392, 1327, 1273, 1161, 1140, 1090,897, 866, 826, 777, 761, 742, 717, 688.

1H NMR (CDCl3)7.65 (1H, s), 7.62 (1H, d, J= 8), 7.40-7.32(4H, m), 7.16 (1H, t, J= 8), 6.32 (1H, s), 2.40 (3H, s).

Molecule4: Yield 75%. Mp 140-142C. IR (KBr, cm-1) 3270,3084, 2917, 1460, 1373, 1331, 1161, 1080, 907, 837, 789, 772, 671.1H NMR (CDCl3) 7.67 (1H, s), 7.52 (1H, d, J= 8), 7.47 (1H, d,J= 8), 7.34 (1H, t, J= 8), 7.03 (1H, t, J= 8), 6.95 (2H, d, J= 8),6.00 (1H, s), 1.99 (6H, s).

Molecule5: Yield 56%. Mp 102-104C. IR (KBr, cm-1) 3260,2961, 1456, 1383, 1339, 1261, 1167, 1080, 907, 872, 793, 773, 671.1H NMR (CDCl3) 7.60 (1H, s), 7.48 (1H, d, J= 8), 7.46 (1H, d,J= 8), 7.30 (1H, t, J= 8), 7.16 (1H, d,J= 2), 7.09-7.03 (2H, m),

6.02 (1H, s), 2.48 (3H, s).Molecule6: Yield 39%. Mp 153-156C. IR (KBr, cm-1) 3259,3085, 1567, 3259, 1567, 1448, 1341, 1167, 1088, 779, 753. 1H NMR(CDCl3) 7.85 (2H, d, J= 8), 7.62(2H, t, J= 8), 7.52(2H, t, J=8),7.28 (2H, d,J= 8), 7.21 (1H, t,J= 8), 6.45 (1H, s).

Molecule7: Yield 70%. Mp 91-93 C. IR (KBr, cm-1) 3217,3040, 2917, 2861, 1464, 1397, 1337, 1298, 1159, 997, 914, 828, 795,673.1H NMR (CDCl3) 1.98 (6H, s), 6.00 (1H, s), 6.95 (2H, d,J=8), 7.02, 10.20 (1H, s), 8.31 (1H, s), 7.72 (1H, d,J= 6), 7.69 (1H, d,J= 6), 7.64 (1H, t,J= 6), 7.04 (2H, d,J= 8), 6.95 (2H, d,J= 8),2.19 (3H, s).

Molecule8: Yield 74%. Mp 98-100 C. IR (KBr, cm-1) 3270,2922, 2856, 1456, 1338, 1298, 1219, 1153, 914, 818, 687. 1H NMR(CDCl3) 7.44 (1H, s), 7.40 (2H, d,J= 8), 7.18-7.12 (2H, m), 6.89(2H, d,J= 8), 6.80 (2H, d,J= 8), 2.21 (3H, s), 2.14 (3H, s).

Molecule9: Yield 65%. Mp 92-94 C. IR (KBr, cm-1) 3283,

3088, 1489, 1447, 1410, 1389, 1335, 1294, 1219, 1163, 1125, 1107,1076, 1011, 941, 908, 883, 847, 785, 717, 675. 1H NMR (CDCl3)7.69 (1H, s), 7.50 (1H, d,J= 8), 7.45 (1H, d,J= 8), 7.32 (1H, t,J= 8), 7.17 (2H, d,J= 8), 6.93 (2H, d,J= 8), 6.40 (1H, s).

Molecule10: Yield 87%. Mp 82-84 C. IR (KBr, cm-1) 3256,2916, 2849, 1491, 1452, 1385, 1329, 1223, 1153, 1082, 1013, 910, 843,781, 698. 1H NMR (CDCl3) 7.59 (1H, s), 7.54 (1H, d, J= 7),7.36-7.31 (2H, m), 7.19 (2H, d, J= 8), 7.01 (2H, d,J= 8), 6.84(1H, s), 2.37 (3H, s).

Molecule11: Yield 80%. Mp 108-111C. IR (KBr, cm-1) 3250,2897, 1497, 1408, 1329, 1273, 1163, 1140, 1090, 917, 897, 818, 773,685.1H NMR (CDCl3) 7.66 (1H, s), 7.23-7.21 (2H, m), 7.14 (1H,t,J= 8), 6.77 (2H, d,J= 8), 6.73 (2H, d,J= 8), 2.36 (3H, s).

Molecule12: Yield 82%. Mp 156-158C. IR (KBr, cm-1) 3235,2924, 1609, 1495, 1458, 1389, 1329, 1287, 1260, 1227, 1161, 1088,1049, 931, 889, 812, 702, 683. 1H NMR (CDCl3) 9.17 (1H, s), 6.99

(2H, d,J= 8), 6.57 (2H, d,J= 8), 6.32 (2H, d, J= 8), 6.13 (1H, d,J= 8), 2.35 (3H, s), 1.98 (3H, s).

Molecule13: Yield 74%. Mp 141-144C. IR (KBr, cm-1) 3235,2928, 2868, 1597, 1510, 1474, 1406, 1333, 1271, 1167, 1116, 1090,966, 901, 810, 679. 1H NMR (CDCl3) 7.65 (2H, d, J= 8), 7.26(1H, s), 7.24 (1H, d,J= 8), 7.06 (2H, d,J= 8), 6.88 (1H, d,J= 4),6.71 (1H, s), 2.39 (3H, s), 2.28 (3H, s).

X-ray Crystallography. Reflections were collected on a BrukerSMART CCD diffractometer. Mo KR(= 0.71073 A ) radiationwas used to collect X-ray reflections on all crystals (1-13). Data

reduction was performed using Bruker SAINT software.19

Struc-tures were solved and refined using SHELX20 with anisotropicdisplacement parameters for non-H atoms. Hydrogen atoms on Oand N atoms were experimentally located in all crystal structures.All C-H atoms were fixed geometrically. A check of the final CIFfile with PLATON21 did not show any missed symmetry. All N-Hand O-H hydrogens were located in difference electron densitymaps. Packing diagrams were prepared in X-Seed.22 Crystallo-graphic .cif files (CCDC Nos. 781569-781588) are available atwww.ccdc.cam.ac.uk/data_request/cif or as part of the SupportingInformation.

X-ray Powder Diffraction. Powder XRD of all samples wasrecorded on a PANlytical 1830 (Philips Analytical) diffractometerusing Cu KR X-radiation ( = 1.54056 A ) at 40 kV and 30 mA.Diffraction patterns were collectedin the2 range 5-50 atthe scanrate 1min-1. Powder Cell 2.323 was used for Rietveld refinement.

Vibrational Spectroscopy. A Nicolet 6700 FT-IR spectrometerwith a NXR FT-Raman Module was used to record IR and Ramanspectra. IR spectra were recorded on samples dispersed in a KBrpellet. Raman spectra were recorded on samples contained instandard NMR tubes or on compressed solids placed on a gold-coated sample holder.

Thermal Analysis. DSC was recorded on Mettler Toledo DSC822e module. A sample of 4-6 mg was placed in a crimped butvented aluminum pan, and the temperature was increased from30 to 250 at 2C min-1. A stream of nitrogen flow at 150 mL min-1

purged the sample.

Acknowledgment. B.S. and P.S. thank CSIR and UGC forfellowships. We thank the DST for research funding (SR/S1/RFOC-01/2007 and SR/S1/OC-67/2006) and DST (IRPHA)

and UGC (PURSE and UPE grants) for providing instru-mentation and infrastructure facilities.

Supporting Information Available: PXRDpatterns, DSC,refcodes,and CIF files. This material is available free of charge via theInternet at http://pubs.acs.org.

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Polymorphism in Secondary Benzene Sulfonamides

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