Quantitative insights into energy contributions of intermolecular interactions in fluorine and trifluoromethyl substituted isomeric N-phenylacetamides and N-methylbenzamides

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Quantitative insights into energy contributions of

intermolecular interactions in fluorine and

trifluoromethyl substituted isomeric

Cite this: CrystEngComm , 2013, 15 ,

711

3

N-phenylacetamides and N-methylbenzamides3

Piyush Panini and Deepak Chopra*

The presence of the C–F bond in organic molecules, particularly in the context of generating different

…

intermolecular interactions of the type C–F F–C, C–H F and C–F p is of extreme significance in the

realm of structural chemistry. These interactions generate different packing motifs in the formation of the

crystal. It is of interest to evaluate the energetic contributions of such weak interactions to evaluate their

important role in crystal packing. In this respect, a library of twelve compounds containing a strong donor

and acceptor, along with the presence of a C–F bond in different electronic environments (fluorine atom

2

3

connected to C(sp ) and C(sp ) carbon atom) have been synthesized and characterized using single crystal

X-ray diffraction studies at low temperature. In addition, the non-fluorinated counterpart has also been

synthesized. These crystal structures have been analyzed to understand the contribution of weak

interactions involving organic fluorine in the crystal packing. Furthermore, the stabilizing–destabilizing

roles of such interactions in terms of favourable energetics have been quantified with inputs from

calculations performed using PIXEL. It is observed that most of the interactions involving fluorine are of a

dispersive character, and in some cases the interaction is also coulombic in origin. These results have been

compared with ab initio quantum-chemical calculations (DFT-D3/B-97D level) performed using

TURBOMOLE. In addition, the lattice energies of all the compounds have been evaluated, and the total

contribution partitioned into the corresponding coulombic, polarization, dispersion and exchange

contributions using the CLP module. The results correlate well with thermochemical data experimentally

determined for these compounds.

Received 29th October 2012,

Accepted 26th February 2013

DOI: 10.1039/c3ce40111a

www.rsc.org/crystengcomm

3

a platform for the molecules to associate with each other. In

Introduction

this regard, the role of strong intermolecular H-bonds of the

type N–H O, O–H O and O–H N is already well established

in addition to weak C–H p and p p interactions. The

In recent years, the determination of accurate crystal and

molecular structures has become a routine process. The

Cambridge Structural Database is a well-established store-

house of such determinations for compounds that are solids at

room temperature. In recent years, the focus has also shifted

towards the investigation of crystal structures of compounds

…

4

…

5

…

6

1

presence of halogens in organic molecules generates a variety

…

7a

…

7b

…

7c

of interactions of the type C–X X–C, C–X O, C–H X

…

8

and C–X p. The interactions in heavier halogens have been

well-investigated from a topological analysis of the electron

densities in crystalline solids. Of particular interest in this

2

that are liquids at room temperature. Most of the crystal-

9

lographic analysis that follows from structure determination

involves interpretation of the molecular geometry and a

working knowledge of a variety of intra- and intermolecular

interactions on pure geometrical considerations. The missing

link is to explore the energetics associated with these

interactions, particularly intermolecular ones, which provide

context are intermolecular interactions of organic fluorine,

which have been postulated to be weak H-bond acceptors,

primarily associated with high electronegativity and tightly

10

contracted lone pairs of electrons. In the last decade, there

have been innumerable crystallographic reports on structure

determinations in organic compounds containing organic

1

12

fluorine. A recent article brings out the significance of

hydrogen bonds with fluorine with detailed inputs from

studies performed in solution, gas phase and in the crystal

Department of Chemistry, Indian Institute of Science Education and Research

Bhopal, ITI (Gas Rahat) Building, Bhopal 462023, India.

E-mail: dchopra@iiserb.ac.in; Fax: +91 0755-4092-392

1

3

Electronic supplementary information (ESI) available. CCDC 907077–907090.

For ESI and crystallographic data in CIF or other electronic format see DOI:

0.1039/c3ce40111a

in fluorine containing compounds. A recent review, high-

14

15

16

light, book and a perspective brings out the versatility

1

This journal is ß The Royal Society of Chemistry 2013

CrystEngComm, 2013, 15, 3711–3733 | 3711

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associated with interactions involving organic fluorine. A

topological analysis of the electron density in fluorine

analogues. It is of interest to note that all the structure

determinations have been performed at low temperatures so

as to minimize the possibility of dynamic disorder, which is

prevalent in fluorine containing substrates.

…

containing solids reveal that C–H F interactions have weak

1

7

H-bonding characteristics. In a recent study, short and

…

directional C–H F intermolecular interactions in the absence

of strong H-bond donors have been observed in mono- and di-

1

8

fluorinated imines. The energetic stabilization of such weak

Experimental section

…

21

C–H F interactions are in the range of 1.0–5.0 kcal mol and

these contribute towards the stability of the crystal packing.

Similar calculations on fluorinated pyridines also bring out

Synthesis, characterization and crystal growth

The starting materials, namely aniline along with fluorine and

trifluoromethyl substituted anilines, and benzoyl chloride

along with fluorine and trifluoromethyl substituted benzoyl

chlorides (ortho, meta and para) were purchased from Sigma

Aldrich and were used without further purification. The other

starting materials, namely methylamine (33% solution in

ethanol), acetyl chloride and triethylamine were purchased

from Spectrochem Pvt. Ltd. India and were used directly from

the bottle. The solvent dichloromethane was dried using

calcium hydride and stored over molecular sieves. All the

solvents used for crystallization were of analytical grade only.

1

9

the subtle effects associated with such interactions. In order

to evaluate the importance of cooperativity in interactions in

…

crystalline solids, it was of interest to investigate weak C–H F

intermolecular interactions in the presence of strong hydrogen

bond donors and acceptors. Such detailed crystallographic

investigations have already been performed in mono- and di-

2

0

fluorinated benzanilides, homo and hetero halogen sub-

2

0b

stituted benzanilides,

and mono- and di-trifluoromethy-

2

0c

lated benzanilides. In all the above-mentioned systems, the

library of compounds synthesized have been so chosen so as to

investigate the nature of interactions in halogen containing

compounds containing a strong H-bond donor, namely N–H

and a strong acceptor, i.e. the CLO group. These systems

contain only one type of hydrogen atom, all being connected to

the aromatic ring. In our present study, the chemical nature of

the synthesized compounds is modified in comparison to the

previously investigated compounds. In addition to containing

a peptide bond (of significance in biomolecules and proteins),

the current library of synthesized molecules contain two types

of fluorine and hydrogen atoms in different electronic

environments. In one case, the fluorine atom is connected to

(A) Synthesis of N-phenylacetamide. The compound, aniline

or fluorinated/trifluoromethylated derivatives (1.1 equiv.) and

triethylamine (1.5 equiv.) were placed in a round bottomed

flask containing dry dichloromethane (12.0 ml). This was

closed with a septum to ensure a dry atmosphere, using a

nitrogen balloon. The reaction set-up was then put over an ice

bath and acetylchloride (1 equiv.) was added drop wise into the

reaction mixture with constant stirring. The reaction mixture

was then allowed to come to RT and the completion of the

reaction was monitored with TLC. At the end of the reaction,

the reaction mixture was quenched with 5% hydrochloric acid,

extracted with dichloromethane, dried using sodium sulphate

and finally purified by column chromatography using 10%

ethyl acetate in dichloromethane as eluent.

2

an sp carbon (a part of an aromatic ring) and in the other case

3

it is connected to the sp carbon (a part of the trifluoromethyl

group). The electron density on the fluorine atoms is more a

case of the latter due to lack of resonance effects with the

benzene nucleus. The hydrogen atoms are of different types,

one constituting the benzene nucleus and the other consisting

of a methyl group. This allows for an investigation into the

Scheme 1 describes all the molecules synthesized and the

method of nomenclature used in this study. Table S1, ESI,

3

lists the melting points (recorded with DSC and compared

with the relevant literature) and the final yields of the product

obtained after performing column chromatography.

3

geometrical and energetic features associated with weak C(sp /

2

…

3

2

sp )–H F–C(sp /sp ) intermolecular interactions, in addition

…

to the well-recognized N–H OLC and C–H OLC hydrogen

bonds. The presence of such functionalities also allows for the

…

possible existence of C–H p and p p interactions. We have

synthesized a library of 12 molecules, containing fluorine and

trifluoromethyl group, varied over the different positions of

the benzene nucleus with respect to PhNHCLOCH₃(aceta-

mides) and PhCLONHCH

3

(benzamides). In addition, the

unsubstituted compounds, namely acetamide and benzamide,

have also been synthesized. The crystal structure of the parent

2

1

22

compounds, acetamide

and benzamide,

are already

reported in the literature. These compounds have been found

to be the main building block in many biologically active

2

3

compounds. For example, paracetamol is a well known

example amongst these and is widely used as an analgesic and

2

4

antipyretic. This allows for a comparison of the packing

features of fluorinated compounds with non-fluorinated

Scheme 1

3

712 | CrystEngComm, 2013, 15, 3711–3733

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B) Synthesis of N-methylbenzamide. 2 equiv. of cold

Paper

(

‘Make HKLF5’ in WinGX. In the case of BZ-1, the inspection of

the reflection data by ‘Cell_Now’ program in APEX-II from

Bruker revealed the presence of a three twin component (the

contributions of the domain being 0.500, 0.0151, 0.485,

respectively). The data-reduction was performed with

TWINABS and the refinement was done with BASF scale

parameter against HKLF5 reflection file. After the final

refinement, in the case of BZ-1, the ratio of unique and

expected reflections was found to be 1.063. In case of BZ-5, the

refinement was done with HKLF4 file of the major twin

component (the ratio being 0.80 : 0.20), which was separated

by the program ‘Cell_Now’ in APEX-II from Bruker.

methylamine (33% solution in ethanol), was added drop wise

with constant stirring into the round bottomed flask placed

over an ice bath along with 1 equiv. of benzoyl chloride or its

fluorinated/trifluoromethylated derivative. The reaction mix-

ture was then stirred at RT for 3 h and the completion of the

reaction was monitored with TLC. After completion of the

reaction, the reaction mixture was poured into water followed

by extraction with diethyl ether and dried using sodium

sulphate. The crude product was then purified by column

chromatography using 10% ethyl acetate in dichloromethane

as eluent.

All the synthesized compounds were characterized by FTIR

1

13

Crystallographic modeling of disorder

[

Fig. S1(a)–(n), ESI

NMR [Fig. S3(a)–(n), ESI

S1, ESI ) were recorded and the DSC traces for all the solid

compounds are given in the ESI [Fig. S4(a)–(n)]. Powder X-ray

3

], H NMR [Fig. S2(a)–(n), ESI

3

] and

C

] spectroscopy. Melting points (Table

Amongst all the 14 compounds whose crystal structures have

been determined accurately using low temperature data, it is

observed that in AC-1 and BZ-1 (containing two molecules in

the asymmetric unit), wherein both the molecules contain a

fluorine atom at the ortho position, these were found to be

disordered at two orientations, the final occupancy ratio being

0.830(2) : 0.170(2) in the case of AC-1, and the corresponding

values being 0.920(2) : 0.080(2) and 0.921(2) : 0.079(2) for the

two independent molecules in the in the asymmetric unit in

the case of BZ-1. The disorder was analyzed using the PART

command in SHELXL97 and were refined for two independent

positions, namely A and B (‘A’ depicting the higher occu-

3

diffraction (PXRD) data were recorded for all the solid

compounds and then compared with the simulated PXRD

patterns generated from the crystal coordinates in Mercury 3.0

and the final plots were done in Origin 6.1 [Fig. S5(a)–(n),

3

ESI ].

Single crystals of all the purified solids were grown from

different solvents and solvent mixtures (Table 1) at low

temperature in a refrigerator. Morphologies ranging from

fibrous needles, to thin plates, to blocks to were obtained.

3

2

pancy). For the purpose of refinement, the carbon atom

positions for A and B in the benzene ring were fixed at same

position using the EXYZ command in SHELXL97. Thermal

parameters were also constrained to be equal for the atoms at

the same position using EADP command in SHELXL97. All the

hydrogen atoms were then positioned geometrically and

Data collection and structure solution and refinement

Single crystal X-ray diffraction data of these compounds

(Table 1) were collected on a Bruker AXS SMART APEX CCD

diffractometer with X-ray generator operating at 50 kV and 35

mA using graphite monochromated Mo Ka (l = 0.7107 Å)

radiation equipped with Oxford cryosystem 700Plus at 100(2)

K. Data reduction and integration were performed by SAINT

V7.685A12 (Bruker AXS, 2009) and absorption corrections and

scaling was done using SADABS V2008/112 (Bruker AXS). All

the crystal structures were solved by direct methods using SIR

2

refined using a riding model with Uiso(H) = 1.2Ueq[C(sp ), N]

3

and Uiso(H) = 1.5UeqC(sp ).

Theoretical calculations

DFT calculations at the B3LYP/6-31G** were performed using

2

5

33

92

and refined by the full matrix least squares method using

TURBOMOLE with crystallographic coordinates as a starting

2

6

27

SHELXL97 present in the program suite WinGX. ORTEP

diagrams of all the compounds were generated using

ORTEP32

set (only the major conformer were considered in the case of

AC-1 and BZ-1) to obtain the optimized geometry of an isolated

molecule. The selected torsion angles obtained from theore-

tical calculations were then compared with the experimentally

obtained values (Table 2). The lattice energies of all the

compounds were calculated by PIXELC module in CLP

2

8

and packing diagrams were generated using

2

9

Mercury software. Geometrical calculations were done using

3

0

31

PARST and PLATON. The non-hydrogen atoms are refined

anisotropically and the hydrogen atoms bonded to C and N

atoms were positioned geometrically and refined using a

riding model with distance restraints of N–H = 0.88 Å,

3

4

computer program package (version 10.2.2012), the total

energy being partitioned into their coulombic, polarization,

dispersion and repulsion contributions. These are listed in

Table 3. The molecular electron densities were calculated by

3

aromatic C–H = 0.95 Å, C(sp )–H = 0.98 and with Uiso(H) =

eq

3

1.2U (N,C). Table S2, ESI, lists all the geometrically relevant

3

5

intra and intermolecular interactions in this class of com-

pounds (considered as the sum of the van der Waals radii

Gaussian09 at the MP2/6-31G** level for the PIXEL energy

calculations. For crystal packing and intermolecular energy

analysis, the stabilizing molecular pairs have been selected in

the crystal related by symmetry operators from mlc output file,

which is generated after PIXEL energy calculation. The

symmetry operator and centroid–centroid distance along with

coulombic, polarization, dispersion, repulsion and total

interaction energies between the molecular pairs are listed

in Table 4. The PIXEL method has been preferred for the

quantification of intermolecular interactions, primarily

because of the following reasons. (1) It is computationally

3

+0.3 Å, angularity .110u). Table S3, ESI, lists all the relevant

non-hydrogen atom contacts in the solid state. Amongst all the

solved crystal structures, the compounds AC-5, BZ-1 and BZ-5

were found to be twinned as observed by the presence of high

K-value in the ‘‘shelxl.lst’’ file. In case of AC-5, the twin law (a

three component non-merohedral twin, the batch scale factors

for the minor components are 0.1892 0.0123) were generated

by ‘TwinRotMat’ tool in WinGx program suit and the

corresponding HKLF5 file were generated by the option tool

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Table 1 Crystallographic and refinement data

Data

AC-0

AC-1

AC-2

AC-3 (Form II) AC-4

NOF

AC-5

AC-6

Formula

C

8

H

9

NO

C

8

H

8

NOF

C

8

H

8

NOF

C

8

H

8

C

9

H

8

NOF

3

C

9

H

8

NOF

3

9 8 3

C H NOF

Formula weight

CCDC no.

Wavelength (Å)

Solvent system, temp

of crystal growth (uC)

Crystal system

Space group

a (Å)

135.16

907077

0.71073

Ether, 220

153.15

907078

0.71073

Ether, 220

153.15

907079

0.71073

DCM + hexane Ether, 220

(1 : 1), 5

153.15

907080

0.71073

203.16

907081

0.71073

203.16

907082

0.71073

203.16

907083

0.71073

Chloroform +

hexane (1 : 1), 5 (1 : 1), 5

Monoclinic

P2 /c

DCM + hexane DCM, 220

Orthorhombic Orthorhombic Orthorhombic Orthorhombic Monoclinic

Pbca

9.4237(4)

7.8685(4)

19.5593(10)

90

1450.3(1)

8

1.238

0.083

576

Orthorhombic

Pbca

9.6701(5)

9.2755(4)

19.8362(11)

90

1779.2(2)

8

1.517

Pbca

P2

1

/n

1

10.5091(2)

9.4298(2)

15.1828(5)

90

1504.6(1)

8

1.352

0.107

640

12.1758(5)

9.4952(5)

12.9071(7)

90

1492.2(1)

8

1.363

0.108

640

9.4117(4)

7.7523(3)

20.2204(7)

90

1475.3(1)

8

1.379

0.109

640

4.7762(1)

13.3736(3)

13.9528(3)

90

92.396(1)

90

890.46(3)

4

1.515

13.5119(6)

9.7785(4)

6.7775(3)

90

99.459(3)

90

883.31(7)

4

1.528

b (Å)

c (Å)

a (u)

b (u)

c (u)

Volume

Z

2

3

Density (g cm

m (mm

F(000)

)

2

1

)

0.142

416

0.143

416

0.142

832

h (min, max)

Treatment of hydrogens

2.08, 27.48

Fixed

2.68, 27.43

Fixed

3.15, 27.44

Fixed

3.55, 27.34

Fixed

211, 11; 29,

9; 226, 22

6555

2.11, 27.51

Fixed

26, 6; 215,

17; 218, 16

7713

1.53, 25.00

Fixed

216, 15; 211, 211, 11; 211,

11; 26, 8

1555

2.05, 24.99

Fixed

hmin, max, kmin, max, lmin, max 212, 11; 210, 213, 13; 212, 215, 15; 28,

8; 225, 24

12; 219, 14

6744

12; 212, 16

6603

10; 223, 12

7655

No. of ref.

7503

No. unique ref./obs. ref.

No. of parameters

1659/1400

92

1693/1515

111

1681/1317

102

1632, 1457

101

2039/1750

128

1555/1372

130

0.0394; 0.0457 0.0424, 0.0477

0.0945, 0.0992 0.1163, 0.1205

20.363, 0.485 20.242, 0.468

1566/1373

128

Robs, Rall

0.0390, 0.0457 0.0408, 0.0453 0.0381, 0.0532 0.0377, 0.0421 0.0356, 0.0421

0.1072, 0.1122 0.1103, 0.1144 0.0910, 0.0988 0.0940, 0.0968 0.0868, 0.0903

20.184, 0.190 20.256, 0.213 20.237, 0.252 20.248, 0.217 20.284, 0.349

wR (obs), wR (all)

2 2

Drmin, max (e Å

23

)

G. o. F

1.069

1.034

1.080

1.066

1.057

1.089

1.068

Data

BZ-0

BZ-1

BZ-2

BZ-3

BZ-4

BZ-5

BZ-6

Formula

Formula weight

CCDC no.

Wavelength (Å)

Solvent system, temp

C

8

H

9

NO

C

8

H

8

NOF

C

8

H

8

NOF

C

8

H

8

NOF

C

9

H

8

NOF

3

C

9

H

8

NOF

3

9 8 3

C H NOF

135.16

907084

0.71073

DCM, 220

153.15

907085

0.71073

Ether (from solvent DCM +

extraction), RT hexane

1 : 1), 5

153.15

907086

0.71073

153.15

203.16

907088

0.71073

DCM +

203.16

907089

0.71073

DCM +

203.16

907090

0.71073

907087

0.71073

DCM +

hexane

(1 : 1), 5

DCM + hexane

of crystal growth (uC)

hexane (1 : 1), 5 hexane (1 : 1), (1 : 1), 5

(

Crystal system

Space group

a (Å)

b (Å)

c (Å)

Orthorhombic Triclinic

Orthorhombic Orthorhombic Monoclinic

Monoclinic

P2 /c

12.8863(6)

10.0799(5)

6.9999(4)

90

103.892(3)

90

882.6(1)

4

Monoclinic

P2 /n

5.0567(3)

11.6521(5)

14.6968(7)

90

91.565(3)

90

865.6(1)

4

Pbca

P¯1

Pbca

P2

1

/c

1

9.509(5)

9.299(5)

16.435(9)

90

7.490(1)

9.776(1)

10.358(1)

88.856(6)

85.667(6)

75.912(7)

733.5(2)

4

9.7830(6)

9.5402(6)

15.4045(9)

90

10.9014(5)

9.9282(4)

13.3080(6)

90

11.3520(3)

8.9766(3)

8.9705(3)

90

a (u)

b (u)

90

98.020(2)

90

c (u)

Volume

Z

1453.3(1)

8

1437.7(2)

8

1.415

0.112

640

1440.3(1)

8

1.413

0.111

640

905.17(5)

4

1.491

0.139

416

2

3

Density (g cm

)

1.235

0.082

576

1.387

0.109

320

1.529

0.143

416

1.559

0.146

416

2

1

m (mm

F(000)

)

h (min, max)

Treatment of hydrogens

2.48, 25.13

Fixed

1.97, 25.00

Fixed

9.69, 26.73

Fixed

3.59, 27.45

Fixed

1.81, 29.44

Fixed

1.63, 25.00

Fixed

2.23, 27.13

Fixed

26, 4; 214,

14; 218, 18

6844

hmin, max, kmin, max, lmin, max 210, 11; 210, 28, 8; 211,

212, 12; 210, 212, 13; 211, 215, 15; 212, 0, 15; 211,

12; 219, 17

7433

11; 213, 19

11; 0, 12

2740

12; 216, 17

6468

11; 212, 12

17 386

0; 28, 8

1549

No. of ref.

5308

No. unique ref./obs. ref.

No. of parameters

1286, 873

93

0.0452, 0.0702 0.0501, 0.0544

0.1125, 0.1502 0.1562, 0.1600

20.213, 0.201 20.281, 0.438

2740/2409

212

1425/1200

101

1633/1395

101

2508/2136

128

1549/1412

128

1904/1543

128

Robs, Rall

0.0410, 0.0496 0.0359, 0.0433 0.0359, 0.0435 0.0481, 0.0525 0.0406, 0.0511

0.1248, 0.1474 0.0924, 0.0972 0.0901, 0.0943 0.1340, 0.1377 0.1042, 0.1105

20.205, 0.262 20.240, 0.229 20.230, 0.357

1.127 1.087 1.061

wR (obs), wR (all)

2 2

Drmin, max (e Å

23

)

20.296, 0.298 20.298, 0.302

1.135 1.103

G. o. F

1.109

1.128

3

4

less demanding. (2) The total interaction energy is parti-

tioned into the corresponding coulombic, polarization, dis-

persion, and repulsion contribution. This facilitates a better

understanding of the nature of intermolecular interactions

3

a,c,e,g

contributing towards the crystal packing.

The results

obtained from PIXEL calculation were found to be comparable

3

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21

Table 2 Selected torsion angles (u). Only major conformers were considered for

disordered molecules. Values in italics are obtained from theoretical B3LYP/6-

Table 3 Lattice energy calculations using CLP (in kcal mol

)

a

3

1G** calculation

Comp. Code

E_C_o_u_l

E_P_o_l

E_D_i_s_p

E_R_e_pE_T_o_t

1

2

3

4

AC-0

AC-1

AC-2

214.1 25.5 222.4 19.0 223.1

215.3 26.2 221.5 20.9 222.1

216.1 26.9 222.0 21.8 223.2

N-Phenylacetamide series

Compound Code

C7–N1–C1–C6

C1–N1–C7–C8

a

AC-3-Form I [SAZLEL] 211.5 24.6 219.0 16.5 218.6

AC-0

161.8(1)

176.0(1)

178.38

177.9(1)

178.99

174.9(1)

178.22

176.3(1)/178.5(1)

179.77

173.3(1)

179.16

178.3(2)

4b AC-3 Form II

215.2 26.3 222.6 20.5 223.6

214.6 25.8 222.7 19.7 223.4

213.6 25.9 223.7 21.1 222.2

214.3 25.6 221.7 18.1 223.5

215.6 27.0 224.2 23.9 222.9

210.5 24.4 222.1 16.9 220.1

215.3 26.6 224.0 22.5 223.4

214.1 26.2 223.6 21.1 222.8

215.0 25.8 221.8 19.3 223.2

213.7 26.2 223.6 21.2 222.2

214.1 25.0 223.8 18.7 224.2

1

71.11

145.8(1)

79.97

168.5(1)

79.64

161.7(1)/177.6(1)

79.77

128.4(1)

73.14

178.7(2)

79.90

172.0(2)

79.43

5

6

7

8

9

AC-4

AC-5

AC-6

BZ-0

BZ-1

AC-1

1

AC-2

1

AC-3 Form I/Form II

10 BZ-2

11 BZ-3

12 BZ-4

13 BZ-5

14 BZ-6

1

AC-4

AC-5

AC-6

1

179.94

179.8(2)

179.47

a

21

Sublimation energies reported in the literature are 23.9 kcal mol

21

and 24.1 kcal mol for N-phenylacetamide and N-methylbenzamide

respectively.

1

39

N-Methylbenzamide series

C2–C1–C7–N1

C8–N1–C7–C1

requirement for the calculation of basis set superposition

3

6b,37

BZ-0

BZ-1

BZ-2

BZ-3

BZ-4

BZ-5

BZ-6

167.1(2)

179.2(2)

176.06

175.65(9)/176.84(9)

177.35/177.37

178.1(1)

176.52

179.5(1)

177.26

179.0(1)

178.41

177.8(2)

176.71

178.5(1)

176.28

error.

For the sake of comparison, the energies obtained

1

58.00

157.26(10)/154.32(9)

62.48/170.60

170.8(1)

58.87

162.6(1)

60.24

105.3(1)

34.52

176.6(2)

59.10

146.6(1)

58.84

from PIXEL calculations with high level theoretical calcula-

tions, we have computed the BSSE corrected energies, using

MP2 and DFT-D2 methods of calculation for only two

molecules namely, AC-1 and BZ-5 (Table S5, ESI ). The

3

interaction energy of the molecular pairs (DE_d_i_m_e_r) were

a

1

calculated using the formula DEdimer = [Edimer 2 (2 6

Emonomer)]. The positions of hydrogen atoms were moved to

1

neutron values (1.08 Å for C–H and 1.00 Å for N–H) before the

calculation. It is to be noted that compound AC-3 exists in two

forms (hereafter referred to Form I and II). The crystal

1

3

8

structure of Form I is already reported in the literature.

a

Equivalent torsion angle of the second molecule in the asymmetric

unit.

Results and discussion

with high level MP2 and DFT-D quantum mechanical

calculations, the latter two being more computationally

3

Fig. S6(a)–(n), ESI, show the ORTEP for all the compounds.

3

b,c,34

demanding.

It is obvious that the molecular pair energy

1. N-Phenylacetamide (AC-0)

calculated in this way may or may not correspond to the energy

minima, as molecules in the solid state are subjected to

The parent compound N-phenylacetamide (AC-0) crystallizes

in a centrosymmetric orthorhombic space group Pbca with Z =

3

e

constant electric fields. Therefore for the sake of compar-

ison, the interaction energy of the selected isolated molecular

pairs at the crystal geometry have also been calculated using

TURBOMOLE at DFT-D3/B97-D level of calculation with the

aug-cc-pVTZ basis set. The final interaction energies are listed

along with the PIXEL energies in Table 4. The new DFT-D3

method is moderately computationally demanding and is

applicable to all the elements of the periodic table. The energy

estimates derived for non-covalent interactions and van der

Waals complexes are accurate. In particular, the estimation of

the dispersion energy has been found to be more accurate

8

[Fig. S5(a), ESI

3

]. The packing of molecules in the crystal

structure depicts the formation of a molecular chain via strong

N–H O hydrogen bonds along with weak C–H O hydrogen

bonds which indicates the existence of a stabilizing molecular

motif 1 (28.8 kcal mol ) in the crystal structure, having a

major coulombic contribution [Table 4, Fig. 1(a)]. The

molecular chains are then interlinked via weak C8–H8A O1

and C3–H3 p hydrogen bonds [Fig. 1(b)], these having a

contribution of 25.0 kcal mol in stabilization, the disper-

sion contribution imparting the maximum stabilization

…

21

…

21

[Table 4, motif 3, Fig. 1(a)]. The second most stabilized

3

6

than the values derived from old DFT-D or DFT-D2 methods.

molecular pair found in the crystal packing are the stacked

dimers [3.576 Å, Fig. 1(a)], these contributing 26.9 kcal mol

to the crystal stabilization, the dispersion contribution again

being a major component [Table 4, Fig. 1(c)]. The interaction

energy of the packing motif 1 in the crystal was found to be

The DFT-D3 method were also found to work better with B97-D

functional than previously employed DFT-D or DFT-D2

21

3

6a,37

methods.

The larger basis set (aug-cc-pVTZ) for DFT-D3/

B97-D level calculation is so chosen that it minimizes the

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2

Table 4 PIXEL interaction energies (I.E.) (kcal mol ) between molecular pairs related by a symmetry operation and the associated intermolecular interactions in the

1

crystal

Centroid–

centroid

distance (Å)

DFT-D3/B97-D

aug-cc-pVTZ

Serial No. Symmetry code

E

Coul

E

Pol

E

Disp

E

Rep

E

Tot

Involved interactions

AC-0 (Pbca)

1

…

x 2 1/2, 2y + 1/2, 2z + 1

5.922

29.3

23.5 25.5 9.5

28.8 28.75

N1–H1 O1, C6–H6 O1,

…

C8–H8B O1

2

3

2x + 1, 2y, 2z + 1

2x + 3/2, y + 1/2, z

4.254

4.735

23.2

22.6

20.8 27.4 4.5

21.0 25.3 3.9

26.9 29.23

25.0 26.38

Molecular stacking

… …

C8–H8A O1, C3–H3 Cg1

AC-1 (Pbca)

1

…

2x + 3/2, y 2 1/2, z

6.334

211.9 24.5 25.2 12.9 28.6 28.50

N1–H1 O1, C8–H8B O1,

…

C8–H8C F1A

2

3

2x + 2, 2y + 2, 2z + 1

x 2 1/2, y, 2z + 3/2

4.274

6.292

20.4

20.5

20.5 26.7 3.7

20.5 24.4 2.3

23.9 25.76

23.2 23.45

Molecular stacking

…

C5A–H5A F1A,

…

C4A–H4A F1A

…

4

5

2x + 2, y + 1/2, 2z + 3/2

x + 1/2, 2y + 3/2, 2z + 1

5.938

7.965

20.7

20.5

20.5 22.2 1.1

20.3 22.0 0.8

22.2 22.56

22.1 22.33

C5A–H5A O1

…

C3A–H3A O1

AC-2 (Pbca)

…

1

2

3

4

5

6

2x + 3/2, y 2 1/2, z

2x + 1, 2y, 2z + 1

2x + 1, y 2 1/2, 2z + 3/2

x 2 1/2, y, 2z + 3/2

2x + 1/2, y 2 1/2, z

x + 1/2, 2y + 1/2, 2z + 1

6.744

3.446

5.910

6.912

8.780

8.198

211.3 24.4 25.2 12.0 28.9 28.41

N1–H1 O1, C8–H8B O1

Molecular stacking

23.4

21.0

0.1

21.0 29.2 7.1

20.6 23.5 2.1

20.6 23.7 2.6

20.2 21.4 0.7

20.2 20.8 0.2

26.7 29.45

23.1 23.41

21.7 22.49

21.1 20.93

20.9 21.00

…

C6–H6 F1, C5–H5 O1

…

C4–H4 N1/p

…

20.3

20.1

C5–H5 F1

…

C8–H8A F1

AC-3-Form I (Cc)

…

1

x, 2y + 1, z + 1/2

6.147

210.5 23.9 24.5 10.8 28.0 28.08

N1–H1 O1, C6–H6 O1,

…

C8–H8B O1

2

3

4

5

6

x + 1, y, z

4.731

7.223

7.063

8.855

11.098

0.2

20.5 25.7 2.4

20.2 22.0 0.8

20.2 21.8 0.9

20.2 21.3 0.5

20.1 20.7 0.5

23.7 25.32

22.3 22.44

21.6 21.92

20.9 21.27

20.7 20.72

Molecular stacking

…

x 2 1/2, 2y + 1/2, z + 1/2

x + 1/2, 2y + 1/2, z + 1/2

x + 1/2, y 2 1/2, z

x + 3/2, y 2 1/2, z

20.9

20.5

0.0

C6–H6 F1

…

C5–H5 Cg1

…

C8–H8A F1

…

20.4

C8–H8C F1

AC-3-Form II (Pbca)

…

1

2

x + 1/2, 2y + 3/2, 2z

2x + 1, 2y + 2, 2z

6.578

5.008

4.562

7.526

10.328

29.7

23.0

21.2

20.1

N1–H1 O1, C6–H6 O1

Molecular stacking

… …

C8–H8A O1, C3–H3 Cg1

3

4

5

2x + 1/2, y 2 1/2, z

2x + 1, y 2 1/2, 2z + 1/2

x, 2y + 3/2, z 2 1/2

…

C6–H6 F1, C5–H5 F1

…

C8–H8A F1

1

AC-4 (P2 /n)

1

…

x 2 1, y, z

4.776

29.7

23.7 26.7 10.9 29.1 29.30

N1–H1 O1, C8–H8B O1,

…

C9–F3 O1–C7,

…

C9–F2 F3–C9

…

2

3

4

5

6

7

2x + 1, 2y + 2, 2z

2x, 2y + 2, 2z

x + 1/2, 2y + 3/2, z + 1/2

x + 1/2, 2y + 3/2, z 2 1/2

2x 2 1/2, y + 1/2, 2z + 1/2 8.819

2x + 1/2, y + 1/2, 2z + 1/2 8.548

7.634

6.114

7.335

7.523

23.3

20.4

21.3

20.4

20.5

20.3

21.4 24.4 3.2

20.6 26.9 4.3

20.5 22.3 1.2

20.6 24.2 2.6

20.1 21.3 0.6

20.2 21.0 0.6

25.9 26.20

23.6 24.62

22.9 23.25

22.7 22.50

21.4 21.22

20.9 20.90

C3–H3 O1

Molecular stacking

… …

C8–H8A F1, H8A H5

…

C3–H3 F2, C4–H4 F2

…

C8–H8C F3

…

C8–H8C F1

1

AC-5 (P2 /c)

…

1

2

3

4

5

6

2x, y 2 1/2, 2z + 1/2

2x, 2y + 2, 2z

2x, 2y + 2, 2z + 1

x, 2y + 3/2, z 2 1/2

2x + 1,2y + 2,2z

2x + 1, y 2 1/2, 2z + 1/2

2x + 1,2y + 2,2z + 1

x, 2y + 5/2, z + 1/2

7.976

6.575

7.812

5.184

8.410

8.721

7.643

6.766

210.1 24.0 26.3 11.6 28.7 28.25

N1–H1 O1, C8–H8B O1

…

22.4

23.3

22.2

20.7

20.3

20.5

1.0

20.8 24.5 1.9

20.7 23.5 1.8

21.0 28.6 6.4

20.1 21.3 0.6

20.2 21.6 0.5

20.1 21.3 0.4

20.1 20.8 0.1

25.8 27.05

25.6 26.70

25.3 27.92

21.5 21.55

21.5 21.36

21.5 21.61

CLO OLC

…

C8–H8A O1, CLO CLO

…

Cg1 Cg1

…

C4–H4 F3, C9–F3 F3–C9

…

C4–H4 F2

…

7

.

C9–F2 F2–C9

…

8

0.2

20.23

C9–F2 F3–C9

AC-6 (Pbca)

1

…

x 2 1/2, y, 2z + 1/2

2x + 3/2, y + 1/2, z

7.756

4.666

210.1 23.8 24.3 10.2 28.1 27.86

N1–H1 O1, C6–H6 O1,

…

C8–H8C O1

2

21.1

20.7 27.3 3.6

25.5 27.02

Stacking moiety,

…

C

C, C–F

…

3

4

5

2x + 1, 2y + 2, 2z + 1

x, 2y + 3/2, z 2 1/2

2x + 2, 2y + 2, 2z + 1

8.315

9.927

7.693

21.5

20.6

20.5

20.3 21.8 1.8

20.1 21.1 0.5

20.2 21.7 1.5

21.8 21.91

21.4 21.63

21.0 21.07

C5–H5 F3, C9–F3 F3–C9

…

C8–H8B F1

… …

C3–H3 F1, C9–F1 F1–C9

BZ-0 (Pbca)

…

1

2

3

x + 1/2, 2y + 1/2, 2z + 1

2x + 1, 2y, 2z + 1

2x + 1/2, y + 1/2, z

5.817

3.731

5.187

211.3 24.6 26.7 13.8 28.8 28.74

N1–H1 O1, C6–H6 O1

Molecular stacking

22.7

21.8

21.2 28.4 6.3

20.8 25.0 3.4

26.0 27.93

24.2 25.20

…

C8–H8A O1

BZ-1 (P ¯1 , Z9 = 2)

…

A

3

716 | CrystEngComm, 2013, 15, 3711–3733

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Table 4 (Continued)

Centroid–

centroid

distance (Å)

DFT-D3/B97-D

aug-cc-pVTZ

Serial No. Symmetry code

E

Coul

E

Pol

E

Disp

E

Rep

E

Tot

Involved interactions

1

2

A

3

2x + 2, 2y + 1, 2z + 1

2x + 1, 2y + 1, 2z + 1

3.795

4.046

21.8

20.5

20.8 26.7 4.1

20.5 27.8 4.9

25.2 27.30

23.9 26.11

Molecular stacking

…

A

B/B

…

x, y + 1, z

6.245

6.324

26.6

26.2

22.5 24.4 6.9

22.3 24.4 6.7

26.6 25.84

26.2 25.61

N2–H2 O1, C16–H16B O1,

…

C8–H8C F2A

…

4

x, y, z

N1–H1 O2, C8–H8B O2,

…

C16–H16A F1A

C11A–H11A O1

C3A–H3A O2

…

5

6

7

8

2x + 1, 2y + 1, 2z

2x + 1, 2y + 1, 2z + 1

2x + 2, 2y, 2z + 1

2x + 2, 2y, 2z

7.973

7.537

7.229

7.165

22.0

21.5

21.0

20.8

20.8 22.2 1.9

20.8 22.4 1.7

20.5 23.3 2.0

20.4 22.9 1.5

23.1 23.15

23.0 23.04

22.8 22.42

22.6 22.33

…

C4A–H4A F2A, C16–H16B F1A

…

C8–H8B F2A, C13A–H13A F1A,

…

C12A–H12A F1A

…

B

9

2x + 2, 2y, 2z

2x + 1, 2y, 2z

3.720

4.268

21.3

20.8

20.8 26.7 4.2

20.6 27.7 5.2

24.7 27.06

23.9 26.33

Molecular stacking

1

0

BZ-2 (Pbca)

1

2

3

4

5

6

…

x + 1/2, 2y + 3/2, 2z + 1

2x + 1, 2y + 2, 2z + 1

2x + 1/2, y 2 1/2, z

2x + 1, y + 1/2, 2z + 3/2

x + 1/2, y, 2z + 3/2

6.563

3.714

5.516

7.208

6.973

8.296

210.3 24.0 26.2 11.6 29.0 28.53

N1–H1 O1, C6–H6 O1

Molecular stacking

23.6

21.4

21.2

20.7

20.6

21.6 29.4 8.6

20.7 24.3 2.6

20.4 22.3 1.2

20.4 22.7 1.9

20.1 20.5 0.1

26.1 28.61

23.7 24.26

22.7 22.82

22.0 21.99

21.2 21.45

…

C8–H8A O1, C–F

p

…

C5–H5 F1, C4–H4

C

…

C4–H4 F1, C5–H5 F1

…

2x + 1/2, 2y + 2, z + 1/2

C8–H8C F1

BZ-3 (Pbca)

…

1

2

3

4

5

6

7

2x + 1/2, y + 1/2, z

2x + 1, 2y + 2, 2z + 1

x 2 1/2, y, 2z + 1/2

x + 1/2, 2y + 3/2, 2z + 1

2x + 1, y + 1/2, 2z + 1/2

2x + 3/2, y 2 1/2, z

x 2 1, y, z

6.795

3.552

6.365

7.648

6.008

7.990

10.901

29.6

21.2

20.9

20.8

20.3

20.5

20.6

23.9 25.9 10.8 28.7 28.15

N1–H1 O1, C6–H6 O1

Molecular stacking, C8–H8C F1

…

20.8 28.7 6.0

20.6 25.1 3.8

20.5 21.9 1.1

20.4 21.9 0.5

20.3 22.0 1.1

20.1 20.7 0.4

24.7 27.12

22.7 23.69

22.1 22.50

22.0 22.42

21.6 21.43

21.0 21.01

…

C6–H6 F1, C8–H8A Cg1

…

C3–H3 O1

…

C5–H5 O1

…

C3–H3 F1, C2–H2 F1

…

C8–H8B F1

BZ-4 (P2

1

/c)

… …

N1–H1 O1, C8–H8B O1,

x, 2y + 3/2, z 2 1/2

5.777

28.8

23.4 26.2 10.2 28.3 28.92

…

C8–H8C Cg1, C9–F2 F3–C9

…

2

3

4

5

2x + 1, 2y + 2, 2z + 2

x, 2y + 5/2, z + 1/2

2x, 2y + 2, 2z + 1

2x, y + 1/2, 2z + 3/2

7.185

6.970

6.559

6.523

25.3

21.8

21.1

21.2

21.6 23.9 3.9

20.9 23.5 2.3

20.2 22.5 1.1

20.3 22.4 1.2

27.0 27.43

23.8 24.42

22.7 22.56

22.6 22.49

C2–H2 O1

…

C

C4–H4 O1, C4–H4

…

C5–H5 F2

… …

C5–H5 F3, C9–F1 F2–C9

BZ-5 (P2

1

… …

N1–H1 O1, C6–H6 O1

1

2

3

4

5

6

7

2x, y 2 1/2, 2z + 1/2

x, 2y + 3/2, z + 1/2

2x, 2y + 2, 2z

2x, 2y + 2, 2z + 1

2x + 1, 2y + 2, 2z + 1

2x + 1, y 2 1/2, 2z + 1/2

2x + 1, 2y + 2, 2z

7.851

5.134

6.209

7.856

7.147

8.523

8.439

210.2 24.3 26.7 12.5 28.7 28.24

…

C C, stacking

22.1

22.2

20.5

20.6

20.2

20.7 27.3 4.5

21.0 25.5 3.2

20.7 23.6 1.9

20.1 22.0 0.6

20.3 21.9 1.1

20.1 21.1 0.3

25.6 27.72

25.6 26.50

24.6 25.87

22.0 21.80

21.6 21.45

21.1 20.93

…

CLO CLO

…

C8–H8A O1

…

C9–F2 F3–C9, C9–F3 F3–C9

…

C5–H5 F3, C4–H4 F2

…

C9–F1 F3–C9

BZ-6 (P2

1

/n)

…

x + 1, y, z

5.057

29.3

23.1 26.4 9.2

29.6 29.63

N1–H1 O1, C3–H3 F1,

…

C9–F1 F2–C9

… …

2

3

4

5

6

7

2x, 2y + 1, 2z + 2

2x 2 1/2, y + 1/2, 2z + 3/2 7.866

2x + 1/2, y + 1/2, 2z + 3/2 7.003

2x + 1, 2y + 1, 2z + 2

2x + 1, 2y, 2z + 2

x, y + 1, z

7.003

24.3

21.6

20.4

0.5

21.6

20.5

21.2 26.1 4.0

20.7 22.8 1.8

20.3 24.2 2.1

21.0 25.3 3.0

20.4 22.2 2.0

20.1 21.5 0.7

27.7 29.45

23.3 23.37

22.8 23.11

22.8 22.79

22.3 22.11

21.4 21.15

C6–H6 O1, C8–H8A Cg1

…

C3–H3 O1, C2–H2 F2

…

C2–H2 F1, stacking

…

7.729

7.798

11.652

Dimeric moiety, C6–H6 N1–C8

…

C5–H5 F3

…

3^…

3

C8–H8C F2, CH CF – moiety

…

0.830(2) : 0.170(2). Strong N–H OLC H-bonds along with

similar to that of the isolated dimer, while that of the stacked

motif 2 has an extra stabilization of 2.3 kcal mol in the gas

phase when compared with the solid state (Table 4).

2

1

3

…

3

…

2

weak C(sp )–H OLC and C(sp )–H F–C(sp ) H-bonds (motif

21

1, 28.6 kcal mol ) are involved in the formation of molecular

chains, with the utilization of the b-glide perpendicular to the

crystallographic a axis [Fig. 2(b)]. The chains thus formed are

2

. N-(2-Fluorophenyl)acetamide (AC-1)

The compound AC-1 crystallizes in an orthorhombic centro-

symmetric space group Pbca with Z = 8 [Fig. S5(b), ESI ]. The

2

…

interconnected with weak C(sp )–H OLC [motif 4 and motif 5,

both having similar interaction energy (22.2 and 22.1 kcal

3

2

1

molecule exhibits positional disorder of the fluorine atom at

two sites, the final occupancy ratio refining to a value of

mol , respectively) in the crystal, Table 4] in addition to

2

1

molecular stacking (Table 4, motif 2, 23.9 kcal mol

)

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Fig. 1 (a) Selected molecular pairs from Table 4 (denoted as red numbers) depicting inter molecular contacts in AC-0. The values in brackets denote interaction

…

energies from PIXEL and DFT-D3 calculations. (b) Packing of molecules down the ab plane in AC-0 via N–H O, C–H O and C–H p hydrogen bonds in AC-0. (c)

Packing of molecular dimers down the bc plane in AC-0.

…

[Fig. 2(b)], which is a primary building block in the crystalline

istic intramolecular C–H OLC hydrogen bond [Fig. S5(c),

structure. The third most stabilizing ‘‘molecular pair’’ found

3

ESI ]. The molecules are packed with the involvement of strong

2

…

2

…

3

…

to link via bifurcated C(sp )–H F–C(sp ) [utilizing the a-glide,

N–H OLC hydrogen bonds along with C(sp )–H OLC gen-

erating a molecular chain with the utilization of b-glide

perpendicular to crystallographic a-axis [motif 1, I.E. = 28.9

2

1

Fig. 2(c), motif 3] with I.E. = 23.2 kcal mol . It is of interest to

note that the major contribution comes from dispersion

2

1

(Table 4) in contrast to coulombic and polarization compo-

kcal mol , Fig. 3(b)]. The chains thus formed are inter-

2

…

connected with weak C(sp )–H F–(sp ) (involves H5 with F1,

2

nents, which for motif 3 are small. It is noteworthy that PIXEL

interaction energies of all molecular pairs are found to be

similar to that of the isolated pair except 2 (behaves 1.9 kcal

more stable as isolated pair than in crystal environment)

2

1

motif 5, I.E. = 21.1 kcal mol ) hydrogen bonds and generate

a molecular sheet down the ab plane. The second most stable

molecular pair in the crystal structure, formed via molecular

stacking, has a contribution of 26.7 (motif 2) to the

stabilization of the crystal packing. Adjacent stacks are

(Table 4).

3. N-(3-Fluorophenyl)acetamide (AC-2)

2

…

2

…

connected via weak C(sp )–H5 OLC and C(sp )–H6 F1–

C(sp ) [motif 3, I.E. = 23.1 kcal mol , the major contribution

2

21

The compound AC-2 crystallizes in the centrosymmetric

orthorhombic space group Pbca with Z = 8, with a character-

being the dispersion energy, Table 4, Fig. 3(c)] intermolecular

3

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2

1

nected with more stabilized motif 4 (I.E. = 21.7 kcal mol

Fig. 3(d)].

It should also be noted that the incorporation of a fluorine

)

[

atom over the phenyl ring of the parent compound, AC-0, at

either ortho (AC-1) or meta (AC-2) position does not change the

total lattice energy but increases the possibility of formation of

different molecular motifs [motif 3 in AC-1, motifs 3, 5 and 6

in AC-2, Fig. 2(a) and 3(a)] which can contribute to the

stabilization of the crystal structure. This results in the

alteration in the crystal packing from the parent compound

while displaying similar packing to each other.

4. N-(3-Fluorophenyl)acetamide (AC-3)

The crystal structure of the compound N-(3-fluorophenyl)ace-

3

7

tamide (AC-3) was already reported in the literature and

retrieved from the CCDC (Ref code SAZLEL), hereby referred as

Form I. Crystals of this compound were obtained by slow

evaporation from ethyl acetate solution, the crystals exhibiting

prism-like morphology. The compound crystallized in the non-

centrosymmetric monoclinic space group Cc with Z = 4

molecules in the unit cell, the cell parameter being: a =

4

7

.731(2) Å, b = 17.067(5) Å, c = 9.634(3) Å, b = 92.871(5)u, V =

76.8 Å . Various attempts to get single crystals of the above-

3

mentioned Form I were unsuccessful. On the contrary, the

obtained crystals [Fig. 4(a)] from ether solution at low

temperature displayed plate-like morphology. The crystal

structure of the new form, referred to as Form II, crystallized

in the centrosymmetric orthorhombic Pbca space group with Z

=

8 molecules in the unit cell [Fig. S5(d), ESI

3

], the lattice

parameters for the new form being a = 9.4117(4) Å, b =

3

7

.7523(3) Å, c = 20.2204(7) Å, V = 1475.3(1) Å . It is of interest to

compare the crystal packing (similarities/differences) and the

energetic features associated with the formation of these

polymorphs.

Crystal packing in AC-3 Form I. The crystal structure of

Form I involves the formation of molecular chains, utilizing

the packing motif 1, having the highest energetic stabilization

2

1

…

(

28.0 kcal mol ), linked via strong N–H OLC along with

…

weak C–H O hydrogen bonds, utilizing c-glide as the

symmetry element in the crystal structure [Fig. 4(c)]. The

2

…

chain is then linked via weak C(sp )–H F hydrogen bonds

2

1

…

motif 3, 22.3 kcal mol ), C–H p (motif 4, I.E. = 21.6 kcal

mol ) and weak C(sp )–H F hydrogen bonds (motif 6, 20.7

kcal mol ), generating a molecular sheet down the bc plane

Fig. 4(c)]. The molecules in the crystal are stacked along the

crystallographic a-axis (motif 2, 23.7 kcal mol ) and forms a

(

Fig. 2 (a) The molecular pairs (red numbers denoting as in Table 4) along with

their interaction energy from PIXEL and DFT-D3 (Table 4) calculations in AC-1.

2

1

3

…

2

1

(

b) Packing view down the bc-plane in AC-1. The number in red denotes

corresponding molecular pairs in Table 4. (c) Packing view down the ac plane,

[

2

…

showing formation of parallel molecular chains via weak C(sp )–H F hydrogen

bonds along a-axis in AC-1.

21

3

layered arrangement which is then linked via weak C(sp )–

H F hydrogen bonds [motif 5, 20.9 kcal mol , and motif 6,

…

21

2

1

2

0.7 kcal mol , Fig. 4(d)].

H-bonds. The decrease in the interaction energy of the

Crystal packing in AC-3 Form II. Packing in the crystal

2

1

21

molecular pair 2, from 29.45 kcal mol to 26.7 kcal mol

in the isolated pair), provides an excellent example to explore

structure displays formation of molecular chain along the

(

…

crystallographic a-axis via strong N–H OLC along with weak

2

…

21

the co-operative nature of weak interactions in the crystal

environment [depicted in the blue circle in Fig. 3(c), where

motifs 2 and 3 are present together]. The packing in the crystal

C(sp )–H OLC (motif 1, 28.8 kcal mol , with mostly

coulombic contribution) H-bonds. The molecular chain is

3

…

connected with C(sp )–H F H-bonds (motif 5, 20.8 kcal

3

2

1

also involves the formation of molecular chains with C(sp )–

mol ) utilizing the c-glide plane [Table 4, Fig. 4(f)]. The

…

2

21

2

…

21

H F–(sp ) (involving H8A), contributing 20.9 kcal mol

1

mainly dispersion contribution, Table 4, motif 6), with 2 -

bifurcated C(sp )–H F (motif 4, I.E. = 22.2 kcal mol with

major contribution from dispersion), is involved in the

formation of ‘‘zig-zag chains’’ along the crystallographic b-axis

(

screw along a-axis. The molecular chains are then intercon-

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Fig. 3 (a) Selected molecular pairs (labelled with red numbers) with their interaction energies calculated with PIXEL and DFT-D3 (Table 4) calculations in AC-2. (b)

…

Packing of molecules viewed down the ab plane forming a molecular sheet with N–H OLC, C–H OLC and C–H F hydrogen bonds in AC-2. (c) Packing view down

…

the bc plane depicting aromatic stacking interactions in AC-2. (d) Packing view down the ac plane in AC-2 via the network of weak C–H N–p and C–H F hydrogen

bonds.

(

utilizing 2

1

screw axis as the symmetry element). The weak

…

stabilization in Form II essentially comes from the presence

3

…

C(sp )–H OLC, along with C–H p (motif 3, I.E. = 25.2 kcal

mol

of motif 3 (connected with weak C–H O and C–H p H-bonds,

2

1

21

with the dispersion contribution being double the

25.2 kcal mol ) but these are absent in Form I. Also the motif

coulombic contribution) interconnect the ‘‘zig-zag chains’’

2 in Form II [anti-parallel stacking of molecules was observed,

Fig. 4(e)] was found to be 3 kcal mol more stable than that in

2

1

21

[Fig. 4(g)]. The dimeric motif 2 (I.E. = 26.6 kcal mol

)

arranges as a zig zag chain running along crystallographic

Form I [wherein parallel stacking of molecules was observed,

Fig. 4(b)].

2

…

c-axis with the utilization of bifurcated C(sp )–H F (motif 4,

2

1

3

…

I.E. = 22.2 kcal mol ) and C(sp )–H F H-bonds (motif 5,

2

1

5. N-(2-(Trifluoromethyl)phenyl)acetamide (AC-4)

0.8 kcal mol ) [Fig. 4(h)].

The molecular conformation of Form II is found to be

The molecule AC-4 crystallizes in the centrosymmetric mono-

similar to the isolated molecule in the gaseous state with an

approximately planar arrangement, while the phenyl ring in

Form I displays a torsion twist of about 19u from the plane of

the amide bond (Table 2). The lattice energy calculations

indicate that Form II is 5 kcal more stable than the previously

reported Form I, the difference in coulombic contribution

being the most significant contributor towards the lattice

energy (Table 3). The most stabilizing motif 1 (connected with

clinic space group P2 /c with Z = 4, having intra-molecular N1–

1

…

H1 F3 hydrogen bond [Fig. S5(e), ESI ]. The strong N–H OLC

3

…

3

…

along with weak C(sp )–H OLC, C(sp )–F OLC and weak

3

…

3

C(sp )–F F–C(sp ) generates the most stabilized molecular

2

1

pair (motif 1, I.E. = 29.1 kcal mol ) in the crystal, which

propagates along the crystallographic a-axis. The molecular

chains thus formed are connected with weak bifurcated

3

…

3

C(sp )–H F–C(sp ) hydrogen bonds [motif 6 (21.4 kcal

…

21

strong N–H OLC H-bonds) in both polymorphs contributes a

similar amount of stabilization to the crystal structure

mol ) and 7 (20.9 kcal mol )] generating molecular sheets

down the ab plane [Fig. 5(b)]. The packing of molecules in the

third direction involves the formation of weak bifurcated weak

(Table 4) but are different in terms of the orientation of the

2

…

3

two molecules in motif 1 [Fig. 4(b) and (e)]. The extra

C(sp )–H F–C(sp ) hydrogen bonds (motif 5, I.E. = 22.7 kcal

3

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Fig. 4 (a) Plate crystal (Form II) from ether solution at low temperature in AC-3. (b) Molecular pairs with their interaction energies from PIXEL and DFT-D3/B-97D

calculations (Table 4) in AC-3 (Form I). (c) Packing of molecules in AC-3 (Form I) down the bc plane. (d) Packing view down the ab plane, depicting the formation of a

molecular layer in AC-3 (Form I). (e) Selected molecular pairs (denoted as red numbers) with interaction energies from PIXEL and DFT-D3/B97-D calculations (Table 4)

…

3

…

in the molecular crystal of AC-3 (Form II). (f) Packing view down the ac plane, showing N–H OLC hydrogen bonds along with weak C(sp )–H F H-bonds in AC-3

…

(

Form II). (g) Packing view down the ab plane, depicting C–H OLC, C–H p and C–H F hydrogen bonds in AC-3 (Form II). (h) Stacking interactions involving

…

dimeric motif 2 down the bc plane, connected via weak C–H F hydrogen bonds in AC-3 (Form II).

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Fig. 5 (a) Selected molecular pairs in the packing of AC-4 along with their interaction energies from PIXEL and DFT-D3/B97-D calculations (Table 4). (b) Packing of AC-

…

3

…

3

4

down the ab plane, displaying network of strong N–H OLC along with weak C–H O, C–H F hydrogen bonds and C(sp )–F F–C(sp ) contacts. (c) Packing view

…

2

…

3

down the ac plane, depicting packing of molecules via strong N–H OLC, weak C–H OLC and C(sp )–H F–C(sp ) hydrogen bonds. (d) Packing view in AC-4,

displaying strong N–H OLC, weak C–H OLC hydrogen bonds, weak C(sp )–F F–C(sp ) interactions and intermolecular stacking.

…

3

…

3

2

mol with contribution from dispersion interaction energy

towards the crystal stabilization) and the occurrence of a

1

…

3

H2 OLC hydrogen bond [Fig. S5(f), ESI ]. The strong N–

…

H OLC along with weak C–H OLC hydrogen bonds (motif 1,

3

21

‘

‘rare’’ motif 4 [Fig. 5(c)]. This motif 4 consists of one C(sp )–

I.E. = 28.7 kcal mol ) participate in the formation of a

molecular chain via 2 screw along the crystallographic b-axis

[Fig. 6(b)]. The chains are then interconnected with the

presence of motif 2 (dimeric CLO CLO dipolar interactions,

…

H F (2.86 Å, 157u, Table S2

acidic H5 due to presence of CF

2

contributing 2.9 kcal mol

dispersion having a major contribution (22.3 kcal mol

3

) and C–H H (relatively more

1

3

group with C(sp )–H8C,

…

.28 Å, /C5–H5 H8C = 129u, /C8–H8C H5 = 142u), H H

2

1

21

…

towards the stabilization with

I.E. = 25.8 kcal mol ), motif 3 (dimeric CLO OLC along with

21

2

1

…

)

C8–H8A OLC hydrogen bond, I.E. = 25.6 kcal mol ) and

21

…

along with a significant contribution from coulombic and

motif 4 (p p interaction, I.E. = 25.3 kcal mol ) [Fig. 6(b)]. It

is to be noted that the molecular pairs consisting of CLO

dimeric motifs are the second and third most stabilizing motif

2

1

polarization (21.8 kcal mol ) energies. The second most

stabilized molecular motifs in the crystal are the molecular

…

40

pair formed via dimeric weak C–H OLC hydrogen bonds

in the crystal with significant coulombic contributions

(Table 4). The packing in the crystal also displays the

formation of molecular layers down the ac plane with the –

3

CF moieties approaching each other. These result in the

formation of motifs 5, 6, 7, 8 [Fig. 6(b) and 6(c)]. The analysis

of these brings out some interesting results. Although the

motif 5 consists of dimeric C(sp )–H F–C(sp ) (2.76 Å, 136u)

along with a C(sp )–F F–C(sp ) (2.988 Å) interaction (present

diagonally in dimeric motif) contribute 1.5 kcal mol to the

2

1

[

motif 2, I.E. = 25.9 kcal mol with comparable contribution

2

1

from dispersion (24.4 kcal mol ) and coulombic energy

23.3 kcal mol ), Table 4]. Finally, the stacked molecular

dimer (motif 3, I.E. = 23.6 kcal mol with mostly dispersion

contribution, Table 4) also contributes towards the stability of

the crystal packing [Fig. 5(d)].

2

1

(

2

1

2

…

3

…

3

6

. N-(3-(Trifluoromethyl)phenyl)acetamide (AC-5)

The compound crystallizes in centrosymmetric monoclinic

P2 /c space group with Z = 4 with an intra-molecular C2–

21

2

…

3

stabilization, the same kind of C(sp )–H F–C(sp ) in motif 6

(2.83 Å, 124u) also contributes 1.5 kcal to the stabilization

1

3

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Fig. 6 (a) Molecular pairs present in the crystal packing with their interaction energies from PIXEL and DFT-D3/B97-D calculations (Table 4) in AC-5. (b) Packing of

…

2

molecules down the bc plane in AC-5 via N–H OLC, weak C–H OLC hydrogen bonds and stacking interactions. (c) Packing view down the ac plane via weak C(sp )–

H

…

3

…

3

F–C(sp ) hydrogen bonds and C(sp )–F F–C(sp ) contacts in AC-5. (d) Formation of tetrameric motif in AC-5. (e) Formation of trimeric motif in AC-5 connected

…

via C–H F and F F contacts.

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Table 4). The calculations from the isolated pair for motif 6

suggest that it is less stable by 0.2 kcal mol than motif 5.

This confirms that the extra stabilization of motif 6 comes

from crystal packing. It is to be noted that the interaction

CrystEngComm

(

2

1

3

…

2

3

energy of motif 7 consisting of C(sp )–F2 F2–C(sp ) (3.096 Å,

1

h

1

= h

21.61 kcal mol ) with dispersion as a major contributor

towards stabilization. It is to be noted that motif 8, although

2

= 122u) is found to be 21.5 kcal mol (isolated pair I.E.

2

1

=

3

…

3

geometrically similar [C(sp )–F F–C(sp ) = 3.113 Å, h

1

=

1

18u,h = 113u] to motif 7, does contribute towards the crystal

2

packing. The energy is positive, hence depicting the slightly

…

repulsive nature associated with F F interaction. This may be

attributed to the repulsion, owing to the arrangement and

orientation of the C–F bond dipole moments with respect to

each other in the crystal environment. In order to evaluate the

additive nature of these interaction energies, we performed

DFT-D3/B97-D calculations to obtain the total interaction

energy for the terameric motif [I.E. = E_t_e_r_a_m_e_r2 4 6 E_m_o_n_o_m_e_r

,

Fig. 6(d), consisting of the molecular motifs 5, 6, 7 and 8]. This

2

1

confers an overall stabilization of 23.81kcal mol . Similar

calculations performed on the molecular trimer, having motifs

6

mol

, 7 and 8, provide stabilization to the extent of 22.75 kcal

2

1

.

7

. N-(4-(Trifluoromethyl)phenyl)acetamide (AC-6)

The compound AC-6 crystallizes in centrosymmetric orthor-

hombic space group Pbca with Z = 8 [Fig. S5(g), ESI ]. As is

observed in the previous cases, the stabilizing molecular pair

3

…

consist of strong N–H OLC along with weak C–H OLC

2

1

hydrogen bonds (motif 1, I.E. = 28.1 kcal mol ). These are

involved in the formation of molecular chains along the

a-glide perpendicular to the crystallographic c-axis. The chains

2

…

3

are interconnected with weak C(sp )–H F–C(sp ) hydrogen

3

…

3

bonds along with C(sp )–F F–C(sp ) interactions (motif 3 and

) [Fig. 7(b)]. The molecules in the crystal stack together

resulting in the formation of a molecular ladder [Fig. 7(c)]. The

5

3

…

3

weak C(sp )–H F–C(sp ) (motif 4) connect the molecular

ladder in a zig zag manner along the c-axis.

Fig. 7 (a) Molecular pairs along with their interaction energies from PIXEL and

DFT-D3/B97-D calculations (Table 4) in AC-6. (b) Packing view down the ac

The motif 2 (stacking of molecules) contributes 5.5 kcal

2

1

…

3

…

2

…

3

mol towards the stabilization of the crystal packing (1.5 kcal

plane, displaying N–H OLC, weak C(sp )–H OLC, C(sp )–H F–C(sp ) hydro-

3

…

3

2

1

gen bonds along with C(sp )–F F–C(sp ) interactions in AC-6. (c) Formation of

mol less stable compared to DFT calculations, the I.E. is

2

1

molecular ladder down the bc plane in AC-6 via stacking interactions and

2

7.02 kcal mol ). Motif 3 and motif 5 are found to be similar

3

…

3

C(sp )–H F–C(sp ) hydrogen bonds.

2

1

to motif 5 in AC-5, these contributing 1.8 kcal mol and 1.0

2

1

kcal mol towards the stabilization, with the major contribu-

tion coming from the dispersion energy, attributed primarily

8. N-Methylbenzamide (BZ-0)

…

to C–H F H-bonds in these motifs (Table 4). It is actually the

increased repulsion contribution in this case of AC-6 (wherein

The compound crystallizes in centrosymmetric orthorhombic

the interatomic distances involving fluorine atoms are less

space group Pbca with Z = 8 [Fig. S5(h), ESI

3

]. The most

…

than the sum of van der Waals radii, Tables S2 and S3, ESI

3

),

stabilized motif 1, formed with strong N–H OLC along with

2

…

compared to that in AC-5, wherein the distance between the

interacting fluorine atoms in motif 5 is greater than the sum of

van der Waals radii that results in decreased repulsion,

although these represent similar type of motifs (Table 4).

weak C(sp )–H OLC hydrogen bonds, provides 28.8 kcal

21

mol . This motif forms molecular chains along the crystal-

lographic a-axis utilizing the 2 screw axis as the symmetry

1

element. The parallel chains are interconnected [Fig. 8(b)]

3

…

3

Motif 4, formed with short and directional C(sp )–H F–C(sp )

utilizing the stacking interactions (motif 2, I.E. = 26.0 kcal

2

1

21

(2.66 Å, 165u), contributes 21.4 kcal mol

towards the

mol ) forming molecular sheets which are further stabilized

3

…

stabilization of crystal structure.

via weak C(sp )–H OLC hydrogen bonds (motif 3, I.E. = 24.2

kcal mol

2

1

with dispersion energy as a major contributor)

propagating along the b axis in the crystal structure. The motif

3

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2

and 10 (I.E. = 23.9 kcal mol )] in the formation of molecular

1

2

layers [Fig. 9(c)] which are connected with bifurcated C(sp )–

…

2

3

…

2

H F–C(sp ) and C(sp )–H F–C(sp ) hydrogen bonds (motif 8,

2

1

…

I.E. = 22.6 kcal mol ) and weak C–H OLC hydrogen bond

2

1

(

motif 6, I.E. = 23.0 kcal mol ).

0. 3-Fluoro-N-methylbenzamide (BZ-2)

The compound crystallizes in the centrosymmetric orthor-

1

hombic space group Pbca with Z = 8 [Fig. S5(j), ESI ]. A well

defined strong N–H OLC along with C(sp )–H OLC (motif 1,

3

…

2

…

1

I.E. = 29.0 kcal mol with coulombic as a main contributor)

directs the formation of a helical molecular chain along the 2

1

screw parallel to crystallographic a-axis [Fig. 10(b)]. These

2

chains are then inter-connected with weak bifurcated C(sp )–

…

21

H F hydrogen bonds (motif 5, offered 2 kcal mol to the

stabilization with dispersion as a major contributor) propagat-

3

ing along the a-glide plane [Fig. 10(b)]. The weak C(sp )–

H OLC hydrogen bond along with C–F p interaction (motif

…

2

1

3

, I.E. = 23.7 kcal mol

with major contribution from

dispersion) pack utilizing the b-glide plane and are then linked

3

…

2

21

via weak C(sp )–H F–C(sp ) (motif 6, I.E. = 21.2 kcal mol

)

H-bonds forming a ladder-like arrangement in the crystal

structure [Fig. 10(c)]. The stacked dimers (motif 2, I.E. = 26.1

2

1

kcal mol ) pack in a herringbone arrangement down the bc

Fig. 8 (a) Molecular pairs with their interaction energy from PIXEL and DFT-D3/

B97-D calculations (Table 4) in BZ-0. (b) Packing of molecule in crystal via N–

2

…

plane, linked with weak C(sp )–H F–C(sp ) and C–H p

hydrogen bonds (motif 4, I.E. = 22.7 kcal with dispersion as

major contributor).

…

2

…

2

…

H

OLC, C(sp )–H OLC, C(sp )–H p hydrogen bonds in BZ-0.

1

1. 4-Fluoro-N-methylbenzamide (BZ-3)

The compound crystallizes in the centrosymmetric monoclinic

space group Pbca with Z = 8 [Fig. S5(k), ESI ]. The packing in

the crystal structure involves the formation of molecular

2

in the crystal is 1.9 kcal mol is less stable than the value

1

2

obtained from DFT calculations.

3

9. 2-Fluoro-N-methylbenzamide (BZ-1)

…

2

…

chains via strong N–H OLC along with C(sp )–H OLC

The molecule crystallizes in a centrosymmetric triclinic space

group P ¯1 with two molecules in the asymmetric unit [molecule

A (carbon atom = grey color) and B (carbon atom = violet

3

color)], thus having Z = 4 [Fig. S5(i), ESI ] molecules in unit

21

hydrogen bonds (motif 1, I.E. = 8.7 kcal mol

with major

coulombic contribution) along the b-glide plane. The chains

…

are inter-linked with the presence of weak C–H F hydrogen

bonds (fluorine is a trifurcated acceptor) [motif 6 (I.E. = 21.6

cell. The fluorine atom on phenyl ring in both the molecules in

the asymmetric unit were found to be disordered at two

positions with the occupancy ratio of 0.920(2) : 0.080(2) for

molecule A and 0.921(2) : 0.079(2) for molecule B. The two

molecules in the asymmetric unit are connected with strong

21

kcal mol ) and 7 (I.E. = 21.0 kcal mol

contribution coming from dispersion)] [Fig. 11(b)]. The motif

with major

21

2

(total I.E. = 24.7 kcal mol ) are arranged as zig zag chains

2

along the crystallographic c-axis with the utilization of C(sp )–

…

2

3

…

H F–C(sp ) and C(sp )–H p hydrogen bonds (motif 3, I.E. =

…

3

…

3

…

1

2

21

N–H OLC, weak C(sp )–H OLC and C(sp )–H F–C(sp )

2

2.7 kcal mol

with major dispersion as contribution)

2

hydrogen bonds (motif 3, I.E. = 26.6 kcal mol ) and the

structure is also stabilized by intra molecular N–H F

3

…

2

[

=

Fig. 11(c)]. Additional weak C(sp )–H F–C(sp ) (motif 7, I.E.

21.0 kcal mol ) hydrogen bonds provide additional

…

21

hydrogen bonds in both the molecules of the asymmetric

unit. The asymmetric unit is connected along the crystal-

lographic b axis with strong N–H OLC, weak C(sp )–H OLC

stability forming molecular chains along the a-axis. The

packing in the crystal is also characterized by the presence

…

3

…

2

…

of two motifs 5 and 6, comprising of weak C(sp )–H O

3

…

2

and C(sp )–H F–C(sp ) hydrogen bonds (motif 4, I.E. = 26.2

hydrogen bonds, the stabilization provided being 22.1 and

2

1

…

21

kcal mol ) and forms molecular chains with an ABAB

arrangement [Fig. 9(b)]. Two such chains are interconnected

22.0 kcal mol

(with major contribution coming from

dispersion) to the crystal packing. These form molecular

3

…

2

…

2

with weak C(sp )–H F–C(sp ) and C(sp )–H F–C(sp ) hydro-

gen bonds [Fig. 9(b)], which is characterized as motif 7 in the

crystal packing [Fig. 9(a)]. These contribute 2.8 kcal mol

Table 4), towards the stabilization of the lattice, with the

chains with the utilization of a 2 screw along crystallographic

1

a-axis and b-axis [Fig. 11(d)].

2

1

12. N-Methyl-2-(trifluoromethyl)benzamide (BZ-4)

(

major contribution coming from the dispersive component.

Furthermore, both molecules of the asymmetric unit are

stacked along crystallographic a-axis [motif 1 (I.E. = 25.2 kcal

The compound crystallizes in the centrosymmetric space

group P2 /c with Z = 4 [Fig. S5(l), ESI

1

3

]. The motif 1 is

…

characterized by the presence of strong N–H OLC, weak

2

1

21

3

…

3

…

mol ), 2 (I.E. = 23.9 kcal mol ), 9 (I.E. = 24.7 kcal mol

)

C(sp )–H O and weak C(sp )–H p hydrogen bonds along

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…

Fig. 9 (a) Molecular pairs with their interaction energies calculated from PIXEL and DFT-D3 (Table 4) in BZ-1. (b) Packing view depicting strong N–H O, weak C–

…

H

O, C–H F hydrogen bonds in BZ-1. (c) Packing view depicting formation molecular layer via stacking, weak C–H O, C–H F hydrogen bonds in BZ-1.

3

…

3

with C(sp )–F F–C(sp ) interaction, [Fig. 12(b)] contribute

2

stabilization of crystal with the major contribution coming

from dispersion (Table 4).

2

1

8.3 kcal mol towards the crystal stabilization, propagating

along the c-glide plane. The molecular chains thus formed are

2

…

13. N-Methyl-3-(trifluoromethyl)benzamide (BZ-5)

inter linked with C(sp )–H O, weak C(sp)–H p (motif 3, I.E. =

2

1

2

3.8 kcal mol with dispersion as a major contributor) also

The molecule crystallizes in the centrosymmetric monoclinic

propagating along the c-glide plane [Fig. 12(b)]. It is to be

noted that the second greatest contributor to the stabilization

of the crystal structure is the molecular pair connected with

1

3

space group P2 /c with Z = 4 [Fig. S5(m), ESI ]. The packing in

the crystal structure involves the formation of a molecular

…

ribbon by strong N–H OLC and weak C–H OLC hydrogen

2

…

short and directional (2.37 Å, 153u) (Table S2

dimeric hydrogen bonds (motif 2, I.E. = 27.0 kcal mol , with

3

) C(sp )–H O

bonds along the 2 screw parallel to the crystallographic b-axis

1

2

1

21

(motif 1, I.E. = 28.7 kcal mol ) [Fig. 13(b)]. The packing of

2

1

major coulombic contribution as 25.3 kcal mol ). The weak

molecules in the crystal is also characterized by the presence

2

…

3

…

3

C(sp )–H F–C(sp ) along with C(sp )–F F–C(sp ) (motif 5, I.E.

of dipole–dipole interactions of the carbonyl group (.CLO) of

2

1

21

=

2.6 kcal mol with major dispersion contribution, Table 4)

the molecule which contribute 5.6 kcal mol

(major

generates a molecular chain utilizing the 2 screw along the

contribution coming from dispersion) to the stabilization of

the crystal (motif 3, Table 4). Such a molecular pair (motif 3)

arranges as molecular layers parallel to the ac plane via weak

1

crystallographic b-axis [Fig. 12(c)]. Such chains are then

interconnected via the dimeric motif 2. The packing in the

crystal also consists of the presence of another dimeric

molecular pair connected with short and directional (2.59 Å,

3

…

C(sp )–H O hydrogen bonds forming dimers (motif 4, I.E. =

2

1

24.6 kcal mol ) [Fig. 13(c)]. The layers thus formed are then

2

…

3

…

1

[

47u) (Table S2

3

) weak C(sp )–H F–C(sp ) hydrogen bonds

connected with weak C(sp )–F F–C(sp ) interactions (motifs 5

and 7) [Fig. 13(c)] forming the characteristic ribbon-like motif.

2

1

Fig. 12(d)] (motif 4), which contribute 2.7 kcal mol to the

3

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Fig. 10 (a) Selected molecular pairs in the crystal structure of BZ-2 with their interaction energy obtained with PIXEL and DFT-D3 calculation (Table 4). (b) Packing

…

2

…

2

…

view down the ac plane displaying network of N–H OLC, C(sp )–H OLC, C(sp )–H F hydrogen bonds in BZ-2. (c) Packing view down the bc plane showing weak

3

…

3

…

2

…

C(sp )–H OLC, C(sp )–H F–C(sp ) hydrogen bonds along with C–F p interaction in the crystal packing of BZ-2. (d) Packing view down the bc plane, showing

formation of the herringbone arrangement in the crystal packing of BZ-2.

The packing of the molecules are also characterized by the

14. N-Methyl-3-(trifluoromethyl)benzamide (BZ-6)

presence of stacking interactions along the c-glide plane which

The compound BZ-6 crystallizes in the centrosymmetric

monoclinic space group P2 /n [Fig. S5(n), ESI ]. The packing

1

3

2

1

contribute 5.6 kcal mol

(motif 2) to the stabilization

[

Fig. 13(d)]. It is to be noted that motif 5 consists of dimeric

in the crystal structure involves formation of molecular sheets

3

…

3

C9(sp )–F2 F3–C9(sp ) (3.072 Å, h

C9(sp )–F3 F3–C9(sp ) (3.007, h = h₂= 93u) interactions.

These contribute 2 kcal mol (Table S3, ESI and Table 4)

3

1

2

= 90u, h = 127u) and

…

with the utilization of a strong N–H OLC (motif 1, 29.6 kcal

3

…

3

1

21

mol ) down the ab plane [Fig. 14(b)]. It is of interest to note

2

1

the occurrence of motif 7 in the crystal packing (the CH and

3

towards the stabilization of the crystal, which is slightly higher

than the stabilization coming from motif 6, consisting of two

CF

kcal mol

3

group come close to each other, thus these provide 1.4

21

of stabilization, with the dispersion being the

2

…

3

C–H(sp ) F–C(sp ) hydrogen bonds. The dimeric C9(sp )–

major contribution), which forms the molecular chain along

the b-axis in the crystal structure [Fig. 14(b)]. The packing also

displays the formation of a molecular sheet with the utilization

…

3

F1 F3–C9(sp ) (3.018 Å, h = 132u,h = 112u) (Table S3 ) are

also found to be stabilized by 21.1 kcal mol . The calculation

1

2

1

for the isolated pairs also gave similar results for these

2

3

…

21

…

of weak C–H O along with C(sp )–H F–C(sp ) (motif 3, I.E. =

4

1

fluorous interactions (Table 4). The DFT-D3/B97-D calcula-

tion of total interaction energy of tetrameric motif [Fig. 13(e)]

2

3.3 kcal mol ) utilizing a 2

1

screw along the b-axis and weak

dimeric C(sp )–H F–C(sp ) hydrogen bonds (motif 6, provides

.3 kcal mol to the stabilization) [Fig. 14(c)]. The second

2

…

3

2

1

gave an overall stabilization by 23.39 kcal mol

.

21

2

most stabilizing dimeric motif 2 [Fig. 14(a), molecular pair

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Fig. 11 (a) Depiction of molecular pairs with their interaction energies in BZ-3 calculated from PIXEL and DFT-D3 calculation (Table 4). (b) Packing view down the ab

…

2

…

2

…

3

…

plane displaying N–H OLC, C(sp )–H OLC, bifurcated C(sp )–H F and C(sp )–H F hydrogen bonds in BZ-3. (c) Packing view down the ac plane, displaying the

2

…

3

…

stacking motif, C(sp )–H F, C(sp )–H F and C–H p hydrogen bonds in BZ-3 (small red ball represents the center of gravity of phenyl ring, the big red ball represents

…

oxygen atom). (d) Packing view down the ab plane depicting weak C–H O hydrogen bonds in BZ-3.

…

3^…

3

…

tions between the CH CF group forming C(sp )–H F–C(sp )

3

linked via weak C–H O and C–H p hydrogen bonds, I.E. =

2

1

21

2

7.7 kcal mol ] arranged down the bc plane with motif 4

contributing 2.8 kcal mol stabilization) and weak interac-

H-bonds (motif 7, I.E. = 21.4 kcal mol ) [Fig. 14(d)].

2

1

(

3

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Fig. 12 (a) Molecular pairs in the crystal structure with their total interaction energy calculated from PIXEL and DFT-D3 (Table 4) in BZ-4. (b) Packing view down the bc

…

2

…

3

…

2

…

3

…

3

plane displaying N–H OLC, C(sp )–H OLC, C(sp )–H OLC, C(sp )–H p and C(sp )–F F–C(sp ) hydrogen bonds in BZ-4. (c) Packing view down the ab plane

…

2

…

3

…

3

…

showing C–H OLC, C(sp )–H F–C(sp ) hydrogen bonds and C(sp )–F F–C(sp ) intermolecular contacts in BZ-4. (d) Packing of molecule in BZ-4 with C–H OLC and

2

…

C(sp )–H F hydrogen bonds.

A comparative study of the key supramolecular motifs, with

inputs from energy calculations in these compounds reveal the

following relevant discussions:

3. The total interaction energies (lattice energies) of all of

the compounds were obtained to be experimentally similar to

the sublimation energies [except for AC-3 (Form I)].

1

. The energy associated with the motif 1 (containing a

4. It was observed that there occurs a change in the crystal

packing associated with substitution with either fluorine or

trifluoromethyl group when compared to the parent com-

pound, thereby signifying the participation of different kinds

of stable supramolecular motifs that contribute towards the

stability in crystal packing.

5. A very important and significant observation is as follows:

It is to be noted that in the case of the parent compounds (AC-

0 and BZ-0) the summation of the interaction energies coming

from contributions of the ‘‘initial’’ most stable molecular pairs

approach the final value of the lattice energy. Interestingly, in

the case of their fluoro or trifluoromethyl analogues, this

requires the contribution of an increased number of molecular

pairs, this resulting from the possibility of increased participa-

tion of organic fluorine in different intermolecular interac-

tions in the crystal. Hence it can be concluded that in reality a

…

strong N–H OLC hydrogen bond) in the crystal structures

were found to be similar (the value lies within the range of 28

2

1

to 29 kcal mol , with a major contribution towards the

stabilization being coulombic in origin) in the case of all the

compounds. Hence the motif 1 can be considered as the main

building block observed in the crystal structure of all the

compounds.

2. The interaction energy of almost all the molecular pairs,

except for the stacked dimer in the crystal environment (the

PIXEL calculations) were found to be similar to those in

isolated state (DFT-D3/B97-D calculations). The molecular

stacking was found to be more stabilized in the latter

compared to that in the crystal environment.

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Fig. 13 (a) Selected molecular pair present in crystal with their interaction energies from PIXEL and DFT-D3 calculation (Table 4) respectively in BZ-5. (b) Packing view

…

2

…

3

down the ab plane, displaying strong N–H OLC, weak C–H O C(sp )–H F–C(sp ) hydrogen bonds in BZ-5. (c) Packing view down the ab plane, displaying

…

3

…

3

…

3

CLO CLO interactions along with weak C(sp )–H O hydrogen bonds and C(sp )–F F–C(sp ) interactions in BZ-5. (d) Packing molecule down the bc plane in BZ-5.

… …

e) Tetrameric motif in BZ-5 depicting C(sp )–F F–C(sp ) and C(sp )–H F–C(sp ).

3

2

3

(

…

C–H O (23 to 5 kcal mol ) . motifs containing mainly

21

re-distribution of the total stabilization energy happens

amongst the different supramolecular motifs observed in the

crystal.

2

1

interactions involving fluorine (21 to 23 kcal mol ).

7. A close analysis of the energetics of different molecular

pairs involving hydrogen bonds with fluorine (explicitly given

in Table S5, ESI ) reveals that motifs containing C(sp )–H F–

…

C(sp /sp ) are more stabilized than those of C(sp )–H F–

6. The order of interaction energies were observed in most of

2

…

the cases in descending order of magnitude as follows: motif

3

…

21

3

2

3

containing N–H O, strong H-bonds (28 to 29 kcal mol ) .

2

1

3

2

3

2

molecular stacking (24 to 27 kcal mol ) . motifs containing

C(sp /sp ). In addition, it is also observed that C(sp /sp )–

3

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Fig. 14 (a) Selected molecular pair with their interaction energies calculated from pixel and DFT-D3 calculation (Table 4) in BZ-6. (b) Packing view depicting the

…

2

…

3

…

3

formation of molecular sheets down the ab plane via strong N–H OLC, weak C(sp )–H F–C(sp ) hydrogen bonds and C(sp )–F F–C(sp ) interactions in BZ-6. (c)

…

3

…

3

Packing view depicting formation of sheets via weak C–H O, C(sp )–H F–C(sp ) and C(sp )–H F–C(sp ) hydrogen bonds in BZ-6. (d) Packing of BZ-6 down the bc

2

…

3

…

3

…

3

plane, showing formation of layers via weak C C(sp )–H O, C(sp )–H p hydrogen bonds and C(sp )–F F–C(sp ) interactions.

…

3

2

H F–C(sp ) are more stabilized than those in C(sp /sp )–

constituted of the basic functional groups that are present in

the current scheme of molecules. This will enable an improved

understanding of such weak interactions, particularly those

involving organic fluorine and enable an identification of

2

3

H F–C(sp ). This indicates that fluorine connected to sp

hybridized carbon has greater propensity of forming H-bonds.

‘‘recurring’’ molecular pairs which are present as key building

Conclusions

blocks in the crystal structure. To summarize, a complete

understanding of fluorine interactions has still not been

achieved and extended investigations in different molecules is

of importance and of focus.

The synthesis, crystallographic investigations and quantitative

estimation of the energetic contributions of different ‘‘key’’

supramolecular motifs, particularly those involving organic

fluorine in the context of crystal packing has been established

in the manuscript. In addition to the significance of the

Acknowledgements

…

coulombic nature of strong N–H OLC and C–H OLC

H-bonds, the stabilizing role of stacking interactions along

with the dispersive nature of C–H F H-bonds and related

The authors thank IISER Bhopal for research and instrument

facilities. PP acknowledges the help from Mahesh, IISER

Mohali for discussions related to PIXEL calculations and UGC

for JRF-SRF funding. We thank Dr V. Srinivasan for help in the

theoretical calculations related to TURBOMOLE. DC thanks

the DST-Fast track scheme 2010 for funding.

…

interactions involving fluorine has been realized in these

library of molecules. Contributions from fluorine interactions

are significant and do contribute towards the overall stability

of the crystal packing. It is now of interest to extend this

evaluation of the energetic contribution of interactions

involving organic fluorine in related complex molecules

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2

0 (a) D. Chopra and T. N. Guru Row, CrystEngComm, 2008,

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Article Doi

Quantitative insights into energy contributions of intermolecular interactions in fluorine and trifluoromethyl substituted isomeric N-phenylacetamides and N-methylbenzamides

DOI: 10.1039/c3ce40111a

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Article abstract of DOI:10.1039/c3ce40111a

Full text of DOI:10.1039/c3ce40111a

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