Acid···Amide Supramolecular Synthon in Cocrystals: From

Apr 26, 2018 - The acid···amide dimer heterosynthon in cocrystals of aromatic acids and primary amides is identified by marker peaks in the IR spec...
1 downloads 0 Views 3MB Size
Subscriber access provided by Universiteit Utrecht

Acid•••Amide Supramolecular Synthon in Cocrystals: From Spectroscopic Detection to Property Engineering Subhankar Saha, and Gautam R. Desiraju J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02435 • Publication Date (Web): 26 Apr 2018 Downloaded from http://pubs.acs.org on April 26, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Acid···Amide Supramolecular Synthon in Cocrystals: From Spectroscopic Detection to Property Engineering Subhankar Saha and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India E-mail: [email protected] Abstract: The acid···amide dimer heterosynthon in cocrystals of aromatic acids and primary amides is identified by marker peaks in the IR spectra that are characteristic of individual N– H···O and O–H···O interactions and also of the extended synthon. The O–H···O hydrogen bond is crucial to heterodimer formation in contrast to the N–H···O bond. A combinatorial study, tuning the chemical nature of acid and amide functionalities, leads to 22 cocrystals out of 36 crystallization attempts. Four quadrants I-IV are defined based on acidity and basicity of the acid and amide components. The strong acid–strong base combination in quadrant I favors the planar acid···amide heterodimer in its eight cocrystals. Quadrant IV with its weak acid–weak base combination is the least favoured for the planar heterosynthon and synthon diversity is observed in the eight cocrystals obtained. The strong–weak and weak–strong combinations in quadrants II and III are expectedly ambivalent. This exercise highlights the effect of molecular features on supramolecular behaviour. Quadrant I crystals, with their propensity for the planar acid···amide heterodimer are suitable for the engineering of crystals that can be sheared. This quadrant favours the formation of elastic crystals too. The overall result is that 57% (4 in 7) of all crystals in this quadrant are deformable, when compared with 14% (1 in 7) in the three other quadrants. This work is a complete crystal engineering exercise from synthon identification to a particular desired crystal packing to property selection. One can virtually anticipate the mechanical property of a putative acid···amide cocrystal from a knowledge of just the molecular structures of the constituent acid and amide molecules. 1. Introduction The acid···amide heterosynthon is a structural module that has been used extensively in experimental crystal engineering,1−4 especially in the design of cocrystals.5 The robustness, and consequent utility, of this synthon owes to the presence of strong and highly directional N–H···O=C and O–H···O=C interactions. The synthon has been used since the early days of the subject.6−10 It finds application in higher order multicomponent crystal design11−13 especially of pharmaceuticals.14−18 Acid and amide functionalities recognize each other in different ways (Figure 1) and many studies attempt cocrystallization of acids with amides.19−31 However, it is the closed acid···amide heterodimer (Figure 1a) that is the most frequently observed. Why is this particular pattern so common? For example, a hetero acid···amide catemer (Figure 1b) has not been observed so far for achiral amides.32,33 On the

1 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

other hand, the coexistence of isolated acid···acid and amide···amide dimers is very rare (Figure 1c).34,35 An understanding of the acid···amide system is important because it can, in principle, lead to new synthetic strategies36 from these easily obtainable components. Any change in the basic synthon patterns of the primary recognition units will alter the structure type completely.37 During molecular association at the late stage of crystallization, it would not be unusual if functionalities from other molecules, cofomer or solvent interrupt the desired synthon formation, as is frequently observed for the acid···acid dimer.38,39 Such possibilities can exist in a dynamic equilibrium during crystal nucleation. Is it possible, under suitable conditions, to image such interruptions in acid···amide synthon formation too (Figure 1d)? And when is such interruption more likely? How does strategize towards other possibilities? What are the connections between molecular structure and synthon selection and how would one map them?

Figure 1: Acid and amide associated synthons. (a) Common heterodimer synthon, (b) hypothetical heterocatemer, (c) rarely observed coexistence of isolated acid···acid and amide···amide homodimer synthons, and (d) interruption (X, Y) during acid···amide synthon formation. Either or both N‒H···O/O‒H···O interactions may be interrupted. Spectroscopic data are usually associated with chemical features. Recently, it has been shown that IR spectroscopy can identify “markers” that may be used to detect supramolecular synthon.40−43 A given synthon is associated with its spectroscopic signature. Can one go directly to crystal engineering from just a synthon marker as input? The present work deals with such a question. We show that one can move from a methodology such as spectroscopy → {synthon} → {crystal structure} → property towards a direct progression, spectroscopy → property using the acid···amide synthon as a case study. The phrases {synthon} and {crystal structure} are in brackets because we attempt to show that they are inherent in the progression from spectroscopy to property. Understanding the structural landscape allows one to follow crystallization pathways.44,45 In principle, a given molecule is associated with a large number of virtual crystal structures within a small energy range.46−50 There are many factors that govern the structure type obtained, such as the molecule itself, its shape and size, its supramolecular recognition characteristics, and the effect of environment (solvent, coformer, temperature, pressure) during the experiment.44,51−53 These possibilities allow one to secure different, 2 ACS Paragon Plus Environment

Page 2 of 29

Page 3 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

perhaps otherwise inaccessible, structures that together constitute the landscape. While the landscape is initially represented by a group of real structures, one can further invoke a virtual library of synthons and in the end, crystal structures.37, 44, 45 Synthons are kinetic units, and contain information pertaining to the process of crystallization.54 As per classical nucleation theory, it is quite possible that these synthons form initially in solution and carry over into the final product. All this information taken together can help to correlate the structural profile with crystallization events, an understanding of which may result in developing new crystal design strategies. Synthon structures in solution can be imaged directly by spectroscopic studies35,55,56 and indirectly through experimental crystal structures37, 57 or by computation.58, 59 IR and NMR spectroscopy is used to correlate synthon structure in the solid state with solution.35,55,56 Computational studies through crystal structure prediction (CSP) explore the crystal energy landscape of a given system, generally in the low energy‒high density region.59 High throughput crystallography could be used to access different structural patterns.44 As a property is associated with a particular structure type,60 any deviation from the structure would result in undesired outcomes. How does one target a particular structure type with specific synthon(s) to obtain a particular crystal property, say mechanical behaviour,61−63 which is completely a supramolecular property, and not a molecular property? Mechanical properties of molecular crystals and structure-property relationships find application in diverse fields.64−71 Design of soft-flexible crystals72−77 is useful from different aspects, ranging from pharmaceuticals to biomaterials.78−80 Permanently deformable shearing crystals are expected to perform well as (1) high density energy materials/explosives;81 (2) easily tabletable drugs;79 (3) highly clean surface materials for organic molecular beam epitaxy through layer exfoliation.82 However, shearing crystals are the rarest kind of mechanically deformable crystals, as they require that multiple structural and interaction criteria are fullfilled.83 Cocrystals are poorly studied, in this context.84 The presence of the amide functionality in molecules results generally only in brittle crystals.73 Can one design an amide to get soft flexible crystals? The present study starts with IR spectroscopic analysis of the titled synthon and continues with a systematic development of the acid···amide structural chemistry to achieve finally, mechanical property engineering for both plastic and elastic crystals. 2. Results and discussion The various acid···amide synthons are discussed in the context of detection, synthon characteristics and property engineering. 2.1. IR analysis of acid···amide dimer synthon We discuss IR spectroscopic aspects of the acid···amide dimer synthon. 2.1.1. Spectroscopic features for N‒H···O interaction To study the chemical nature of the acid···amide heterodimer synthon through IR spectroscopic analysis, we started with a known cocrystal of 3,5-dinitrobenzoic acid and 3 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 29

benzamide that contains the acid···amide dimer synthon (Figure 2b).85 The corresponding single component molecules, 3,5-dinitrobenzoic acid and benzamide respectively, contain acid···acid (Figure 4a) and amide···amide homodimers (Figure 2a) in their native structures. The acid···amide dimer synthon contains one N‒H···O and one O‒H···O interaction, as shown in Figure 1. We focus on the changes in the molecular functional group vibrations in the cocrystal with respect to the single component systems to understand the chemical basis for heterodimer formation. Attention is paid to the vibration frequencies of the N‒H group of amide and O‒H group of acid molecules. The former functionality, N‒H, is easy to monitor as it shows characteristic high intensity, sharp stretching bands in the higher wavelength region (~3400 cm‒1) of the IR spectrum. The cocrystal shows asymmetric (νas) and symmetric (νs) stretching vibrations of N‒H at 3491 and 3213 cm‒1, respectively (Table 1, Figure 2b). On the other hand, the amide···amide homodimer of the single component benzamide displays νas = 3364 and νs = 3166 cm‒1 at lower vibration energy (Table 1, Figure 2a). The extent of IR band shifts (∆ν) from the single molecular crystal to the cocrystal are respectively ∆νas: 3364 ‒ 3491 = ‒127 cm‒1 and ∆νs: 3166 ‒ 3213 = ‒47 cm‒1, in other words it is blue shifted. This means that the N‒H···O interaction is more stable in the single component amide crystal when compared to the cocrystal. Why does the primary acid···amide synthon even form?

(a)

(b)

Figure 2: Amide N‒H band positions in the IR spectra of (a) benzamide and (b) 3,5dinitrobenzoic acid + benzamide cocrystal. Cocrystal formation shows significant blue shifting in the N‒H band vibration.

4 ACS Paragon Plus Environment

Page 5 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Table 1: IR band positions of functionalities under discussion. N‒H (cm‒1) Compound

Benzamide

νas

νs

3364

3166

∆ν ν (N‒H) (cm‒1) ∆ν νas

∆ν νs

3,5-Dinitrobenzoic acid

O‒H broad band (cm‒1)

∆ν ν (O‒H) (cm‒1)

~ 2800

3,5-Dinitrobenzoic acid + Benzamide

3491

3213

4-Chlorobenzamide

3362

3172

3,5-Dinitrobenzoic acid + 4-Chlorobenzamide

3479

3206

‒127

‒47

~ 2400, ~ 1900

> 300

‒117

‒34

~ 2400, ~ 1900

> 300

Pentaflurobenzoic acid

~ 2800

Pentaflurobenzoic acid + Benzamide

3428

3223

‒64

‒57

3-Nitrobenzoic acid

~ 2400, ~ 1900

>300

~ 2800

3-Nitrobenzoic acid + Benzamide

3472

3224

‒108

‒58

~ 2500, ~ 1900

> 200

It is possible that the result is specific to this system. Accordingly, IR spectroscopic data of some other cocrystals: 3,5-dinitrobenzoic acid + 4-chlorobenzamide;86 pentaflurobenzoic acid + benzamide;2 and 3-nitrobenzoic acid + benzamide85 having the same heterosynthon were further analysed (Table 1, see Figure S1-S2 in ESI). In all cases the N‒H stretching bands are blue shifted due to the formation of acid···amide dimers. These consistent blue shifts suggest that while the N‒H···O interaction does form, it is actually destabilized in the heterodimer relative to the native amide. The reasons for such an unexpected observation are suggested in Figure 3 (see ESI S6 for detailed explanation) in which the replacement of a more basic O-atom in the amide (in the amide···amide homodimer) by a less basic O-atom from the acid (in the acid···amide heterodimer) leads to weakening of N‒H···O interaction and thus results in a blue shift. So, the N‒H···O interaction is not primarily responsible for acid···amide dimer formation. Where does the stability arise then in this apparently destabilized system?

5 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 3: Dimer synthons of interest. (a) Amide···amide homodimer with stronger N‒H···O hydrogen bonds (HBs) compared with those in (b) Acid···amide heterodimer. (c) Acid···acid homodimer contains weaker O‒H···O interactions with respect to that in acid···amide dimer. (d) The electrostatic surface potential (ESP) calculation using DFT-B3LYP method and 6311G(d,p) basis set for the model systems formamide and formic acid shows higher negative ESP charge on carbonyl O-atom of the amide (–157 kJ) compared to the acid (–116 kJ), supporting the above explanation. ESP maps are obtained for molecular electron density 0.0004 electron/Å. 2.1.2. Spectral features for O‒H···O contact We focus now on the other part of the acid···amide dimer, i. e. the O‒H···O interaction. If we extend the same analogy of strong/weak basicity of carbonyl O-atom, the O‒H···O interaction in an acid···amide dimer must be stronger compared to that in an acid···acid dimer (Figure 3b,c; see ESI S7 for detailed explanation). So, there should be a red shift in the O‒H stretching band on cocrystal formation. This is exactly what was found in all cases (Table 1). When these relatively less intense, broad bands were carefully inspected (Figure 4 and also see Figure S3-S5 in ESI), it was found that the O–H broad stretching bands are red shifted from ~2800 cm–1 in single component crystals to ~2400 cm–1 and ~1900 cm–1 in the cocrystals.

6 ACS Paragon Plus Environment

Page 6 of 29

Page 7 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

(a)

(b)

Figure 4: Acid O‒H broad band positions in the IR spectra of (a) 3,5-dinitrobenzoic acid and (b) 3,5-dinitrobenzoic acid + benzamide cocrystal. Anticipated red shift (> 200 cm–1) is observed on cocrystal formation and shows acid···amide dimer formation. Corroboration of the spectral shifts of N‒H···O and O‒H···O interactions in going from the native crystals to the cocrystals is also obtained by computation.1 This stabilization from the O‒H···O interaction to heterodimer formation is indicated from the combined energies of one acid homodimer and one amide homodimer, with two acid···amide heterodimer synthons. The former is ‒120 kJ/mol (two O‒H···O = ‒ 64.8 kJ/mol and two N‒H···O = ‒ 54.8 kJ/mol). The latter is ‒124 kJ/mol (one O‒H···O and one N‒H···O taken overall twice) in other words ‒ 62 kJ/mol per heterodimer. The energy difference between the two homodimer versus two heterodimer possibilities is admittedly small. Therefore, the reason for the near preponderance of the latter structure type for acid···amide cocrystals could be kinetic: it may simply be easier to assemble heterodimers in solution rather than two sets of homodimers, acid and amide. In summary, the large red shift and energy associated with the concerned interactions mean that the O‒H···O hydrogen bond is the major factor for acid···amide dimer synthon formation. In other words, an increase in the acidity of the carboxylic proton and basicity of the carbonyl O-atom of amide leads to its formation. What happens when these chemical preferences are altered or tuned? This is the methodology of crystal engineering in the acid···amide system and is what we try to address in the following section.

7 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 29

BZM BA

4-OMe (A)

4-OH (B)

4-Me (C)

4-Cl (D)

4-NO2 (E)

3,5-NO2 (F)

3,5-NO2 (1)

1A

1B

1C

1D

1E

1F

3-NO2 (2)

2A, acid···amide catemer

2B

2C

2D

2E

2F, acid···amide ···HO trimer

3-CN (3)

3A

3B

3C

3D

3E

3F

Quadrant I 3-OH (4)

4-OH (5) 4-NH2 (6)

4A

5A, acid···amide catemer

6A

Quadrant II

4B

4C

4D, acid···acid,am ide···amide dimer

5B

5C, acid···acid dimer

5D, acid···acid dimer

5E, acid···acid dimer

6B, acid···amide catemer

6C

6D

6E

Quadrant III

4E

4F, acid···amide ···HO–Ar trimer 5F, acid···amide ···HO–Ar trimer 6F

Quadrant IV

Figure 5: Combinatorial landscape. BA = Benzoic acid derivatives, BZM = benzamide derivatives. Numerical digit(s) before functional groups indicates substitution positions. Blue: cocrystal with acid···amide dimer; Red: cocrystal without acid···amide dimer; Grey: cocrystal did not form; Yellow: new phase found from PXRD. 2D and 5B form poor quality crystals. 6E form charge transfer (CT) cocrystal, but refinement was not possible due to stacking associated functional group disorder. 2.2. IR study to structural landscape This chemical information from the IR study is now used for a combinatorial analysis (Figure 5) by systematic variation of the chemical nature of the molecules through substitution changes. The leftmost column represents the aromatic carboxylic acids (BA) and the uppermost row shows the aromatic amides (BZM) that are used. The acidity of carboxylic acids decreases down the column as the functional group changes from electron withdrawing to electron donating. In a similar way, basicity of the amides is also monitored from the left (more basic) to the right side (less basic). This arrangement divides the whole combination into four quadrants (Figure 5), I through IV. Quadrant I has a combination of strong acids with strongly basic amides. This should be the most preferred chemical situation for acid···amide dimer formation, and is so indicated by IR analysis. On the other hand, quadrant IV with just the opposite chemical trend, weaker acids and weakly basic amides, should disfavour the concerned dimer synthon formation. Quadrant II represents a combination of strong acids with weakly basic amides and vice versa quadrant III with weak acids and strongly basic amides. In neither of these cases (II and III), is the condition for dimer 8 ACS Paragon Plus Environment

Page 9 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

optimally satisfied. It is of interest to see whether these chemical inputs/predictions from IR analysis can shed some light on the structural behaviour/variation in terms of supramolecular synthons and whether one can construct a structural landscape combinatorially to explore the various crystallization possibilities for the acid‒amide system.

Figure 6: Structures in quadrant I show predominance of the acid···amide dimer synthon. Out of the total of eight structures, seven form the heterodimer. Only 2A forms an acid···amide catemer synthon. 2.2.1. Synthon patterns for different quadrants Quadrant I: Strong acid + strongly basic amide In this quadrant, we select carboxylic acids, 3,5-dinitrobenzoic acid, 3-nitrobenzoic acid, 3-cyanobenzoic acid and the amides, 4-methoxybenzamide, 4-hydroxybenzamide and 4toluamide. Strong electron withdrawing capability of nitro and cyano groups enhances the acidity of carboxylic acids. On the other side, methoxy, hydroxyl and methyl groups with their electron donating nature increase the basicity of the amide carbonyl O-atom. Combining three amides with three acids results in nine cocrystal possibilities—of these we got eight cocrystals. Cocrystal formation between 3-cyanobenzoic acid and 4-methoxybenzamide was not observed. Among these eight cocrystal structures, seven take the acid···amide heterodimer synthon (1A, 1B, 1C, 2B, 2C, 3B and 3C; Figure 6) and the last one forms an

9 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

acid···amide catemer synthon (2A). This clearly shows the dominance of the titled dimer synthon in this quadrant.

Figure 7: Structures in quadrant IV show preference for synthons other than the acid···amide dimer. Out of total seven structures, five form the non-heterodimer and only two 4E and 6F form the acid···amide dimer. Quadrant IV: Weak acid + weakly basic amide One next tries to switch the chemical functionality, i. e. use a weak acid and weakly basic amide. In quadrant IV, the carboxylic acids taken are 3-hydroxybenzoic acid, 4hydroxybenzoic acid and 4-aminobenzoic acid. 4-Chlorobenzamide, 4-nitrobenzamide, and 3,5-dinitrobenzamide are the selected weakly basic amides. Heterodimer formation is disfavoured and is seen in just two (4Eand 6F) of eight cocrystals obtained out of nine cocrystallization attempts. Five others form non-dimer synthons. One of them has acid···acid and amide···amide homodimers (4D). Two have acid···acid dimers with phenol···amide interactions (5D and 5E) while two others have acid···amide···phenol mediated trimer synthons (4F and 5F) (Figure 7). Structures of 1B in quadrant I and 5F in quadrant IV are noteworthy. Both systems have the same functionalities but switched between acid and amide. 1B contains 3,5dinitrobenzoic acid and 4-hydroxybenzamide, whereas 5F contains 4-hydroxybenzoic acid 10 ACS Paragon Plus Environment

Page 10 of 29

Page 11 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

and 3,5-dinitrobenzamide. This exchange, not unexpectedly, changes the major synthon pattern. The former shows the heterodimer whereas the latter exhibits an interrupted dimer. In summary, quadrant IV with its weak acid and waekly basic amide combination shows a greater diversity in synthon preferences.

Figure 8: Quadrants II and III together show a variety of synthon possibilities, acid···amide dimer, acid···amide catemer, acid···acid dimer and other acid···amide non-dimer. Quadrant II: Strong acid + weakly basic amide Quadrant II is composed of strong acids 3,5-dinitrobenzoic acid, 3-nitrobenzoic acid, 3-cyanobenzoic acid and weakly basic amides 4-chlorobenzamide, 4-nitrobenzamide, and 3,5-dinitrobenzamide. Here, only three cocrystals are obtained out of the possible nine. Two of them (1D, 3D) contain the acid···amide dimer and the other has the acid···amide···phenol trimer (2F) (Figure 8). The crystal structure 1D has been reported with refcode AJAKUR.85 Quadrant III: Weak acid + strongly basic amide Quadrant III is constructed combining weak acids with strongly basic amides. The acids taken are 3-hydroxybenzoic acid, 4-hydroxybenzoic acid and 4-aminobenzoic acid; the amides are 4-methoxybenzamide, 4-hydroxybenzamide and 4-toluamide. Like quadrant II, only three cocrystals are obtained. Of these, two have the acid···amide catemer (5A and 6B), and the other has an acid···acid homodimer with phenol···amide interactions (5C) (Figure 8).

11 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 9: Energy versus density plot for top 100 predicted structures of the 1:1 formic acid : formamide cocrystal in P21/c space group using COMPASS force field. Occurrence of different acid–amide synthons is shown. 2.2.2. Crystal Structure Prediction (CSP) Does this diversity of acid and amide associated synthons belong to the same structural landscape or not? To ascertain this, a computational crystal structure prediction (CSP) was set up for the 1:1 cocrystal of the model system formic acid : formamide. The computation was performed with Materials Studio 6.0 where geometry optimization and electrostatic charge assignment were done in the DMol3 suite of programs. The optimized geometry with assigned ESP charges were taken as an input model for the computational exercise with Polymorph Predictor using the COMPASS force field. To simplify the analysis, the calculation was restricted to the most common space group P21/c (for organic molecules). The top 100 predicted crystal structures were analysed based on low energy and high density as shown in the plot (Figure 9). Analysis of the structures shows that there exists a total of 12 structures with the acid···amide heterodimer (Ranks: 5, 6, 9, 16, 18, 26, 37, 55, 64, 74, 82 and 96); 10 structures with the acid···amide heterocatemer (Ranks: 12, 20, 36, 43, 47, 60, 70, 78, 83 and 95) and also insulated acid···acid and amide···amide homodimers in five structures (Ranks: 48, 54, 76, 79 and 81). The number of hits for heterodimer (12) and heterocatemer (10) are comparable. However, the former is found at relatively lower energies with respect to the latter. This may be due to the higher stabilization associated with twopoint recognition over single-point recognition.87 The occurrence of insulated homodimers in the predicted cocrystals is much less when compared to heterosynthons. This is well in accord with the experimental outcome which shows only one structure with the same insulated synthons (4D). This further indicates the role of heterosynthon recognition for 12 ACS Paragon Plus Environment

Page 12 of 29

Page 13 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

cocrystal formation. The existence of these three major recognition types for the same binary system, within a very small energy window (~0.2 kcal/mol) suggests that any of them may present during the late nucleation stage and all together constitute the structural landscape for acid‒amide systems. 2.2.3. Synthons and structural landscape Taken as a whole, all the quadrants grossly follow the IR guidelines for primary acid and amide associated synthons. Quadrant I favours the acid···amide dimer whereas quadrant IV prefers to adopt synthons other than the acid···amide dimer. Quadrants II and III have a variety of possibilities for acid···amide recognition with more or less the same preferences for different types. The acid···amide dimer is a well-known synthon which occurs frequently, suggesting a possible prenucleation stage. However, other associations can be explored using molecular chemical tuning and this study hinted at some virtual synthons which may be possible during the nucleation process. The multiple occurences of the acid···amide catemer pattern indicates that this can also be a convenient recognition pattern to proceed towards nucleation. Catemer synthons with single point contacts are a generally kinetically favoured entity in comparison to the thermodynamically favoured multipoint recognition in dimer formations.87 Acid···acid homodimers are also found frequently. There is also a case (4D) in which acid···acid and amide···amide dimers are insulated. In summary, one may say that homodimer, heterodimer, heterocatemers and other related synthons are in a state of equilibrium during nucleation and that the chemical nature of molecules can influence the formation of a particular type in the actual crystal structure. 2.2.4. Cambridge Structural Database (CSD) study The presence of isolated acid···acid and amide···amide dimers within a cocrystal is not commonly observed as their mutual recognition is primarily responsible for cocrystal formation in the absence of other strong interactions. To ascertain the coexistence of these in the literature, we searched the CSD (version 2016 with two updates) for multicomponent organic systems with insulated acid···acid (at vdw+0.2) and amide···amide (at vdw+0.2) dimers. The acid and amide functionalities are considered from different molecules and without the presence of any other strong competing group, like pyridine. This results in two cocrystals, one of which, the cocrystal of gallic acid and acetamide, which has two polymorphs (Refcode: PEFGEO01, PEFGEO02)34 and the other one is a cocrystal of 3,5dihydroxybenzoic acid and 4-aminobenzamide (Refcode: ZOHXAX).35 No report is also found in the CSD when we searched for cocrystals with the acid···amide catemer for aromatic primary amides. The CSD also shows that ours is the first report of the acid···amide catemer in cocrystals of achiral molecules. 2.2.5. Other synthons of significance Mention should be made of some other synthons which occur in this study, although they are not associated just with acid and amide groups. These are (a) phenol···amide catemer and (b) acid···amide···phenol trimer. The former one is observed in five structures 13 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(1B, 5D, 5E, 5A and 5C) and latter is seen in three cases (4F, 5F and 2F). The high frequency of occurrence for the former one suggests that a cocrystal can be designed using phenol···amide as major synthon. The latter synthon is preferred by 3,5-dinitrobenzamide, and may be due to significantly decreased basicity of the amide O-atom and simultaneous increase in N‒H acidity by the two nitro groups, so that the (amide)N‒H···O(acid) becomes significantly stabilized and the earlier major concerned interaction (acid)O‒H···O(amide) gets destabilized. At this stage, the sp3 hybridised O-atom of the phenolic O‒H is probably sufficiently basic to compete with the sp2 hybridised O-atom of the amide so that one finally gets an acid···amide···phenol trimer synthon. Interestingly, there is a system (2F, Figure 8) which does not have any O‒H functionality in either of the coformers, but possesses the trimer synthon,using water of crystallization. The presence of this water mediated synthon interruption suggests that such synthons can persist during the late stages of nucleation, possibly for amides with strong electron withdrawing groups (Figure 1d). 2.3. From structural landscape to mechanical properties Layered structures lead easily to crystals that can be sheared.83 Among the acid···amide associated synthons, the planar zero-dimensional heterodimer can be a constituent of a planar sheet and, in principle, lead to a crystal that can be sheared. The onedimensional heterocatemer is non-planar and cannot be a part of a lamellar structure. To obtain a sheet structure in an acid–amide cocrystal, there is the additional requirement that the various functional groups should also be compatible with the sheet; in other words, groups like NO2, CN, OH, OMe are suitable while say, tert-butyl and sulfonyl are not, resulting in brittle crystals.73 Presence of planar functionalities can further assist by providing in-plane directional interactions. Quadrant I with its combination of a strong acid and a strongly basic amide has a higher propensity for acid···amide dimer formation,which in turn increases the chance of planar sheet structure construction.This is why this quadrant I is preferred to obtain shearing crystals. In contrast, elasticity is favoured by any structural feature that promotes higher packing dimensionality and this may be achieved with either heterodimers or heterocatemers based on the specific circumstances.72, 74−77 As IR spectra provide evidence of the presence of synthon patterns, and especially the occurrence of the acid···amide heterodimer, we are in effect proposing a linking of synthon signature with property engineering. 2.3.1. Testing mechanical properties

A. Shearing When crystals of 1A and 2B are supported with a pair of forceps and poked at the other end, a movement of the part of the crystal over the other was observed (Figure 10). The movement was irreversible and hence created permanent deformation. Such mechanical property by permanent molecular migration demonstrates shearing crystals. This property results from irreversible layer migrations. Although we found only two shearing cocrystals, we believe this to be noteworthy. The corresponding single component crystals are brittle in their native states. 14 ACS Paragon Plus Environment

Page 14 of 29

Page 15 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Figure 10: Permanent change in the crystal shape after shearing for a crystal of 2B.

B. Elasticity When long acicular straight crystals of 2C, 2A, 3D, 6B and 4D were fixed at one end with glue and force applied at the other end using a metallic needle, they adopted a semicircular arc shape (Figure 11). Unloading of the mechanical force brought them back to the initial straight shape. This is a case of reversible deformation and seen here for the first time in acid···amide cocrystals. These crystals are elastic. This process of deformation can be repeated many times as shown in the video (see ESI). They break beyond a threshold limit with conservation of the elastic nature within the broken parts. Crystals of the other binary systems we studied were found to be brittle.

Figure 11: Snapshot of a crystal of 2C during elastic deformation.

15 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1A

Page 16 of 29

2B

Figure 12: Crystal packing of shearing crystals. 2.3.2. Identifying structural features and mechanism for shearing Cocrystals 1A and 2B crystallize in the space group P1 and P21/n, respectively. As per expectation, both of them are from quadrant I and exhibit the acid···amide heterodimer synthon. The acid···amide bonded units are assembled via X–H···O (X = O, N and C) interactions in the (212) and (101) plane for 1A and 2B, respectively (Figure 13a1-b1). This in turn generates planar sheet structures. One can realize that the extra hydrogen from the amide N‒H group is helpful in sheet structure formation, as it can direct the secondary assembly formation with adjacent molecules through hydrogen bonding in the same plane of acid···amide dimer. Such sheets with aromatic rings are then π-stacked along the crystal long axis (Figure 13a2-b2). Face indexing shows the existence of such extended planar sheet structures throughout the crystals (Figure 12). Here, the structures are anisotropic in the sense that the interaction strength within a planar sheet is stronger than between sheets. Upon application of external force these loosely bound sheets can move along the direction of applied force with expected rupture and reformation of stacking interactions (Figure 16a). This process leads to permanent molecular migration, that is irreversible plastic deformation. These examples show a route through which one can engineer permanently deformable crystals using the amide functionality. The structure of 3B is similar to the shearing type with nearly sheet type arrangement (Figure 13c). However, there exists solvate water mediated O– H···O interactions in between sheets. These strong interactions remove the structural anisotropy and make the crystal brittle.61 Two other cases 1C and 3C with layer structures, are brittle and are discussed in the SI for a better understanding of shearing behaviour (ESI

16 ACS Paragon Plus Environment

Page 17 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

S11). In both cases, there is an easily understood chemical reason why layer slippage is difficult.

Figure 13: Structural characteristics of quadrant I structures 1A, 2B and 3B. (a1-c1) Strong interactions within planar sheets. (a2, b2) Shearing crystals 1A and 2B. Hydrogen bonded sheets are weakly π-stacked, facilitating irreversible layer migration perpendicular to the direction of stacking. The planar acid···amide dimer is required for such planar sheet structure formation. The catemer or any other non-planar synthon is incompatible with such a structure. (c2) A nearly similar structure (3B) is found to be brittle due the presence of strong O‒H···O interactions between layers, which prohibits slippage of layers. 2.3.3. Identifying structural features and mechanism for elasticity Cocrystals 2C, 2A, 3D, 6B and 4D crystallize in the space groups P21/c (Z’=1), P1 (Z’=2), P21/c (Z’=1), P21/c (Z’=1) and P1 (Z’=1), respectively. Among these five structures, two contain acid···amide dimer (2C and 3D), one contains the acid···acid dimer along with the amide···amide dimer (4D) and the other two have the acid···amide catemer (2A, 6B). Face indexing (ESI S10) shows that in all cases, the aromatic rings of the strongly bonded dimer or catemer units are π-stacked along the crystal needle axis (Figure 14). This is a common structural feature among the elastic crystals in our study. Interlocking is achieved 17 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

with other isotropic interactions along orthogonal directions (Figure 15a1-d1). Such stacking results in the formation of columns and adjacent columns are oriented along a similar direction. This type of packing of stacked columns helps in the adjustment of the structures in various deformed portions of the bent crystal, like inner arc, center and outer arc (Figure 16b). The presence of isotropic interactions along orthogonal directions with interlocked packing forbids permanent deformation of crystals and allows restoration of the deformed structure back to their pristine state. One can notice that π-stacking in elastic crystals may generate corrugated or zigzag layers (Figure 15a2-d2). Such layers with bumps and hollows will not allow permanent slippage of molecules within layers, in other words, they prohibit shearing. The orthogonal geometry of electrostatic halogen bonds [here, Cl···O (3.23 Å) in 4D] are useful in obtaining corrugated layer packing.

18 ACS Paragon Plus Environment

Page 18 of 29

Page 19 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

2C

2A

3D

4D

Figure 14: Packing diagrams for elastic cocrystals in this study viewed down the major faces.

19 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 15: Structural features of elastic cocrystals 2C, 2A, 3D and 4D. (a1-d1) Important interactions that lead to isotropic structures. (a2-d2) π···π stacking generates column structures which are oriented along the crystal needle axis. Such columns can further assemble to form (a2, d2) corrugated/zigzag layer, but they should not create a planar sheet structure. Corrugated structures with isotropic interactions along orthogonal directions prohibit permanent molecular slippage. Structural pattern of 6B is similar to other elastic cases.

20 ACS Paragon Plus Environment

Page 20 of 29

Page 21 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

2.3.4. Mechanical property and relation to landscape A total of seven cocrystals from the landscape show shearing (two) and elastic (five) behaviour; of these four (two shearing and two elastic) are from quadrant I (percent of overall success 57% compared to the three other quadrants with only 14% success each), signifying the special significance of this quadrant for property engineering towards shearing crystals. The structural analysis shows that both dimer and catemer synthons can adopt the requisite structural pattern for elasticity. However, only the dimer (here, acid···amide) is useful to obtain shearing crystals. This is exactly what was anticipated. The heterodimer provides a flat assembly which is a necessary condition for planar sheet formation which is further extended/supported by in plane X–H···O interactions involving planar functionalities, NO2, OMe, OH. In the case of the catemer synthon, the two interacting entities are out of the plane and therefore cannot form the required sheet structure for shearing, but the structure is suitable for elasticity. However, dimer synthons are suitable for both the mechanical properties, elasticity and shearing and this is seen in five of the cocrystals studied. In summary, one may choose the combination of strong acids with stronger basic amides to obtain both elastic and shearing crystals. The IR study provides a quick and reliable indicator of obtaining the targeted property in that the presence or absence of a marker band would allow the researcher to quickly sort out crystals that tend to show a particular mechanical property; in practical terms, crystals that are more likey to be plastic or elastic may be differentiated from those that would be more likely to be brittle based on IR synthon markers.

Figure 16: Mechanism for (a) shearing and (b) elasticity. 2.3.5. Models The above structural analysis helps to derive models for shearing and elastic crystals (Figure 17). The models can be considered as the basis for property engineering in the future.

21 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 17: Derived models for (a) shearing and (c,d) elastic crystals. (b) 3D schematic projection showing necessity of planar sheet structure for shearing crystals. In case of elastic crystals π-stacked columns should be oriented along the same direction, crystal needle axis and there should be absence of planar sheet structure. 3. Conclusions Taken as a whole, the present exercise demonstrates how spectroscopic information can be used to guide organic solid state design, and how this can in turn be translated towards property engineering. Since the acid···amide heterodimer is suitable for both mechanical properties, plasticity and elasticity, quadrant I where it predominates is the most suitable chemical combination. Thus one can start with spectroscopic identification and directly go into crystal property engineering, without getting into any deep structural analysis involving supramolecular synthons. In the end, the presence of the synthon is indicated through its spectroscopic signature and one then tests the sample for its mechanical properties immediately. Spectroscopy is the sampling techniques that tells one where the chance of getting the desired property is greater and where it is lesser. A more ambitious venture would be to associate a particular type of mechanical property with a particular IR spectral signature. In this study, the IR marker bands relate to bending and stretching of covalent bonds. However, plasticity, elasticity and brittleness are associated with specific intermolecular interactions and how these interactions relate to one another. IR markers for such phenomena would be expected to lie in the low energy IR region (< 200 cm‒1) because these effects have to do with particular types of vibrational mode mixing in the form of phonon coupling in the crystal lattice. For example, the IR distinction between plastic and elastic crystals, with their differing degrees of isotropy, would be 22 ACS Paragon Plus Environment

Page 22 of 29

Page 23 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

connected with the coupled modes of the interactions themselves (say π···π as a whole with C‒H···π as a whole). Modern crystal engineering uses crystallography, spectroscopy and computation. These three are the pillars for advancement of the field. It is perhaps difficult to consider/utilize all these together/simultaneously to develop/understand in any given crystal engineering problem, and specially for property engineering. Accordingly this study may raise some questions in the mind of the reader: (1) Is it possible to apply a molecular cut off for the appearance of a synthon, beyond which the recognition pattern/geometry would change? (2) How can one achieve more control, in other words address small deviations from the expected synthon patterns in the respective quadrants? (3) How can unusual synthons be controlled and utilized for crystal engineering purposes? (4) At what point does the same synthon lead to different structures that reflect differences towards macroscopic properties, shearing and elasticity? (5) How can one get more control over the design of a particular property, especially shearing crystals? (6) Can one establish IR markers for different types of mechanical response, as discussed above? These queries may be taken up as future research problems. 4. Experimental and computational details 4.1. Crystallization Equimolecular amounts (1:1) of the corresponding compounds were taken in a mortar and pestle and then liquid (ethanol) assisted grinding was performed on each binary mixture. Individual sets of ground powders were dissolved in different solvents in glass vials. The glass vials were wrapped with an aluminium foil with a small hole on it. The vials were kept at room temperature for slow evaporation of solvent. Crystals suitable for single crystal X-ray diffraction were obtained after ~ 7 days. The solvent of crystallization for individual cases are, 1A: MeOH; 1B: EtOAc; 1C: MeOH; 2A: MeOH; 2B: MeOH; 2C: EtOH; 3B: EtOAc; 3C: Me2CO; 2F: EtOAc; 3D: MeOH; 5A: EtOAc; 5C: THF; 6B: MeOH; 4D: MeNO2; 4E: MeCN; 4F: EtOAc; 5D: MeNO2; 5E: MeOH; 5F: MeOH; 6E: THF; 6F: THF. 4.2. Experimental techniques

A. FTIR spectroscopy Solid state IR spectra of the compounds were recorded on a Perkin Elmer frontier infrared spectrometer in ATR mode using diamond grid and at a resolution of ±2 cm–1. B. Single crystal X-ray diffraction (SCXRD) SCXRD data were collected on a Rigaku Mercury 375R/M CCD (XtaLAB mini) diffractometer using graphite monochromatic MoKα radiation, with a Rigaku low temperature gas spray cooler facility. Data were processed with the Rigaku CrystalClear 2.0 software.88 Structure solution and refinements were performed using SHELX9789,90 implemented in the WinGX suite.91 Crystallographic information table is given in the ESI S9. C. Powder X-ray diffraction (PXRD) 23 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Powder X-ray data (ESI S8) were collected on a Philips X’pert Pro X-ray powder diffractometer with attached X’cellerator detector. The sample was scanned for 2θ = 5°‒40°. 4.3. Computation

A. Electrostatic surface potential (ESP) calculation Electrostatic potential surface maps were calculated for model compound formamide and formic acid (Figure 3). All the DFT calculations were performed in Gaussian 0992 using B3LYP function and 6-311G (d,p) as basis set. Atom coordinates from chemcraft were used as input in Gaussian for each molecule. Electrostatic potential surfaces were obtained by molecular electron density 0.0004 electron/Å. Colour coding shows the charge distribution from positive (blue) to negative (red). B. Crystal structure prediction (CSP) See the section 2.2.2. Associated content Supporting information IR spectra of single and multicomponent crystals in this study; analysis of N‒H···O and O‒H···O IR features; PXRD patterns for 2D and 5B, crystallographic information table, face indexing images of shearing and elastic crystals, descriptions of crystal structures of brittle cocrystals 1C and 3C. Acknowledgements SS thanks the IISc for a RA. GRD thanks the DST for the award of a J. C. Bose fellowship. 5. References 1. Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2003, 3, 783−790. 2. Reddy, L. S.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2004, 4, 89−94. 3. Aakeröy, C. B.; Desper, J.; Scott, B. M. T. Chem. Commun. 2006, 1445−1447. 4. Clarke, H. D.; Arora, K. K.; Bass, H.; Kavuru, P.; Ong, T. T.; Pujari, T.; L.Wojtas, Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 2152−2167. 5. Tothadi, S.; Desiraju G. R. Cryst. Growth Des. 2012, 12, 6188−6198. 6. Huang, C. M.; Leiserowitz, L.; Schmidt, G. M. J. J. Chem. Soc., Perkin Trans. 2 1973, 503−508. 7. Berkovitch-Yellin, Z.; Leiserowltz, L.; Nader, F. Acta Cryst. 1977, B33, 3670−3677. 8. Leiserowitz, L.; Hagler, A. T. Proc. R. Soc. Lond. A 1983, 388, 133−175. 9. Videnova-Adrabinska, V.; Etter, M. C. J. Chem. Crystallogr. 1995, 25, 823−829. 10. Ohba, S.; Hosomi, H.; Ito, Y. J. Am. Chem. Soc. 2001, 123, 6349−6352. 11. Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem. Int. Ed. 2001, 40, 3240−3242. 12. Tothadi, S., Desiraju, G. R. Chem. Commun. 2013, 49, 7791−7793.

24 ACS Paragon Plus Environment

Page 24 of 29

Page 25 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

13. Seaton, C. C.; Blagden, N.; Munshi, T.; Scowen, I. J. Chem. Eur. J. 2013, 19, 10663– 10671. 14. Almarsson, Ö.; Zaworotko, M. J. Chem. Commun. 2004, 1889−1896. 15. Bolla, G.; Nangia, A. Chem. Commun. 2015, 51, 15578−15581. 16. Báthori, N. B.; Lemmerer, A.; Venter, G. A.; Bourne, S. A.; Caira, M. R. Cryst. Growth Des. 2011, 11, 75−87. 17. Banik, M.; Gopi, S. P.; Ganguly, S.; Desiraju, G. R. Cryst. Growth Des. 2016, 16, 5418−5428. 18. Aitipamula, S.; Mapp, L. K.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2015, 17, 9323−9335. 19. Edwards, M. R.; Jones, W.; Motherwell, W. D. S. CrystEngComm (2006), 8, 545−551. 20. Lemmerer, A.; Fernandes, M. A. New J. Chem. 2012, 36, 2242−2252. 21. Zhang, S. W.; Harasimowicz, M. T.; de Villiers, M. M.; Yu, L. J. Am. Chem. Soc. 2013, 135, 18981−18989. 22. Lemmerer, A.; Bernstein, J. CrystEngComm 2010, 12, 2029−2033. 23. Luo, Y. H.; Xu, B.; Sun, B. W. J. Cryst. Growth 2013, 374, 88−98. 24. Drozd, K. V.; Manin, A. N.; Churakov, A. V.; Perlovich, G. L. Eur. J. Pharm. Sci. 2017, 99, 228−239. 25. Chan, H. C. S.; Woollam, G. R.; Wagner, T.; Schmidt, M. U.; Lewis, R. A. CrystEngComm 2014, 16, 4365−4368. 26. Thompson, L. J.; Voguri, R. S.; Male, L.; Tremayne, M. CrystEngComm 2011, 13, 4188−4195. 27. Orola, L.; Veidis, M. V. CrystEngComm 2009, 11, 415−417. 28. Rao Khandavilli, U. B.; Lusi, M.; Bhogala, B. R.; Maguire, A. R.; Stein, M.; Lawrence, S. E. Chem. Commun. 2016, 52, 8309−8312. 29. Urbanus, J.; Roelands, C. P. M.; Mazurek, J.; Verdoes, D.; ter Horst, J. H. CrystEngComm 2011, 13, 2817−2819. 30. Bevill, M. J.; Vlahova, P. I.; Smit, J. P. Cryst. Growth Des. 2014, 14, 1438−1448. 31. Sarmah, K. K.; Boro, K.; Arhangelskis, M.; Thakuria, R. CrystEngComm 2017, 19, 826−833. 32. This motif is, however, seen in chiral amides. Springuel, G.; Robeyns, K.; Norberg, B.; Wouters, J.; Leyssens, T. Cryst. Growth Des. 2014, 14, 3996−4004. 33. George, F.; Tumanov, N.; Norberg, B.; Robeyns, K.; Filinchuk, Y.; Wouters, J.; Leyssens, T. Cryst. Growth Des. 2014, 14, 2880−2892. 34. Kaur, R.; Row, T. N. G. Cryst. Growth Des. 2012, 12, 2744−2747. 35. Mukherjee, A.; Dixit, K.; Sarma, S. P.; Desiraju, G. R. IUCrJ 2014, 1, 228−239. 36. Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311−2327. 37. Sreekanth, B. R.; Vishweshwar, P.; Vyas, K. Chem. Commun. 2007, 2375−2377. 38. Desiraju, G. R. J. Chem. Soc., Chem. Commun. 1991, 426−428. 39. Zafar, A.; Yang, J.; Geib, S. J.; Hamilton, A. D. Tetrahedron Lett. 1996, 14, 2327−2330. 40. Mukherjee, A.; Tothadi, S.; Chakraborty, S.; Ganguly, S.; Desiraju, G. R. CrystEngComm 2013, 15, 4640−4654. 41. Chakraborty, S.; Ganguly, S.; Desiraju, G. R. CrystEngComm 2014 , 16, 4732−4741. 42. Saha, S.; Ganguly, S.; Desiraju, G. R. Aust. J. Chem. 2014, 67, 1840−1848. 25 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

43. Saha, S.; Rajput, L.; Joseph, S.; Mishra, M. K.; Ganguly, S.; Desiraju, G. R. CrystEngComm 2015 , 17, 1273−1290. 44. Mukherjee, A.; Grobelny, P.; Thakur, T. S.; Desiraju, G. R. Cryst. Growth Des. 2011, 11, 2637−2653. 45. Dubey, R.; Pavan, M. S.; Desiraju, G. R. Chem. Commun. 2012, 48, 9020−9022. 46. Lehn, J.-M. Chem. Eur. J. 1999, 5, 2455−2463. 47. Lehn, J.-M. Chem. Soc. Rev. 2007, 36, 151−160. 48. Davey, R. J.; Schroeder, S. L. M.; ter Horst, J. H. Angew. Chem., Int. Ed. 2013, 52, 2166−2179. 49. Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342−8356. 50. Desiraju, G. R. J. Am. Chem. Soc. 2013, 135, 9952−9967. 51. Be̅rziņš, A.; Actiņš, A. Cryst. Growth Des. 2016, 16, 1643−1653. 52. Khoj, M. A.; Hughes, C. E.; Harris, K. D. M.; Kariuki, B. M. Cryst. Growth Des. 2013, 13, pp 4110−4117. 53. Katrusiak, A. Acta Cryst. 2008, A64, 135−148. 54. Desiraju, G. R. Nat. Mater. 2002, 1, 77−79. 55. Parveen, S.; Davey, R. J.; Dent, G.; Pritchard, R. G. Chem. Commun. 2005, 1531−1533. 56. Davey, R. J.; Dent, G.; Mughal, R. K.; Parveen, S. Cryst. Growth Des. 2006, 6, 1788−1796. 57. Mukherjee, A.; Desiraju, G. R. Cryst. Growth Des. 2014, 14, 1375−1385. 58. Price, S. L. Acc. Chem. Res. 2009, 42, 117−126. 59. Thakur, T. S.; Dubey, R.; Desiraju, G. R. Ann. Rev. Phys. Chem. 2015, 66, 21−42. 60. van de Walle, A. Nat. Mater. 2008, 7, 455−458. 61. Reddy, C. M.; Padmanabhan, K. A.; Desiraju, G. R. Cryst. Growth Des. 2006, 6, 2720−2731. 62. Naumov, P.; Chizhik, S.; Panda, M. K.; Nath, N. K.; Boldyreva, E. Chem. Rev. 2015, 115, 12440−12490. 63. Kim, T.; Zhu, L.; Mueller, L. J.; Bardeen, C. J. J. Am. Chem. Soc. 2014, 136, 6617−6625. 64. Facchetti, A. Chem. Mater. 2011, 23, 733−758. 65. Horiuchi, S.; Tokura, Y. Nat. Mater. 2008, 7, 357−366. 66. Cao, Y.; Li, H. Nat. Nanotechnol. 2008, 3, 512−516. 67. John, G.; Jadhav, S. R.; Menon, V. M.; John, V. T. Angew. Chem., Int. Ed. 2012, 51, 1760−1762. 68. Cui, Q. H.; Zhao, Y. S.; Yao, J. J. Mater. Chem. 2012, 22, 4136−4140. 69. Garcia-Garibay, M. A. Angew. Chem., Int. Ed. 2007, 46, 8945−8947. 70. Fratzl, P.; Barth, F. G. Nature 2009, 462, 442−448. 71. Rupasinghe, T. P.; Hutchins, K. M.; Bandaranayake, B. S.; Ghorai, S.; Karunatilake, C.; Bučar, D.-K.; Swenson, D. C.; Arnold, M. A.; MacGillivray, L. R.; Tivanski, A. V. J. Am. Chem. Soc. 2015, 137, 12768−12771. 72. Ghosh, S.; Mishra, M. K.; Kadambi, S. B.; Ramamurty, U.; Desiraju, G. R. Angew. Chem., Int. Ed. 2015, 127, 2712−2716. 73. Krishna, G. R.; Devarapalli, R.; Lal, G.; Reddy, C. M. J. Am. Chem. Soc. 2016, 138, 1356−3567. 74. Saha, S.; Desiraju, G. R. Chem. Commun. 2016, 52, 7676−7679. 26 ACS Paragon Plus Environment

Page 26 of 29

Page 27 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

75. Saha, S.; Desiraju, G. R. J. Am. Chem. Soc. 2017, 139, 1975−1983. 76. Saha, S.; Desiraju, G. R. Chem. Eur. J. 2017, 23, 4936−4943. 77. Saha, S.; Desiraju, G. R. Chem. Commun. 2017, 53, 6371−6374. 78. Karki, S.; Friščić, T.; Fábián, L.; Laity, P. R.; Day, G. M.; Jones, W. Adv. Mater. 2009, 21, 3905−3909. 79. Chattoraj, S.; Shia, L.; Sun, C. C. CrystEngComm 2010, 12, 2466−2472. 80. Lv, S.; Dudek, D. M.; Cao, Y.; Balamurali, M. M.; Gosline, J.; Li, H. Nature 2010, 465, 69−73. 81. Armstrong, R. W.; Elban, W. L. Mater. Sci. Technol. 2006, 22, 381−395. 82. Vilan, A.; Aswal, D.; Cahen, D. Chem. Rev. 2017, 117, 4248−4286. 83. Reddy, C. M.; Kirchner, M. T.; Gundakaram, R. C.; Padmanabhan, K. A.; Desiraju, G. R. Chem. Eur. J. 2006, 12, 2222−2234. 84. Hutchins, K. M.; Sumrak, J. C.; Swenson, D. C.; MacGillivray, L. R. CrystEngComm 2014, 16, 5762–5764. 85. Seaton, C. C.; Parkin, A. Cryst. Growth Des. 2011, 11, 1502−1511. 86. Aakeroy, C. B.; Beatty, A. M.; Helfrich, B. A.; Nieuwenhuyzen, M. Cryst. Growth Des. 2003, 3, 159−165. 87. Kirchner, M. T.; Reddy, L. S.; Desiraju, G. R.; Jetti, R. K. R.; Boese, R. Cryst. Growth Des. 2004, 4, 701−709. 88. Rigaku Mercury375R/M CCD. Crystal Clear-SM Expert 2.0, rc14; Rigaku Corporation: Tokyo, 2009. 89. Pflugrath, J. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1999, 55, 1718−1725. 90. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. 91. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838. 92. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09; Gaussian, Inc.: Wallingford, CT, 2009.

27 ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Table of contents (TOC) Acid···Amide Supramolecular Synthon in Cocrystals: From Spectroscopic Detection to Property Engineering Subhankar Saha and Gautam R. Desiraju*

28 ACS Paragon Plus Environment

Page 28 of 29

Page 29 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Input from IR spectroscopy is used to construct a structural landscape for the acid•••amide supramolecular synthon, varying the chemical nature of the acids and amides used. A particular chemical combination with specific synthon(s) is used to obtain shearing and elastic cocrystals. 84x47mm (150 x 150 DPI)

ACS Paragon Plus Environment