Aromatic versus Aliphatic Carboxyl Group as a Hydrogen Bond Donor

Subscriber access provided by The Libraries of the | University of North Dakota

Article

Aromatic vs. Aliphatic Carboxyl Group as Hydrogen Bond Donor in Salts and Cocrystals of an Asymmetric Diacid and Pyridine Derivatives Nikola Bedekovic, Vladimir Stilinovi#, and Tomislav Piteša Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00746 • Publication Date (Web): 29 Sep 2017 Downloaded from http://pubs.acs.org on October 1, 2017

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 free 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 accessible to all readers and 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.

Crystal Growth & Design 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 32

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

Crystal Growth & Design

Aromatic vs. Aliphatic Carboxyl Group as Hydrogen Bond Donor in Salts and Cocrystals of an Asymmetric Diacid and Pyridine Derivatives Nikola Bedeković, Vladimir Stilinović,* Tomislav Piteša Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a Zagreb, Croatia.

ABSTRACT: A series of 15 salts and cocrystals of an asymmetric aromatic-aliphatic dicarboxylic diacid, N-(2-carboxyphenyl)glycine, and pyridine derivatives was synthesized in order to study whether there is a preference of pyridine binding to either of the carboxylic groups. In 9 structures the pyridine was bonded to the aliphatic group, in 3 to both carboxylic groups, and in 3 to aromatic group alone. The preference of pyridine derivatives to bond to the aliphatic group correlates with the more positive electrostatic potential on the aliphatic carboxyl hydrogen atom. The occurrence of proton transfer within the structures was found to follow the basicity of the pyridine derivative, 4 of the least basic pyridines forming cocrystals, 2 intermediate bases solids with proton disorder and the more basic pyridine derivatives salts. Proton transfer had considerable effect on the crystal packing, cocrystals mostly comprising discrete molecular complexes, and salts chains of monoanions.

Vladimir Stilinović, Department of Chemistry, Faculty of Science, Horvatovac 102a, 10002 Zagreb, Croatia. Tel: +385 1 4606371 Fax: +385 1 4606341 Email: [email protected]

ACS Paragon Plus Environment

0


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 2 of 32

Aromatic vs. Aliphatic Carboxyl Group as Hydrogen Bond Donor in Salts and Cocrystals of an Asymmetric Diacid and Pyridine Derivatives Nikola Bedeković, Vladimir Stilinović, Tomislav Piteša Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a Zagreb, Croatia.

ABSTRACT: A series of 15 salts and cocrystals of an asymmetric aromatic-aliphatic dicarboxylic diacid, N-(2-carboxyphenyl)glycine, and pyridine derivatives was synthesized in order to study whether there is a preference of pyridine binding to either of the carboxylic groups. In 9 structures the pyridine was bonded to the aliphatic group, in 3 to both carboxylic groups, and in 3 to aromatic group alone. The preference of pyridine derivatives to the aliphatic group correlates with the more positive electrostatic potential on the aliphatic carboxyl hydrogen atom. The occurrence of proton transfer within the structures was found to follow the basicity of the pyridine derivative, 4 of the least basic pyridines forming cocrystals, 2 intermediate bases solids with proton disorder and the more basic pyridine derivatives salts. Proton transfer had considerable effect on the crystal packing, cocrystals mostly comprising discrete molecular complexes, and salts chains of monoanions.

Introduction The central goal of crystal engineering is targeted preparation of solid materials of custom designed structures and properties.1,2 A vital step towards achieving this goal is identification and characterization of specific and reliable supramolecular connections between given functional groups. 3,4 The majority of these supramolecular synthons described to date are based on hydrogen bonding between molecules,5-7 ACS Paragon Plus Environment

1

Page 3 of 32

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


although recently halogen bonding has started to seriously threaten the primacy of hydrogen bond in crystal engineering.8-11 Among the most studied ‘classical’ synthons based on hydrogen bond is the carboxylic acid-pyridine heterosynthon, formed through an O–H···Npyr hydrogen bond between a carboxyl group and a pyridine nitrogen atom.12,13 In some cases, proton transfer may occur (forming O−···H–N+pyr hydrogen bonded ion pair) which can have significant effect on the overall crystal structure.14,15 The question of predicting in which cases the proton transfer will occur is far from trivial. The usual approach is based on the difference of the pKa values of the acid and the (protonated) pyridine as measured in solution (∆pKa = pKa(protonated base) − pKa(acid)). A general consensus is that for ∆pKa > 3, the major products are salts, negative ∆pKa values lead toward co-crystal formation, while within the interval 0 > ∆pKa > 316-19 it is generally not possible to predict whether proton transfer will occur or not. However, in a recent study based on a large sample of structures deposited with the CSD, Cruz-Cabeza has shown that the region in which both salts and cocrystals occur is somewhat wider, −1 > ∆pKa > 4, with the probability of proton transfer increasing approximately linearly within this interval; salts and cocrystals occurring with equal probabilities at ∆pKa ≈ 1.20 When several hydrogen bond donors or acceptors are present, competition arises between different acceptors for a given donor (and vice versa). The expected outcome of this competition is, as originally stated in a succinct maxim by M. Etter, that the best available donor will bind to the best available acceptor.4 Therefore, knowing beforehand the ‘goodness’ of a hydrogen donor/acceptor is necessary for targeted preparation of solids based on molecules with multiple functionalities. A useful method arises from thermodynamic consideration of hydrogen bond donors and acceptors as (Brønsted) acids and bases – acidity and basicity in solution (expressed by pKa values) can be used to predict binding in the solid state. Based on this, the Gilli group have suggested the rule that strongest bonds will form between acceptors and donors of similar pKa values, and evaluated this rule over a wide range of functionalities and pKa values (–14 < pKa < 53).21-23 Alternative approach was suggested by the Aakeröy group who have demonstrated that the discriminating factor between the two hydrogen donor groups (carboxyl and ACS Paragon Plus Environment

2


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 32

hydroxyl) was not the acidity, but rather the electrostatic potential on the hydrogen atom.24 Using either approach is therefore possible to produce a list of best donor and acceptor sites on a given group of molecules and, in principle, to predict which groups will form hydrogen bonds with one another. The question remains how sensitive either measure is – while it is possible to predict the behavior of different functional groups, is it possible to use the solution based pKa values, or the computed electrostatic potentials, in order to rank chemically inequivalent instances of the same functionality. In order to attempt answering this question, we have decided to study a series of cocrystals and salts formed from pyridine derivatives and an asymmetric aliphatic-aromatic carboxylic diacid. While pyridine derivatives and carboxylic acids are very common building blocks in solid state supramolecular chemistry, to the best of our knowledge only 7 structures which contain asymmetric diacids in combination with pyridine derivatives have been deposited with the CSD25 to date.26-30 We have therefore decided to synthesize a simple asymmetric aliphatic-aromatic carboxylic diacid and cocrystalize it with a series of pyridine derivatives in order to observe which carboxyl group (if any) is the preferred hydrogen donor, and how this correlates with pKa values and electrostatic potentials of the carboxyl groups. As the model diacid we have chosen cindroic acid (N-(2-carboxyphenyl)glycine, H2cin; Scheme 1), a precursor of indigo in the classical Heumann synthesis31 – the first commercially affordable route to synthetic indigo.32 This was cocrystalized with 15 pyridine derivatives of variable basicity (spanning a pKa range of ca. 5.5 units) and with a wide range of additional functionalities (Scheme 1). The pKa range of the pyridine derivatives (Table 1) was chosen so that it encompasses the pKa values of both carboxyl groups of H2cin, allowing us to study not only the preferential binding of pyridine to one of the carboxyl groups, but also whether this can be influenced by proton transfer.


3

Page 5 of 32

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


Scheme 1. Molecular diagrams of H2cin and the pyridine derivatives used in this study. Table 1. The pyridine derivatives used in this study, their pKa values in aqueous solutions,33 and the formulae of the obtained products.

a

#

Pyridine derivative

pKa

ESP / kJ mol−1

Product

I

4-cyanopyridine

2.10

−129.45

[(I)2(H2cin)]

II

methylisonicotinate

3.19

−165.42

[(II)2(H2cin)]

III IV

4-benzoylpyridine 4,4'-bipyridine

3.35 4.80

−167.46 −168.73

[(III)(H2cin)] [(IV)(H2cin)]

V

quinoline

4.85

−167.06

[(VH)(Hcin)]a

VI VII

isoquinoline 2-methylpyridine

5.14 5.97

−180.37 −173.81

[(VIH)(VI)(Hcin)]a [(VIIH)(Hcin)]

VIII

4-methylpyridine

6.02

−182.68

[(VIIIH)2(Hcin)2(H2cin)]

IX X XI XII XIII XIV XV

3,5-dimethylpyridine 4-methoxypyridine 2-amino-5-methylpyridine 2-amino-4-methylpyridine 2,4,6-trimethylpyridine 2-amino-6-methylpyridine N,N-dimethylaminopyridine

6.24 6.42 7.19 7.38 7.48 7.60 9.50

−181.99 −181.15 −174.11 −174.08 −185.24 −162.58 −209.63

[(IXH)(Hcin)] [(XH)(Hcin)(H2O)] [(XIH)(Hcin)] [(XIIH)(Hcin)] [(XIIIH)(Hcin)] [(XIVH)(Hcin)] [(XVH)2(cin)(H2O)2]

– the hydrogen atom is disordered over two positions ACS Paragon Plus Environment

4


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 6 of 32

Results and Discussion

Crystal structures of H2cin and its derivatives The pKa values for H2cin had been determined by potentiometric titrations in aqueous solution at 25 °C by Uhlig and Walter to be 3.0 and 4.9.34 These values correspond reasonably to the values calculated by ACE JChem pKa predictor35 which gives pKa of 3.6 for the aliphatic and 4.6 for the aromatic carboxyl group. Although intuitively it may seem improbable that the aliphatic carboxyl group should have a lower pKa value than the aromatic group (particularly as the latter is involved in the intramolecular hydrogen bonding with the amine nitrogen), such assignment of pKa values is in line with the measured pKa values of structurally similar (mono)acids; N-phenylglycine being stronger acid (pKa = 4.41)36 than 2-(methylamino)benzoic acid (pKa = 5.34)37. The molecular electrostatic potential of the H2cin molecule (Figure 1) shows an equivalent difference in the two carboxyl hydrogen atoms, the maximum value (at the 0.002 a.u. isosurface) for aliphatic group markedly more positive (289.33 kJ mol–1) than for the aromatic (225.86 kJ mol–1), the difference between the two being ca. 63.5 kJ mol–1, rendering the electrostatic potential of the aliphatic hydrogen atom ca. 28% higher than for its aromatic counterpart. It is noteworthy that this difference is not followed by the minima corresponding to the carbonyl atoms of the carboxyl groups, the aromatic being merely ca. 3.2% lower than the aliphatic.


5

Page 7 of 32

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 1. Electrostatic potential (ESP) mapped on the electron density isosurface (isovalue 0.002 a.u.) in H2cin molecule, calculated on M06-2X/6-311G(d,p) level of theory. Its highest values near carboxylic hydrogen atoms and the lowest values near the carbonyl oxygen atoms are displayed

This difference in electrostatic potentials is vividly depicted in the hydrogen bond lengths in the crystal structure of pure cindroic acid. It crystallizes in the P–1 space group with two independent molecules in the asymmetric unit. Each molecule participates in four hydrogen bonds with four neighboring molecules interconnecting the molecules into a 2D hydrogen bonded framework (Figure 2). The hydrogen bonding scheme requires four hydrogen bonds independent by symmetry, allowing both aromatic and aliphatic carboxyl groups to act as both hydrogen bond donors and acceptors. This is a fortunate circumstance, as it allows for a preliminary assessment of the hydrogen bonding and accepting proclivity of the two groups. The hydrogen bond length appears to depend exclusively on the donor – the two bonds in which the aromatic carboxyl group acts as donor are ca. 0.03 Å longer (Oar–H···Oal of 2.703(1) Å and Oar–H···Oar of 2.696(1) Å) than those where the aliphatic group is the donor (Oal–H···Oal of 2.664(1) Å and Oal–H···Oar of 2.671(1) Å), while the nature of the acceptor does not appear to have a significant effect. This is in perfect accord with the above mentioned differences of the ESPs in the vicinity of the corresponding atoms in acid molecule. Aliphatic hydrogen atom has more positive ESP than the aromatic one (and consequently, aliphatic group is a stronger hydrogen bond donor), while these values on carbonyl oxygen atoms (hydrogen bond acceptors) are very similar, and therefore do not lead to a significant difference in the hydrogen bond lengths.


6


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 32

Figure 2. Packing diagram of H2cin viewed a) along a hydrogen bonded layer b) perpendicular to the hydrogen bonded layer showing the interconnection of the molecules.

Scheme 2. Hydrogen bonding supramolecular synthons encounters in the H2cin–pyridine system.

The above results are indicative that H2cin follows the same general scheme, in that the more acidic and more positively charged carboxyl group is a stronger hydrogen bond donor. To study whether this conclusion holds more generally, H2cin was crystallized with 15 pyridine derivatives (Scheme 1, Table 1). While the pyridine was always present in excess, only in three obtained cocrystals both carboxyl groups were found to be bonded to pyridine nitrogen atoms. All three correspond to weakly basic ACS Paragon Plus Environment

7

Page 9 of 32

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


pyridines: I, II and IV. The relative lengths of O–H···Npyr hydrogen bonds do not appear to follow the above rule – while in [(II)2(H2cin)] the molecule of II forms shorter hydrogen bond with the aliphatic carboxyl group (Figure 3a), in [(I)2(H2cin)] the opposite is the case. It should be noted however that the aliphatic carboxyl group in [(I)2(H2cin)] also acts as an acceptor of a C–H···O hydrogen bond (C17– H018···O4 of 3.419(4) Å, (Figure 3b) which affects the electron density about the oxygen atom and therefore the hydrogen bonding potential. To enable the formation of this additional C–H···O contact the conformation of the H2cin molecule changes significantly from the approximately planar in pure acid (and the optimized structure). The major difference between these two conformations is in the C7-N1C8-C9 torsional angle in the aliphatic tail of the molecule, which approaches 180° in the pure acid (both optimized and crystal structure), as well as in the majority of crystals (e.g. in [(II)2(H2cin)] this angle is 178.6(5)°), but in [(I)2(H2cin)] it is 98.5(6)°, orienting the aliphatic carboxyl group approximately perpendicularly to the mean plane of the aromatic part of the molecule (Figure 3 b).

Figure 3. Discrete molecular complexes of a) [(II)2(H2cin)] and b) [(I)2(H2cin)] with an additional C– H···O hydrogen bond (shorter dashes) which affects HB length on aliphatic carboxyl group.

Another compound where both carboxyl groups are involved in hydrogen bonding with the pyridine nitrogen is [(IV)(H2cin)], where 4,4’-bipyridine molecules bridge between aliphatic and aromatic groups of two molecules forming hydrogen bonded chains. The structure comprises two series of chains unrelated by symmetry. Of these, one is approximately planar (179.6(5)°; Figure 4d), while the other is somewhat bent (162.4(6)°; Figure 4b). This bending is achieved through the decrease of the Oal–H···N ACS Paragon Plus Environment

8


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 10 of 32

hydrogen bond angle (169.9(4)°), weakening the bond and increasing its length. As the result, the hydrogen bond lengths on the aromatic (2.679(1) Å) and aliphatic (2.653(2) Å) carboxyl group follow the expected trend in the planar chain, whereas in the bent one the Oal–H···N bond length is increased to 2.675(2) Å, making it somewhat longer than the Oal–H···N (2.662(2) Å).

Figure 4. Hydrogen bonded chains in the structure of [(IV)(H2cin)] a) The bent chain viewed along the c axis and b) the b axis; c) The planar chain viewed along the c axis and d) the b axis.

The fourth weak base covered by this study, 4-benzoylpyridine (III), also crystallizes with H2cin, however unlike, I and II, it forms a 1:1 cocrystal [(III)(H2cin)], with two acid molecules bonded into a centrosymmetric dimer through the aromatic carboxyl groups, with pyridine molecules bonded to the remaining aliphatic groups (Figure 5).

Figure 5. Molecular complex of [(III)(H2cin)].


9

Page 11 of 32

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


Using more basic pyridine derivatives leads to a series of structurally similar 1:1 pyridinium salts, where Hcin– anions form chains with pyridinium cations bonded to one of the carboxyl group. This general motif is present in all the remaining structures, with exception of (VIIH)(Hcin)(H2cin) and [(XVH)2(cin)(H2O)2]. In several compounds ([(IXH)(Hcin)], [(XIIIH)(Hcin)], [(VH)(Hcin)] and [(VIH)(Hcin)(VI)]) these chains are the sole hydrogen binding motif present in the structure. A typical representative of this group is [(XIIIH)(Hcin)] (Figure 6), where the interconnection of Hcin– anions is achieved through hydrogen bonding of the aromatic carboxyl groups to the deprotonated aliphatic group of the neighboring Hcin– anion, with the protonated carboxyl group forming a hydrogen bond with the same atom of the aliphatic carboxylate (synthon B, Scheme 2). The identical hydrogen bonding scheme is also present in the structures of [(VH)(Hcin)] and [(VIH)(Hcin)(VI)], while in [(IXH)(Hcin)] (Figure 7), the 3,5-dimethylpyridinium cation forms a hydrogen bond with the (deprotonated) aromatic carboxylate group (N2-H2n···O2 of 2.762(1) Å), while the other oxygen atom of the aromatic carboxylate is an acceptor of a very short hydrogen bond (O1-H1o···O4 of 2.458 Å) from a neighboring aliphatic carboxyl which is in an uncharacteristic syn conformation (C8-C9-O4-H10 torsion angle of ca, –9°; synthon C, Scheme 2)

Figure 6. Hydrogen bonded chain in the crystal structure of [(XIIIH)(Hcin)].


10


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 12 of 32

Figure 7. Hydrogen bonded chain in the crystal structure of [(IXH)(Hcin)].

Of the above mentioned four compounds only the isoquinoline derivative [(VIH)(Hcin)(VI)] has not formed a simple 1:1 salt. The hydrogen bonding of VIH+ and Hcin− ions into chains in this structure is identical as in the case of [(XIIIH)(Hcin)] (synthon B, Scheme 2). These chains form closely packed layers perpendicular to the a axis. However, due to the shape and size of the cations, layers cannot achieve further close packing, leaveing voids in the structure. These are filled by additional (neutral) isoquinoline molecules (Figure 8) forming C–H⋅⋅⋅π contacts with the neighboring Hcin− anions.

Figure 8. Structural diagram of [(VIH)(Hcin)(VI)] viewed along the hydrogen bonded chains showing additional isoquinoline molecules (green) in voids between the layers of chains.

Using 2-aminopyridines introduces two additional hydrogen donors on the pyridine molecule. In spite of this, the chains of interconnected Hcin− anions have been conserved in all three studied 2aminopyridine derivatives – [(XIIH)(Hcin)], [(XIH)(Hcin)] and [(XIVH)(Hcin)] – modified only with an 2-aminopyridinium–carboxylate two-point hydrogen bonding synthon D replacing the synthon B. This leaves the other hydrogen atom of the amino group free to participate in further hydrogen bonding. In all three structures this is achieved through binding of the amine N-H to the aliphatic carboxylate oxygen of a Hcin− anion from a neighboring chain, thus interconnecting the chains via centrosymmetric synthons E with two amino groups bridging between pairs of carboxylates from separate chains.


11

Page 13 of 32

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


Although the principal synthons of the hydrogen bonding network are the same in all three structures, the resulting structures significantly differ. While the topologies of the chains are identical in all three structures their geometry differs – the relative alignment of neighboring Hcin− anions within a chain is parallel in [(XIIH)(Hcin)] (Figure 9 a), and approximately antiparallel in [(XIH)(Hcin)] and [(XIVH)(Hcin)] (Figure 10 a). Because of this, in [(XIIH)(Hcin)] all the amine hydrogen and carboxylate oxygen atoms of a chain are on the same side of the chain and thus interconnect the chain through centrosymmetric synthons E with only one neighboring chain leading to a double-chain (1D) structure (Figure 10 b). In [(XIH)(Hcin)] and [(XIVH)(Hcin)], however, the amine hydrogen and carboxylate oxygen atoms alternate on both sides of the chain, so that each chain is interconnected by two neighbors, leading to 2D networks (Figure 10 b)

Figure 9. a) Hydrogen bonded chains in the crystal structure of [(XIIH)(Hcin)]; b) interconnection of two chains (red and green) into a double chain along the crystallographic a axis.


12


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 14 of 32

Figure 10. a) Hydrogen bonded chains in the crystal structure of [(XIH)(Hcin)]; b) interconnection of chains (blue, red and green) into a hydrogen bonded layer perpendicular to the crystallographic a axis.

Unlike the previously described compounds, the crystal structures of [(VIIH)(Hcin)(H2cin)] and [(VIIIH)2(Hcin)2(H2cin)] contain additional (neutral) acid molecules which participate in the hydrogen bonding network. In the case of [(VIIIH)2(Hcin)2(H2cin)] two series of Hcin− anions and 4methylpyridinium cations form chains connected via the synthon B. The carbonyl aliphatic groups of the two chains are interconnected by bridging neutral H2cin molecules forming a ladder-like structure along the crystallographic a axis (Figure 11a). As was found in the crystal structure of the pure acid, the O8H8···O11 hydrogen bond where the donor is the aliphatic group is markedly shorter (2.535(2) Å) than the O5-H20···O3 hydrogen bond with the aromatic donor group (2.603(1) Å). In [(VIIH)(Hcin)(H2cin)], the even higher content of the neutral acid (one per ion pair) disrupts the hydrogen bonding chains present in the majority of structures. The aliphatic carboxylate in the Hcin− anion is deprotonated and does form hydrogen bonds equivalent to synthon B, with the difference that the hydrogen donor is not a neighboring Hcin− anion, but rather the aliphatic carboxyl group of a neutral acid molecule. The aromatic carboxyl groups of both the anions and the neutral molecules form hydrogen bonds with aromatic groups (of neighboring anions and neutral molecules, respectively) 2

through classic centrosymmetric bis(carboxylic acid) motifs of R2 (8) topology (Figure 11b). The overall hydrogen bonding pattern leads to chains of alternating pairs of deprotonated and neutral acid molecules extending along the [−1−11] direction.


13

Page 15 of 32

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 11. a) Hydrogen bonded double chain (red and blue) of ions interconnected with bridging neutral acid molecules in [(VIIIH)2(Hcin)2(H2cin)]; b) Hydrogen bonded chains of alternating pairs of ions and neutral molecules (green) in the crystal structure of [(VIIH)(Hcin)(H2cin)];

Only two solvates (hydrates) have been obtained in the studied series of compounds. Of these, [(XH)(Hcin)(H2O)] comprises chains of Hcin− anions mostly identical to those in [(IXH)(Hcin)]. However, as the 4-methoxypyridinium cation is sterically less demanding then the 3,5dimethylpyridinium in [(IXH)(Hcin)], in [(XH)(Hcin)(H2O)] the aliphatic carboxyl group which is not involved in hydrogen bonding with the neighboring anion is accessible to a water molecule which forms a single O8-H32···O6 hydrogen bond of 2.886(2) Å (Figure 12a). The second hydrogen atom of the water molecule lies out of the mean plane of the chain, and forms a O6-H31···O2 hydrogen bond of 3.213(3) Å with an aliphatic oxygen from a neighboring chain. The structure of [(XVH)2(XV)(cin)(H2O)2] was the only one in which cindroic acid was found to be fully deprotonated, 4-N,N-dimethylaminopyridine (XV) being the strongest base used in this study (pKa = 9.50). Due to the absence of the hydrogen bond donor sites on the cin2− anion, formation of chains such as those in the majority of hydrogencindroates is not possible, and the anions are interconnected through water molecules, two water molecules bridging between an aromatic carboxylate of one anion and the aliphatic carboxylate of a neighbor. The two 4-N,N-dimethylaminopyridinium cations bind to ACS Paragon Plus Environment

14


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 16 of 32

the chains, one forming a hydrogen bond with the aliphatic carboxylate and the other to a bridging water molecule. This leaves voids between the bound cations which are occupied by neutral molecules of XV (Figure 12b).

Figure 12. Hydrogen bonded chains in the crystal structure of a) [(XH)(Hcin)(H2O)]; b) [(XVH)2(XV)(cin)(H2O)2] with interposed neutral molecules of XV.

The above structural data indicate a strong preferential binding of pyridine to the aliphatic group. In the majority of structures (9 out of 15) the pyridine was found to bind exclusively to the aliphatic group, and only in 3 to the aromatic. It is noteworthy that the binding to either group is closely interconnected with the characteristic hydrogen bonding synthons – while in the majority of structures (9) with pyridine bonded to the aliphatic group, the hydrogen bonding is achieved through the synthon B, all three structures with the pyridine bound to the aromatic group achieve this through the synthon C. The main differences between the two are in the topology of the hydrogen bonds formed by the carboxylate (in B both hydrogen bonds are formed by the same carboxyl oxygen, while in C one carboxylate oxygen is hydrogen bonded to the pyridine and the other to the neighboring Hcin−), and the conformation of the protonated carboxyl group participating in the synthon (in all instances of B the conformation is the expected anti – with carboxyl C8-C9-O4-H torsion angle of ca. 180°; while C is only found when the ACS Paragon Plus Environment

15

Page 17 of 32

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


hydrogen donating carboxyl group is of rather unusual syn conformation – C8-C9-O4-H torsion angle of ca. 0°). The unusual conformation of the carboxyl group would seem to indicate that there are some specific packing effects in the instances of C which cause such hydrogen bonding motif to become prevalent over B. As C occurs only when pyridine binds to the aromatic group (and vice versa), it follows that pyridine will not bind to the aliphatic group only if there are some specific structural reasons which prevent it from happening. This conclusion is also borne out by the three structures in which both the aliphatic and the aromatic groups form hydrogen bonds with the pyridine derivatives – as a rule the aliphatic O-H···N bonds are shorter than the aromatic ones, although specific structural features can invert this order in given structures (see e.g. [(I)2(H2cin)] as discussed above).

Proton transfer in H2cin–pyridine derivative systems: As the position of the hydrogen atom cannot always be accurately determined from diffraction data, it was necessary to establish a more reliable criterion whether proton transfer had occurred. For that we have employed a combination of three indicators of the proton transfer: position of the proton as determined by the electron difference map, difference between C−O bond lengths of the aliphatic carboxyl group (∆d = dC−O4 − dC−O3; ideally, ∆d ≈ 0 Å for a carboxylate anion and ∆d ≈ 0.1 Å for a protonated carboxyl group), and the C=O stretching bands of the carboxyl group in the IR absorption spectra (usually ca. 1600 cm–1 for carboxylate and ca. 1700 cm–1 for protonated carboxyl group).38,39 The ∆d values were found to span between 0.02 Å and 0.12 Å, however without a clear distinction between salts and cocrystals – while three structures with ∆d > 0.1 Å ([(I)2(H2cin)], [(II)2(H2cin)] and [(IV)(H2cin)]) clearly correspond to cocrystals with molecules connected via O–H···N hydrogen bonds, and four with ∆d < 0.04 Å ([(XVH)2(cin)(H2O)2], [(XIIH)(Hcin)], [(XIH)(Hcin)], and [(XIVH)(Hcin)]) to salts with ions connected via O–···H–N+ hydrogen bonds, the ∆d values for the remaining structures fall in the intermediate region. The IR spectra of all the compounds show multiple C=O stretching bands with maxima falling in three specific regions: 1720-1745 cm–1, 1660-1680 cm–1 and 1605-1645 cm–1. The maxima of the first region correspond to protonated carboxyl groups, and appear in the spectra of ACS Paragon Plus Environment

16


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 18 of 32

the three cocrystals as identified above, two structures containing additional bridging H2cin molecules ([(VIIH)(Hcin)(H2cin)], and [(VIIIH)(Hcin)(H2cin)]), as well as in the spectrum of [(III)(H2cin)], which, in spite of the intermediate ∆d of 0.087 Å can on this ground also be classified as a cocrystal. As spectra of [(VIIH)(Hcin)(H2cin)] and [(VIIIH)(Hcin)(H2cin)] also exhibit maxima at low wavenumbers (1606 and 1635 cm–1 respectively), the 1720-1745 cm–1 bands present in their spectra are clearly ascribable to the additional H2cin molecules, while the carboxyl group bonded to the pyridine is deprotonated, i.e in these structures the proton transfer has occurred. A band in the 1606 and 1635 cm–1 is present in all the structures corresponding to salts, and is absent from the spectra of the four structures identified as cocrystals, as well as the quinoline and isoquinoline derivatives, [(VH)(Hcin)] and [(VIH)(Hcin)]. However, the spectra of the latter two also lack the high wavenumber bands corresponding to protonated carboxylic group, but rather have only a single band at ca. 1675 and 1680 cm–1 respectively. The probable explanation is that in these two structures the hydrogen atom is in disorder, quickly changing position along the O···H···N hydrogen bond. This also is supported by the electron difference map for [(VH)(Hcin)] which shows two joined maxima corresponding to O-H···N and O···H-N hydrogen positions. Although the data quality of [(VIH)(Hcin)] was unfortunatelly insufficient to justify a similar examination of the electron difference map, we are inclined to conclude, based on above considerations, that both structures are disordered, i.e. comprise an (equilibrium) mixture of species with and without proton transfer. Therefore, only four structures of the studied 15 – [(I)2(H2cin)], [(II)2(H2cin)], [(III)(H2cin)] and [(IV)(H2cin)]) – clearly comprise only neutral molecules, two – [(VH)(Hcin)] and [(VIH)(Hcin)] – are solids with proton disorder, and the remaining structures correspond to salts. The occurrence of proton transfer within the structures with the pyridine bonded to the aliphatic group correlates perfectly with the basicity of the pyridine derivative, four of the least basic pyridines forming cocrystals, the more basic pyridine derivatives forming salts, and two intermediate bases form solids with proton disorder (Figure 13a). More precisely, all bases with pKa values up to 4.82 (4,4’-bipyridine, inclusively) have formed cocrystals, all above 5.97 (2-methylpyridine) have formed salts and both ACS Paragon Plus Environment

17

Page 19 of 32

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


disordered solids have been formed by bases of pKa values between the two. The clear-cut transitions from cocrystals to solids with proton disorder (1.82 < ∆pKa < 1.85) and from disordered solids to salts (2.14 < ∆pKa < 2.97) within such narrow ∆pKa regions seem to contradict the generally accepted rule of appearance of all three types of solids within the 0 < ∆pKa < 3 range. However, this is almost certainly due to the somewhat limited sample size of only 12 data points, and additional cocrystalizations of H2cin with bases with pKa values in the 3-6 range can be expected to show existence of a finite range in which either salts, cocrystals, or solids with proton disorder may occur.

Figure 13. a) The difference between the C-O bond lengths (∆d) of the aliphatic carboxyl group in the 12 structures with pyridine bonded to the aliphatic group plotted against pKa values, b) the wavenumbers of the C=O stretching bands in structures with pyridine bonded to the aliphatic group plotted against pKa 18 ACS Paragon Plus Environment


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 20 of 32

values; circles – 1720-1745 cm–1 (cocrystal) band; squares – 1660-1680 cm–1; triangles – 1605-1645 cm–1 (salt) band; c) The difference between the C-O bond lengths (∆d) of the aliphatic carboxyl group in the 12 structures with pyridine bonded to the aliphatic group plotted against the lengths of the corresponding O···H···N hydrogen bonds; d) The length of the O···H···N hydrogen bond between the aliphatic carboxyl group and the pyridine nitrogen atom in the 12 structures with pyridine bonded to the aliphatic group, plotted against ∆pKa values. Filled symbols correspond to structures identified as salts, empty to cocrystals and half-filled to solids with proton disorder.

As noted earlier, the differences between C−O bond lengths of the aliphatic carboxyl group (∆d) within the studied series of compounds are not clearly separated into groups corresponding to salts and cocrystals, but rather span the whole 0 Å < ∆d < 0.12 Å range relatively uniformly. When these distances are plotted against the corresponding pKa values (Figure 13 a), a rather reasonable correlation is achieved with lower pKa values corresponding to larger ∆d values, i.e. more asymmetric carboxylates. The correlation holds also for the intermediate values, in particularly in the two solids with proton disorder. For comparison, the ∆d values were also plotted against calculated electrostatic potentials on the pyridine nitrogen atoms. Interestingly, while the same general trend is observed (more negative ESP values corresponding to lower ∆d values), the observed correlation is much poorer (see Supplementary Information, Figure S33). Also, the regions corresponding to salts and cocrystals overlap – proton transfer occurred with pyridine derivatives with nitrogen atom ESP from –209.6 kJ mol–1 to –162.6 kJ mol–1, cocrystals are found with pyridine derivatives with nitrogen atom ESP from –168.8 kJ mol–1 to – 129.5 kJ mol–1, and the two solids with proton disorder were formed by bases with nitrogen ESP-s of – 180.4 kJ mol–1 and –167.0 kJ mol–1. This may seem contrary to the above noted predictive power of acid contact atom ESP-s; however, one should keep in mind that the values of the contact atom ESP computed for the free acid and base molecules are descriptors of electron distribution on the neutral molecule only. The pKa value, on the contrary, is defined by the overall thermodynamics of the proton ACS Paragon Plus Environment

19

Page 21 of 32

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


transfer. While it generally will hold that more negative ESP on the base will correspond to a stronger base (and therefore a larger pKa), this is not necessary, as the (de)protonation can be influenced by various effects, other than the electrostatics of the donor and acceptor molecules. It is indicative that XIV, with its highly sterically crowded nitrogen atom forms a salt in spite of relatively small negative ESP on the nitrogen atom (smaller than that of the cocrystal forming II, III and IV; Table 1). Other ‘outliers’ in the ∆d vs. ESP plot include VII, XIII, XI and XII – all of them with sterically hindered approach to the nitrogen atom. This steric hindrance is not taken into account by the calculated ESP, but it does affect the pKa value of the pyridine, thus making the pKa a more accurate descriptor for prediction of proton transfer. The observed continuity of the ∆d values in conjunction with the IR correlation with pKa values might indicate that the structures classified as salts or cocrystals are also to an extent disordered, the intermediate values of C−O bond lengths found in the crystal structures being in fact a time and space average of single bonds (in neutral acid molecules) and delocalized bonds (in carboxylate anions). The coexistence of neutral and protonated/deprotonated species however is not confirmed by the IR spectra which seem to indicate that there are no considerable amounts of the other protonation state (i.e. the 1720-1745 cm–1 bands are completely absent from the spectra of salts, and the 1605-1645 cm–1 bands from the spectra of cocrystals; figure 13 b). The alternative explanation is that the C−O bond lengths are influenced by supramolecular interactions, most obviously the O···H···N hydrogen bond between the carboxyl group and the pyridine. The plot of ∆d values vs. the O···H···N hydrogen bond length does indeed reveal that the ∆d values in cocrystals increase with the increase of the O···H···N hydrogen bond length (Figure 13c) – the longer (and weaker) the hydrogen bond, the bond lengths of the carboxyl group more closely approach those in pure (neutral) acid. Conversely, in salts the ∆d values in cocrystals decrease with the increase of the O···H···N hydrogen bond length – weaker hydrogen bonds corresponding to more symmetrical carboxylate groups. It would seem therefore that the intermediate C−O bond lengths are caused primarily by deformation of the carboxylate/carboxylic acid group due to hydrogen bonding, and not by partial hydrogen transfer. This conclusion is confirmed by observing the ACS Paragon Plus Environment

20


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 22 of 32

changes of the corresponding bands in the IR spectra of the salts and cocrystals: while there is no apparent correlation between the vibration frequencies and the ∆pKa values (indicators of proton transfer; figure 13c), stretching frequencies of the C-O bonds in cocrystals monotonously decrease, while those in salts increase, with the increase of the hydrogen bond length (Figure 14).

Figure 14. The wavenumbers of the a) 1720-1745 cm–1 band in cocrystals and b) 1605-1645 cm–1 stretching band in salts plotted against the length of the O···H···N hydrogen bond.

The hydrogen bond lengths in turn show a noteworthy dependence on pyridine basicity (Figure 13 d). Both the weakest and the strongest bases bind through relatively long hydrogen bonds. The hydrogen bond length thus shows a minimum at ∆pKa ≈ 3 (the shortest hydrogen bond of 2.569(2) Å in the structure of [(VIIH)(Hcin)(H2cin)] with ∆pKa = 2.97). This is apparently at odds with the general rule that the strongest hydrogen bonds are expected as ∆pKa approaches zero. However, one should keep in mind that the pKa values are not a measure of the proton affinity in the solid state, but rather describe the equilibrium composition of an acid (or base) solution in a given solvent at a given temperature. As charged species can be expected to be better solvated (particularly in aqueous solutions) than the neutral ones, the equilibrium content of the charged species in the solution will be larger (as compared to vacuum). The pKa values (particularly if measured for aqueous solutions, which is most commonly the case) will be systemically biased toward charged species (i.e. lower for deprotonation of neutral acids). 21 ACS Paragon Plus Environment

Page 23 of 32

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


In crystals, however, the charge separation is not facilitated by solvation (although in a particular crystal it can be facilitated by supramolecular environment), and consequently proton transfer (equalization of proton affinities) does not occur at ∆pKa = 0, but rather at positive values (cf. the ∆pKa range where generally both salts and cocrystals occur is 0 < ∆pKa < 3; i.e. corresponding to low positive values, rather than centered about 0), depending on the system at hand and supramolecular surroundings of the acid-base pair within a particular crystal structure. In the H2cin–pyridine (pyridine bonded to the aliphatic group of H2cin) solid system at hand, the equalization of the proton affinities apparently occurs in the 2 < ∆pKa < 3 range (the ∆pKa range where the solids with proton disorder appear) and this coincides reasonably well with the shortest hydrogen bonds observed.

Figure 15. Length of the O···H···N hydrogen bonds as a function of the difference between the C-O bond lengths (∆d) of the carboxyl group in in salts (filled circles) and cocrystals (empty circles) formed from pyridine derivatives and a) aliphatic; or b) aromatic acids from data retrieved from the CSD.

As such a dependence of hydrogen bond length on proton transfer should hold generally, we have decided to test it by performing a search of the CSD in order to observe whether there is a discernable variation of the O···H···N hydrogen bond length with the proton transfer if a larger sample of (aliphatic and aromatic) acids and bases (pyridine derivatives) are used. As proton position is crucial for this ACS Paragon Plus Environment

22


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 24 of 32

discussion, only the highest quality data (R < 5%) were taken into consideration, and the difference between the C-O bond lengths (∆d) of the carboxyl group was taken as a means of determining whether proton transfer had occurred, along with the reported hydrogen position. The search retrieved 312 datasets corresponding to salts (64) and cocrystals (248) of aliphatic and 1381 datasets corresponding to salts (396) and cocrystals (985) of aromatic acids. Figure 15 shows the hydrogen bond length as a function of ∆d for both cases. Although the scatter of the datapoints is considerable (particularly in case of aromatic acids, Figure 15b) there is an obvious trend of shortest hydrogen bonds (ca. 2.5 Å) occur at intermediate ∆d values – around 0.5 Å – which could correspond to partial proton transfer or unresolved proton disorder. Either eventuality is a result of equal proton affinities to the acid and the base, in line with the above argumentation. It is also noteworthy that, according to the reported proton positions, there are equal numbers of salts and cocrystals with ∆d values around 0.5 Å – as per the Cruz-Cabeza equation,20 salts and cocrystals appear with equal probability at ∆pKa ≈ 1, the shortest hydrogen bonds can be concluded to appear in structures where ∆pKa values are small and positive, again, in line with the specific observation made for H2cin. As the majority of the data deposited with the CSD correspond to aromatic acids, it would be interesting to attempt a detailed analysis of the hydrogen bonds between the pyridine derivatives and the aromatic carboxyl group of H2cin. Unfortunately, as this has occurred only in three structures of salts, there is insufficient data for a reasonable discussion. It is however noteworthy that binding of the pyridine to the aromatic group has only been noticed with three pyridines (VIII, IX and X) with pKa values in the 6-6.5 range. If these pyridine derivatives had bonded to the aliphatic group, the ∆pKa would have been greater than 3, while for the less acidic aromatic group, the ∆pKa for these three pyridines fall in the 1-1.5 range, more closely to the values at which the proton transfer (and thus stronger hydrogen bonds) can be expected. However, this trend is not continued with the more strongly basic pyridines (pKa > 7) covered by this study – there again the pyridine binds (solely) to the aliphatic group. This might indicate that VIII, IX and X fall in the optimal pKa range to form strongest hydrogen bonds with the aromatic group, which in these cases becomes sufficiently large contribution to the ACS Paragon Plus Environment

23

Page 25 of 32

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


lattice energy to render these structures more favorable. The only pyridine derivative which falls within the same region of pKa values but binds to the aliphatic group is 2-methylpyridine (VII; pKa = 5.97), possibly due to steric hindrance due to the methyl group in the 2-position. The probable specific structural cause of binding of the pyridine to the aromatic group alluded to at the end of the last section can thus be identified, based on the hydrogen bond strength due to the equalization of the proton affinities, indicated by the (small and positive) ∆pKa values.

Conclusion Both the electrostatic potentials of carboxylic hydrogen atoms and the pKa values have shown to accurately predict the predominant binding of pyridine derivatives to the aliphatic carboxyl group of H2cin, in particularly if less basic pyridine derivatives are used. Hydrogen bonding was sufficiently sensitive to the electrostatic potentials on oxygen and hydrogen atoms of the two carboxyl groups to make them correlate with the four inequivalent hydrogen bond lengths in the structure of H2cin. The proton transfer along the hydrogen bond between the acid and the pyridine, on the other hand, has shown an exceptional correlation with the pKa value of the pyridine used (rather than the ESP on the pyridine nitrogen), with very sharp transitions between ∆pKa regions where cocrystals, salts and disoredered solid forms are produced (at least within the studied group of pyridine derivatives). The hydrogen bonding synthons which include the carboxyl groups, as well as the supramolecular architectures they lead to, are extremely sensitive to both proton transfer and the carboxyl group which binds to the pyridine – only in cocrystals finite hydrogen bonded structures through the synthon A are formed; in salts with the pyridine bonded to the aromatic group the molecules are further interconnected through the synthon C, while in salts (and solids with proton disorder) with the pyridine bonded to the aliphatic group, the dominant hydrogen bonding motif are chains formed through the synthon B. Furthermore, while there is little variability in the stoichiometries of the obtained solids among cocrystals, additional acid, base and/or solvent molecules were found in several structures of salts.


24


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 26 of 32

In the solids with pyridine bonded to the aliphatic group the O···H···N, hydrogen bond lengths (as an indicator of bond strength) correlate with the proton transfer in the crystals – minimal lengths coincide with the ∆pKa region where the solids with proton disorder are formed (which is intermediate to that of salts and of cocrystals) falling in the positive 2 < ∆pKa < 3 range, indicating this to be the range in which the difference between proton affinities of the pyridine and the aliphatic group of H2cin in the solid state is minimal. Binding of the pyridine to the aromatic group has occurred only in three structures, all of them salts with pyridine derivatives for which ∆pKa values for the aromatic carboxyl group falls in the 1 < ∆pKa < 1.5 range and thus can expectedly lead to particularly strong hydrogen bonds rendering the structure more favorable. Further increase of the basicity of the pyridine again leads to binding to the aliphatic group, as the ∆pKa for the aromatic group increases beyond the optimal range. The H2cin-pyridine system thus once more confirms that proton transfer in carboxylic acid-pyridine systems not only determines the formal classification of a solid as a salt or a cocrystal, but has a significant role in controlling the supramolecular interconnections, dimensionality of hydrogen bonding networks and hydrogen bond strength, as well as probability of producing solvates or compounds of unexpected soichiometries. A possibility to predict proton transfer, and therefore supramolecular behavior, within given acid-base systems as accurately as possible thus remains an important question of crystal engineering.

Experimental Section All reagents and solvents were purchased from Sigma-Aldrich Company and used as received. Cindroic acid was prepared according to a modified method by condensation reaction of 2aminobenzoic (3.5 g) and chloroacetic acid (2.5 g) in aqueus solution of sodium carbonate (5.6 g in 25 cm3). Binary solids single crystals were obtained by dissolving cindroic acid (50 ± 5 mg) and corresponding pyridine derivative in slight (ca. 50 %) excess in hot ethanol (2 cm3) whereupon solutions were left to cool and evaporate. Crystals suitable for single crystal X-ray diffraction experiment appeared in three to five days. ACS Paragon Plus Environment

25

Page 27 of 32

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


X-ray crystallography The diffraction data for molecular and crystal structure determination were collected at 295 K for all crystals. Diffraction measurements were made on an Oxford Diffraction Xcalibur Kappa CCD X-ray diffractometer with graphite-monocromated MoKα (λ = 0.71073 Å) radiation.40,41 The structures were solved by direct methods and refined using SHELXS and SHELXL programs.42 The structural refinement was performed on F2 using all data. All calculations were performed and the figures were prepared using WINGX crystallographic suite of the programs. Hydrogen atoms involved in hydrogen bonding were located from electron difference map, while those which do not participate in such interactions were placed on the calculated positions. All hydrogen atoms were refined isotropically. CSD survey The Cambridge structural database25 (CSD, version 5.38 with one update) was searched for hydrogen bonded contacts between pyridine nitrogen atoms (protonated and unprotonated) and carboxyl groups (unprotonated and protonated). Aromatic acid fragment was defined as carboxyl group bonded to an aromatic six membered ring, and aliphatic acid fragment as carboxyl group bonded to a methylene group. Both C-O bonds of the carboxyl group were treated as ‘any’ bond type. As the position of hydrogen atom, as well as minute differences in heavy atom positions were of importance, stringent exclusion criteria were employed to ensure the analysis is performed on the highest quality data only: all structures has to have 3D atom coordinates with R < 5%, and had to be free of errors and not disordered. Polymeric structures, structures containing metal atoms and those determined from powder diffraction data were also excluded. Computational methods All calculations were carried out with the Gaussian 09 (Revision D.01) program,43 employing M062X44/6-311G(d,p) level of theory with ultrafine integration grid (99 radial shells and 590 points per shell). Molecular geometry of H2cin and the pyridine derivatives were optimized to minima, confirmed by harmonic frequencies calculation. Cubegen utility of G09 was used to calculate electron density cube (grid = 803 points) in H2cin and pyridine molecules and electrostatic potential (ESP) was mapped on the ACS Paragon Plus Environment

26


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 28 of 32

electron density isosurface (isovalue = 0.002 a.u.). The lowest and the highest ESP value on the surface were found by our own Fortran 90 code. Molecule and the mapped surface were visualized by GaussView 5.0.8. program.45

Acknowledgment This research was supported by the Croatian Science Foundation under the project IP-2014-09-7367.

Supporting Information Available. Crystallographic data for all compounds, ORTEP plots of asymmetric units with atom labels, IR spectra and tables with hydrogen bond data. X-ray crystallographic information files (CIF) are available for all compounds. Crystallographic information files are also available from the Cambridge Crystallographic Data Center (CCDC) upon request (http://www.ccdc.cam.ac.uk, CCDC deposition numbers 1552929-1552944). References 1) Desiraju, G. R. J. Am. Chem. Soc., 2013, 135, 9952–9967. 2) Jagadeesh Babu, N.; Sanphui, P.; Nagnia, A. Chem. Asian J., 2012, 7, 2274–2285. 3) Desiraju, G. R. Angew. Chem. Int. Ed. Engl., 1995, 34, 2311–2327. 4) Etter, M. C. Acc. Chem. Res., 1990, 23, 120–126 5) Aakeröy, C. B.; Seddon, K. R. Chem. Soc. Rev., 1993, 22, 397–407. 6) Aakeröy, C. B.; Salmon, D. J. CrystEngComm, 2005, 7, 439–448. 7) Aakeröy, C. B.; Nieuwenhuyzen, M. J. Mol. Struct., 1996, 223–239. 8) Metrangolo P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res., 2005, 38, 386–395. 9) Priimagi, A.; Cavallo, G.; Metrangolo, P.; Resnati, G Acc. Chem. Res., 2013, 46, 2686–2695. 10) Rissanen, K. CrystEngComm, 2008, 10, 1107–1113.


27

Page 29 of 32

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


11) Stilinović, V.; Horvat, G.; Hrenar, T; Nemec, V.; Cinčić, D. Chem. Eur. J. 2017, 23, 5244– 5257. 12) Stilinović, V.; Cinčić, D.; Zbačnik, M.; Kaitner, B. Croat. Chem. Acta, 2012, 85, 485–493. 13) Akiri, K.; Cherukuvada, S.; Rana S.; Nangia A. Cryst. Growth Des. 2012, 12, 4567–4573. 14) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des., 2008, 8, 4533–4545. 15) Sarma, B.; Nath, N. K.; Bhogala, B. R.; Nangia, A. Cryst. Growth Des., 2009, 9, 1546–1557. 16) Stilinović, V; Kaitner, B. Cryst. Growth Des., 2011, 11, 4110–4119. 17) Lemmerer, A.; Govindraju, S.; Johnston, M.; Motloung, X.; Savig, K. L. CrystEngComm, 2015, 17, 3591–3595. 18) Mohamed, S.; Tocher, D. A.; Vickers, M.; Karamertzanis, P. G.; Price, S. L. Cryst. Growth Des., 2009, 9, 2881−2889. 19) Stilinović, V.; Kaitner, B. Cryst. Growth Des., 2012, 12, 5763–5772. 20) Cruz-Cabeza, A. J. CrystEngComm, 2012, 14, 6362–6365. 21) Gilli, P.; Pretto, L.; Gilli, G. J. Mol. Struct., 2007, 844–845, 328–339. 22) Gilli, P.; Bertolasi, V.; Pretto, L.; Gilli, G. J. Mol. Struct., 2006, 790, 40–49. 23) Gilli, G.; Gilli, P. J. Mol. Struct., 2000, 552, 1–15. 24) Aakeröy, C. B.; Epa, K.; Forbes, S.; Schultheiss, N.; Desper, J. Chem. Eur. J., 2013, 44, 14998– 15003. 25) Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. Acta Cryst., 2016, B72, 171–179. 26) Guo, X.; Liu, H.; Lu, J. Zeitschrif Fur Krist. Cryst. Struct. 2007, 222, 437–438. 27) Yu, Z. L.; Wang, S. W. Zeitschrif Fur Krist. New Cryst. Struct. 2008, 223, 465–467. 28) Yu, Z. L.; Li, X. D. Zeitschrif Fur Krist. New Cryst. Struct. 2008, 223, 271–272. ACS Paragon Plus Environment

28


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 30 of 32

29) Tai, X. S.; Liu, L. L. J. Chem. Pharm. Res., 2014, 6, 905–906. 30) Barooah, N.; Singh, W. M.; Baruah, J. B., J. Mol. Struct., 2008, 875, 329–338. 31) Friedländer, P.; Ber. Dtsch. Chem. Ges. 1900, 23, 3431. 32) Schmidt, H. Chemie in unserer Zeit, 1997, 31, 121–128. 33) CRC Handbook of Chemistry and Physics 85th ed. CRC Press: Boca Raton, FL, 2004-2005. 34) Uhlig, Von E.; Walther, D. Z. Anorg. Allg. Chem., 1973, 397, 187–197. 35) ACE/JChem, ACE and JChem acidity and basicity calculator. 2016, https://epoch.uky.edu/ace/public/pKa.jsp 36) Bryson, A.; Davies, N. R.; Serjeant, E. P. J. Am. Chem. Soc., 1963, 85, 1933–1938. 37) Uhlig, E. Chem. Ber., 1960, 93, 2470–2474. 38) Johnson, S. L.; Rumon, K. A. J. Phys. Chem., 1965, 69, 74–86. 39) Trivedi, D. R.; Ballabh, A.; Dastidar, P. CrystEngComm, 2003, 5(64), 358–367. 40) CrysAllis CCD v171.26, Oxford Diffraction 2003, Oxford Diffraction LTD., Abingdon, Oxfordshire, UK. 41) CrysAllis RED v171.26, Oxford Diffraction 2003, Oxford Diffraction LTD., Abingdon, Oxfordshire, UK. 42) Sheldrick, G. M. Acta Crystallogr. Sect. A Found. Crystallogr. 2008, 64 (1), 112–122. 43) Gaussian 09, Revision D.01, 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, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, ACS Paragon Plus Environment

29

Page 31 of 32

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


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, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. 44) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–241. 45) GaussView, Version 5.0.8, Dennington, Roy; Keith, Todd; Millam, John. Semichem Inc., Shawnee Mission, KS, 2009.


30


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 32 of 32

For Table of Contents Use Only Aromatic vs. Aliphatic Carboxyl Group as Hydrogen Bond Donor in Salts and Cocrystals of an Asymmetric Diacid and Pyridine Derivatives Nikola Bedeković, Vladimir Stilinović, Tomislav Piteša

Synopsis: Out of 15 salts and cocrystals of an asymmetric aromatic-aliphatic dicarboxylic diacid, N-(2carboxyphenyl)glycine and pyridine derivatives, in 9 structures included pyridine was bonded to the aliphatic group, 3 to aromatic group and in 3 to both carboxylic groups. The occurrence of proton transfer within the structures was found to follow the basicity of the pyridine derivative. TOC Graphic


31

Aromatic versus Aliphatic Carboxyl Group as a Hydrogen Bond Donor

Recommend Documents