Cyanophenyloximes: Reliable and Versatile Tools for Hydrogen-Bond Directed Supramolecular Synthesis of Cocrystals Christer B. Aakero¨y,* Debra J. Salmon, Michelle M. Smith, and John Desper Department of Chemistry, Kansas State UniVersity, Manhattan, Kansas 66506
CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 4 1033-1042
ReceiVed January 25, 2006; ReVised Manuscript ReceiVed February 1, 2006
ABSTRACT: A systematic structural and spectroscopic examination of the products resulting from cocrystallization reactions between three types of phenyloximes R-CdN-OH (where R ) H, Me, or CN) and a series of N-heterocyclic hydrogen-bond acceptors demonstrates that the acidity of the oxime -OH hydrogen-bond donor is crucial to the efficacy of the supramolecular assembly process. Cyanophenyloximes are comparable to carboxylic acids, in terms of success rate, whereas the significantly less acidic CH3and H-substituted analogues are not effective at generating cocrystals despite close similarities in steric and geometric parameters. The importance and validity of using experimental pKa values and calculated electrostatic potential surfaces as a basis for predicting the supramolecular yield of an O-H‚‚‚N interaction for driving the formation of cocrystals (within a functional group class) is unambiguously established, and six new crystal structures of cocrystals assembled using oxime‚‚‚heterocycle-based hydrogen bonds are presented. Introduction Access to a wide array of highly specific and mutually complementary molecular recognition events are necessary to compile a “dictionary” that can be used to extend the language of supramolecular synthetic chemistry.1 Within this context, it would be particularly useful to be able to identify or establish a robust hierarchy of supramolecular synthons,2 as this would enable the development of modular noncovalent assembly processes of more complex supermolecules with predetermined and desirable connectivities and dimensionalities.3 Synthesis without making and breaking covalent bonds is, arguably, a very difficult proposition as most crystalline molecular solids are homomeric;4 effective close-packing of discrete building blocks is more readily achieved if all the components are identical. There have, however, in recent years been many reports of the deliberate synthesis of binary5 and ternary6,7 cocrystals,8 and considerable success has been achieved when a carboxylic acid moiety is allowed to interact with a suitable N-heterocycle.9 This group of related intermolecular interactions (the most notable representative is the carboxylic acid‚‚‚pyridine synthon), Scheme 1a, shows great reliability, versatility, and selectivitysall important features of a practical supramolecular synthetic tool. Amides, on the other hand, are generally not capable of forming N-H‚‚‚N hydrogen-bond interactions with an Nheterocycle of sufficient strength to drive the assembly of binary cocrystals, even though the two moieties are geometrically complementary, Scheme 1b. A survey of the current version of the CSD10 contains approximately 70 examples of cocrystals constructed primarily from a carboxylic acid‚‚‚N-heterocycle synthon, whereas there are very few examples of binary cocrystals prepared with the aid of an amide‚‚‚N-heterocycle hydrogen bond. This discrepancy is not simply the result of the number of crystallographically characterized compounds of each type, as there are only five times more carboxylic acids than amides. Instead, the dramatic differences in supramolecular behavior between these functional groups may be ascribed to the acidity of the protons in the two different hydrogen-bond donors. Generally speaking, the pKa values of carboxylic acids * To whom correspondence should be addressed. E-mail: aakeroy@ ksu.edu.
Scheme 1. (a) Common Carboxylic Acid‚‚‚Pyridine Synthon Capable of Driving the Assembly of Molecular Cocrystals. (b) A Plausible Amide‚‚‚Pyridine Synthon Which, in Practice, Is Not Generally Capable of Directing the Assembly of Cocrystals
are substantially lower than the values for the analogous amide; the resulting strength of an (acid) O-H‚‚‚N interaction is also significantly greater than that of an (amide) N-H‚‚‚N hydrogen bond (given the same acceptor site). The greater strength of the former seems to translate into a more effective tool for hydrogen-bond directed cocrystal formation. It is important to note, at this point, that it can be perilous to make general statements about the relative ability of different functional groups to engage in intermolecular hydrogen-bond interactions based upon simple concepts such as acidity, e.g., benzenethiol is more acidic than phenol but an inferior hydrogen-bond donor. Consequently, carboxylic acids and carboxamides are, in chemical and structural ways, rather too dissimilar to provide suitable structural probes of the idea that selective and directed supramolecular assembly can be achieved using relatively simple modular strategies based upon a hierarchy of intermolecular interactions. Therefore, to determine if acidity (as determined by pKa values) and/or electrostatics (from calculated electrostatic potential surfaces) can be used as guidelines for predicting supramolecular reactivity within a functional group class, we have examined the ability of three families of oximes to form binary cocrystals with a variety of N-heterocyclic hydrogen-bond acceptors. Oximes are reasonably effective hydrogen-bond donors and are known to form hydrogen-bonding interactions with pyridines when the two functionalities are located on the same molecule.11 This demonstrates that the interaction between the pyridine nitrogen atom and the oxime proton is perfectly viable even in competition with plausible alternative oxime‚‚‚oxime motifs such as dimers, tetramers, and polymers. However, if the oxime moiety and the N-heterocycle belong to a different molecular
10.1021/cg0600492 CCC: $33.50 © 2006 American Chemical Society Published on Web 03/01/2006
1034 Crystal Growth & Design, Vol. 6, No. 4, 2006 Scheme 2. Possible Hydrogen-Bond Interactions between Oximes and a Few N-Heterocyclic Compounds
Scheme 3. Three Families of Oximes with Distinctly Different pKa Values: (a) 11.30-11.44; (b) 10.80-11.05; and (c) 8.97-9.0112
Aakero¨y et al. Scheme 4.
General Synthesis of Cyanophenyloximes
very similar sterics, the electronics of each group is different, and, consequently, the pKa values for each set of oximes cover a different range. The primary focus of this investigation is two-fold: (a) will a simple electrostatically-driven increase in hydrogen-bond strength translate into an increased supramolecular yield of cocrystal formation, and (b) will a new effective supramolecular reagent be found within any of these three types of oximes? Experimental Section
fragments, what will happen? Is the oxime O-H‚‚‚N (N-heterocycle) hydrogen bond sufficiently strong to effectively bring about the formation of cocrystals, Scheme 2? The oxime functional group displays pKa values in a range between that of carboxylic acids and amides. More significant, however, is the fact that the acidity and the precise electrostatic nature of the oxime proton can be altered readily without making dramatic steric or geometric modifications in close proximity of the -OH donor site. Since the importance and potential synthetic usefulness of a simple molecular electrostatic switch for modulating supramolecular synthesis reside at the very center of this investigation, oximes are ideal candidates for testing our hypotheses, Scheme 3. The acidity of the oxime proton can be increased by adding a strong electron-withdrawing group (R ) CN) to create cyanophenyloximes. In combination with two of their less acidic counterparts, Scheme 3, we have access to a set of molecules that will allow us to directly relate the acidity and electrostatics of the oxime functional group to its ability for forming cocrystals. This can be done without unwanted steric bias in any of the three families of oximes and, furthermore, all oximes to be employed in this study are unlikely to cause proton transfer to the N-heterocycle acceptorsthe synthetic supramolecular target in all these reactions is a molecular cocrystal instead of an organic salt.13 Much work has been done with the coordination chemistry14 and biological and agricultural properties15 of cyanophenyloximes and their complexes over the past decades. These compounds are relatively simple to prepare; however, the supramolecular chemistry of these compounds in organic cocrystals has not yet been explored. To date, there are only a handful of crystallographically characterized examples in the CSD of cocrystals driven by an oxime‚‚‚pyridine O-H‚‚‚N hydrogen-bond interaction,16 but, clearly, a broad systematic structural study is required to determine the general usefulness of oximes in cocrystal synthesis.17 Herein we present a comparative study of the extent of cocrystal formation (as determined by X-ray crystallography and vibrational spectroscopy) in reactions between three “families” of oximes and a variety of nitrogen-containing heterocycles. While these families contain the same functional group and have
Synthesis of Cyanophenyloximes. The preparation of the cyanophenyloximes, Scheme 4, was carried out as previously reported.18,19 2-Propanol (250 mL) was placed into a 500-mL Erlenmeyer flask, and a magnetic stir bar was added. A nitrogen (N2) atmosphere was introduced by bubbling nitrogen gas into the 2-propanol via a Pasteur pipet. The N2 was allowed to flow into the solution for 10 min before sodium metal (7.94 × 10-3 mol, 0.183 g) was added in tiny pieces over a 15-min period of time. The Na metal was allowed to dissolve under the N2 atmosphere (generally 2-3 h). The X-phenylacetonitrile (X ) 4-Br, 3-Cl; 7.94 × 10-3 mol) was dissolved in 5 mL of additional 2-propanol and added to the stirring i-PrONa solution. The solution changed from colorless to a light peach color. A separate 500-mL three-necked flask was equipped with a stir bar, 10 g of NaNO2, 100 mL of distilled H2O, and 50 mL of methanol. The NaNO2 was allowed to dissolve with stirring. A greased septum was introduced into one neck, and a greased one-hole rubber stopper was placed firmly into the central neck. A dropper funnel (125 mL) was greased and attached to the third neck with a Keck clip. A solution of 2:1 H2O/H2SO4 (32 mL/16 mL) was prepared and kept in an ice bath (∼4 °C). After a glass U-tube apparatus was assembled between the i-PrONa/acetonitrile solution in the Erlenmeyer flask and the NaNO2/ H2O/MeOH solution in the three-necked flask, the acid/water solution was placed into the dropper funnel, and the acid/water solution was slowly added dropwise to the NaNO2/H2O/MeOH solution inside the flask. Small bubbles of the evolving CH3ONO gas were immediately seen upon the reaction of the acid with the sodium nitrite. Evidence of the methyl nitrite gas flow into the Erlenmeyer flask was seen as evidence of gas bubbles under the surface of the i-PrONa/acetonitrile solution. This solution immediately changed from the light peach color to a bright yellow. The acid/water mixture was continuously added to the NaNO2/H2O/MeOH solution in small aliquots until all was added (about 1 h). The U-tube apparatus was dismantled, and the now bright yellow i-PrONa/acetonitrile/CH3ONO solution was placed under N2 atmosphere. The Erlenmeyer flask was placed into an ice bath and allowed to stir overnight at ∼4 °C. The next morning a small amount of white solid had precipitated from the bright yellow solution. This solid was filtered off and determined to be the sodium cyanophenyloximate salt via 1H NMR. The remaining solvent was removed from the reaction mixture via rotary evaporation, resulting in a light yellow solid. 1H NMR evidence showed starting material present, so the solid was dissolved in 50 mL of water at room temperature, and excess starting material was filtered off (the cyanophenyloximate salt is soluble in water). The water was removed, and the resulting solid was determined to be the pure sodium cyanophenyloximate salt via 1H NMR and thin-layer chromatography. All of the sodium cyanophenyloximate salt was collected in a 250 mL beaker and dissolved in 40 mL of distilled water. A magnetic stir bar was added, and the beaker was placed in an ice bath on a stir plate. The starting pH of the mixture was ∼10. HCl (1 M) was added in 2-mL aliquots, and the pH was measured via pH paper after each addition. A white precipitate began forming when the solution was at
Cyanophenyloximes
Crystal Growth & Design, Vol. 6, No. 4, 2006 1035 Table 1. Ligand Names and Structures of Some Heterocyclic Ligands Used in Cocrystallizations
a
4,4′-bipy ) 4,4′-bipyridine; 4,4′-bpe ) trans-1,2-bis(4-pyridine)ethylene. Table 2. IR Data (O-H‚‚‚N Stretches) from Cocrystallization Experiments IR O-H‚‚‚N bands (cm-1) oximes acetophenoneoximes heterocycle (N) 4,4′-bipy 4,4′-bpe 1,4-bix 1,4-bibix 1,4-(2-Me)-bix 1,4-(2-Me)-bibix 1,3-bix 1,3-bibix
3
4
benzaldoximes 5
2614, 1878 2707, 1898
pH 8. Acid was continuously added until the pH of the solution was determined to be ∼5. At pH 5, the solution was very cloudy and white. This white precipitate was filtered off, determined to be the free oxime, and characterized by melting point, 1H NMR, ESI-MS, and IR. 4-Bromo-cyanophenyloxime 1. Yield: 1.408 g (79%) mp: 129131 °C (lit. 135 °C)19; 1H NMR: δH (400 MHz; DMSO-d6) 7.4187.528 (4H, dd), 14.1 (1H, broad s); m/z ) 225.5; V(CtN) 2245 cm-1, V(N-O) 1070, 977 cm-1. 3-Chloro-cyanophenyloxime 2. Yield: 0.880 g (61%) mp: 107108 °C (lit. 105 °C)19; 1H NMR: δH(200 MHz; CDCl3) 7.401 (1H, t), 7.462 (1H, d), 7.675 (1H, d), 7.810 (1H, s), 8.583 (1H, broad s); m/z ) 180.0; V(CtN) 2236 cm-1, V(N-O) 1063, 1003 cm-1. Synthesis of Acetophenoneoximes and Benzaldoximes. The syntheses of 3-7 were carried out according to published procedures,20 whereas benzaldoxime, 8, was obtained from commercial sources. 3-(Bromobenzene)acetophenoneoxime 3. 3-Bromoacetophenone (2.45 g; 1.23 × 10-2 mol) was dissolved in ethanol (40 mL) with stirring. NH2OH‚HCl (1.71 g; 2.47 × 10-2 mol) in 15 mL of distilled water and Na2CO3 (1.31 g; 1.23 × 10-2 mol) in 25 mL of distilled water were added to the ethanolic 3-bromoacetophenone solution. The mixture was heated under reflux for 48 h. Upon cooling of the sample to room temperature, a white precipitate had formed. The mixture was concentrated under reduced pressure and then cooled in an ice bath. The white precipitate was collected via vacuum filtration, washed with cold water, and dried with an aspirator. Yield: 2.38 g (97%); mp: 99.5-100.5 °C (lit. 100-101 °C)21; 1H NMR: δH (400 MHz; DMSOd6) 2.14(3H, s), 7.34-7.38(1H, t), 7.56(1H, d), 7.65(1H, d), 7.80(1H, s), 11.39(1H, s); V(CdN) 1633 cm-1, V(N-O) 1005, 936, 886 cm-1. 4-(Bromobenzene)acetophenoneoxime 4. 4-Bromoacetophenone (2.45 g; 1.23 × 10-2 mol) was dissolved in ethanol (40 mL) with
6
2575, 1845
7
cyanophenyloximes 8
1
2
2522, 1845 2488, 1859 2488, 1819 2482, 1812 2462, 1825 2482, 1799 2501, 1845 2515, 1859
2482, 1839 2449, 1839 2442, 1825 2442, 1819 2508, 1912 2488, 1806 2535, 1878 2522, 1865
stirring. NH2OH‚HCl (1.71 g; 2.47 × 10-2 mol) in 15 mL of distilled water and Na2CO3 (1.31 g; 1.23 × 10-2 mol) in 25 mL of distilled water were added to the ethanolic 4-bromoacetophenone solution. The mixture was heated under reflux for 48 h. Upon cooling of the sample to room temperature, a white precipitate had formed. The mixture was concentrated under reduced pressure and then cooled in an ice bath. The white precipitate was collected via vacuum filtration, washed with cold water, and dried with an aspirator. Yield: 2.34 g (89%); mp: 131-132 °C (lit. 129-130 °C)22; 1H NMR: δH (400 MHz; DMSO-d6) 2.13(3H, s), 7.58-7.59(4H, d), 11.33(1H, s); V(CdN) 1646 cm-1, V(N-O) 1003, 917 cm-1. Acetophenoneoxime 5. Acetophenone (1.48 g; 1.23 × 10-2 mol) was dissolved in ethanol (40 mL) with stirring. NH2OH‚HCl (1.71 g; 2.47 × 10-2 mol) in 15 mL of distilled water and Na2CO3 (1.31 g; 1.23 × 10-2 mol) in 25 mL of distilled water were added to the ethanolic acetophenone solution. The mixture was heated under reflux for 48 h. Upon cooling of the sample to room temperature, a white precipitate had formed. The mixture was concentrated under reduced pressure and then cooled in an ice bath. The white precipitate was collected via vacuum filtration, washed with cold water, and dried with an aspirator. Yield: 1.24 g (75%); mp: 59-60 °C (lit. 57-59.7 °C)23; 1H NMR: δH (400 MHz; DMSO-d6) 2.13(3H,s), 7.35-7.40(3H,m), 7.63-7.66(2H,dd), 11.20(1H,s); V(CdN) 1639 cm-1, V(N-O) 1003, 928 cm-1. 3-Bromo-benzaldoxime 6. 3-Bromo-benzaldehyde (2.28 g; 1.23 × 10-2 mol) was dissolved in ethanol (40 mL) with stirring. NH2OH‚ HCl (1.71 g; 2.47 × 10-2 mol) in 15 mL of distilled water and Na2CO3 (1.31 g; 1.23 × 10-2 mol) in 25 mL of distilled water were added to the ethanolic 3-bromo-benzaldehyde solution. The mixture was heated under reflux for 48 h. Upon cooling of the sample to room temperature, a white precipitate had formed. The mixture was concentrated under
1036 Crystal Growth & Design, Vol. 6, No. 4, 2006
Aakero¨y et al.
Figure 1. (a) IR spectrum of 1 (b) IR spectrum of 1 + 4,4′-bipy. reduced pressure and then cooled in an ice bath. The white precipitate was collected via vacuum filtration, washed with cold water, and dried with an aspirator. Yield: 1.82 g (74%); mp: 74-75 °C (lit. 72-73 °C)24; 1H NMR: δH (400 MHz; DMSO-d6) 7.34-7.38(1H, t), 7.587.61(2H, dd), 7.77(1H, s), 8.14(1H, s), 11.44(1H, s); V(CdN) 1627 cm-1, V(N-O) 977, 904, 871 cm-1. 4-Bromo-benzaldoxime 7. 4-Bromo-benzaldehyde (2.28 g; 1.23 × 10-2 mol) was dissolved in ethanol (40 mL) with stirring. NH2OH‚ HCl (1.71 g; 2.47 × 10-2 mol) in 15 mL of distilled water and
Na2CO3 (1.31 g; 1.23 × 10-2 mol) in 25 mL of distilled water were added to the ethanolic 4-bromo-benzaldehyde solution. The mixture was heated under reflux for 48 h. Upon cooling of the sample to room temperature, a white precipitate had formed. The mixture was concentrated under reduced pressure and then cooled in an ice bath. The white precipitate was collected via vacuum filtration, washed with cold water, and dried with an aspirator. Yield: 2.20 g (89%); mp: 109-113 °C (lit. 114-115 °C)25; 1H NMR: δH (400 MHz; DMSO-d6) 7.53-7.61-
Cyanophenyloximes
Crystal Growth & Design, Vol. 6, No. 4, 2006 1037
Figure 2. (a) IR spectrum of 4 + 4,4′-bipy. (b) IR spectrum of 7 + 4,4′-bipy. (4H, dd), 8.13(1H, s), 11.37(1H, s); V(CdN) 1646 cm-1, V(N-O) 1003, 957, 871 cm-1. Commercially available heterocycles were purchased from Aldrich. Bis-imidazoles and bis-benzimidazoles employed in this study, Table 1, were synthesized using published procedures.26 Synthesis of Cocrystals. Cocrystals of the cyanophenyloxime plus a nitrogen-containing heterocycle (Table 1) were set up in a 2:1 ratio of oxime:heterocycle. Each heterocycle was measured on an analytical
balance, placed in an 18 × 150 mm test tube, and dissolved in ethyl acetate. A stock solution of each oxime was prepared. The oxime solution was then added to each heterocycle solution. Solids that did not dissolve in ethyl acetate were heated with a heat gun until the mixture produced a homogeneous solution. In cases when heating did not completely dissolve the solid, ethanol was added. Crystals/solids were obtained via slow evaporation on the bench at room temperature. These crystals/solids were then utilized for IR studies. Experiments
1038 Crystal Growth & Design, Vol. 6, No. 4, 2006 that produced crystals suitable for single-crystal X-ray analysis were also analyzed crystallographically. This procedure was also utilized for acetophenoneoximes and benzaldoximes. Details for reactions that produced crystals suitable for single-crystal X-ray diffraction are presented below. 1 +1,4- bibix 1a. 1 (15 mg, 6.67 × 10-5 mol) from a stock solution in ethyl acetate was placed in a test tube. A solution of 1,4-bibix (11 mg, 3.33 × 10-5 mol) in ethanol was added to produce a clear and colorless solution. Colorless plates were obtained via slow evaporation after 14 days; mp ) 205-208 °C. 1 + 1,4-bix 1b. 1 (15 mg, 6.67 × 10-5 mol) from a stock solution in ethyl acetate was placed in a test tube. A solution of 1,4-bix (9 mg, 3.33 × 10-5 mol) in ethanol was added to produce a clear and colorless solution. Colorless plates were obtained via slow evaporation after 16 days; mp ) 138-141 °C. 1 + 1,4-(2-Me)-bibix 1c. 1 (15 mg, 6.67 × 10-5 mol) from a stock solution in ethyl acetate was placed in a test tube. A solution of 1,4(2-Me)-bibix (12 mg, 3.33 × 10-5 mol) in ethanol was added to produce a clear and colorless solution. A noncrystalline white solid resulted after 6 days and was redissolved in 3 mL of ethanol. Colorless prisms were obtained via slow evaporation from this solution after 10 days; mp ) 212-217 °C. 1 + 1,4-(2-Me)-bix 1d. 1 (15 mg, 6.67 × 10-5 mol) from a stock solution in ethyl acetate was placed in a test tube. A solution of 1,4(2-Me)-bix (9 mg, 3.33 × 10-5 mol) in ethanol was added to produce a clear and colorless solution. A noncrystalline white solid resulted after 6 days and was redissolved in 2 mL of ethanol and 2 mL of ethyl acetate. Colorless prisms were obtained via slow evaporation from this solution after 13 days; mp ) 100-103 °C. 2 + 1,4-bix 2a. 2 (15 mg, 8.33 × 10-5 mol) from a stock solution in ethyl acetate was placed in a test tube. A solution of 1,4-bix (11 mg, 4.17 × 10-5 mol) in ethyl acetate was added to produce a clear and colorless solution. Colorless plates were obtained via slow evaporation after 9 days; mp ) 138-142 °C. 4 + 1,4-(2-Me)-bibix 4a. 4 (11 mg, 5.00 × 10-5 mol) from a stock solution in ethanol was placed in a test tube. A solution of 1,4-(2-Me)bibix (9 mg, 2.50 × 10-5 mol) in ethanol was added to produce a clear and colorless solution. Colorless plates were obtained via slow evaporation from this solution after 10 days; mp ) 130-133 °C. IR Spectroscopy. Infrared data of the products obtained in the cocrystallizations were acquired using a potassium bromide pellet. An approximate 8:1 ratio of KBr to solid product was combined in an oven-dried mortar and ground to a uniform powder with a pestle. A pellet press was employed to create a transparent KBr pellet that was used for analysis. A Nicolet FT-IR instrument equipped with OMNIC software was used to analyze the data. The resulting IR spectra were printed and analyzed. The main features used for identification are the O-H‚‚‚N hydrogen-bonding bands at 2500 and 1900 cm-1.27 X-ray Crystallography. X-ray datasets were collected on a Bruker SMART APEX diffractometer using molybdenum KR radiation at 100 K. Data were collected using SMART.28 Initial cell constants were found by small widely separated “matrix” runs. An entire hemisphere of reciprocal space was collected. Scan speed and scan width were chosen based on scattering power and peak rocking curves. Unit cell constants and orientation matrix were improved by leastsquares refinement of reflections thresholded from the entire dataset. Integration was performed with SAINT,29 using this improved unit cell as a starting point. Precise unit cell constants were calculated in SAINT from the final merged dataset. Lorenz and polarization corrections were applied, and data were corrected for absorption using the multiscan method, with the exception of 1a, for which data correction significantly worsened the fit. Data were reduced with SHELXTL.30 The structures were solved in all cases by direct methods without incident. The asymmetric units for all structures contained one oxime and one-half bis(imidazole) molecules. Hydrogen atoms were assigned to idealized positions and were allowed to ride, with the exception of the imidazole amine hydrogen atoms, whose coordinates were allowed to refine. Calculations. The unsubstituted representatives for the three families of oximes examined in this study were constructed using Spartan ‘04 (Wavefunction, Inc. Irvine, CA). Three molecules were optimized using AM1, and the maxima and minima in the molecular electrostatic potential surface (0.002 e/au isosurface) were determined using a positive point charge in a vacuum as the probe.
Aakero¨y et al. Scheme 5. Magnitude of the Maxima and Minima (in kJ/mol) on the Electrostatic Potential Surfacea
a In both acetophenoneoxime and benzaldoxime, a and b, respectively, the imine nitrogen is the location of the minimum value. The minimum in the electrostatic potential for cyanophenyloxime, c, however, occurs on the CtN nitrogen atom.
Results IR Spectroscopy. A summary of the results from the attempted cocrystallizations between cyanophenyloximes and various heterocycles is presented in Table 2. On the basis of information provided by IR spectroscopy all 16 reactions resulted in the formation of cocrystals. The IR spectrum of cyanophenyloxime 1 alone, Figure 1a, does not show any significant bands in the 2500 or 1900 cm-1 regions, whereas the product resulting from the reaction between 1 and 4,4′-bipy displays broad bands indicative of O-H‚‚‚N hydrogen bonding, Figure 1b, and, thus, of cocrystal formation. In contrast, the attempted cocrystallizations of the same set of N-heterocycles with acetophenoneoximes and benzaldoximes only produced three cocrystals from a total of 48 reactions, Table 2, a dramatic difference in reactivity compared to that demonstrated by the cyanophenyloximes. Two representative IR spectra for solids resulting from attempted cocrystallizations between 4,4′-bipy and an acetophenoneoxime (4) and a benzaldoxime (7), respectively, are shown in Figure 2. The absence of broad bands in the 2500 and 1900 cm-1 regions indicates a lack of oxime‚‚‚N-heterocycle hydrogen bonds, and, thus, it is very unlikely that binary cocrystals have formed in either reaction.31 To complement the solution-based reactions, melt experiments were also performed in an attempt to form cocrystals. The oxime-heterocycle reactants were mixed in 2:1 ratios in an 18 × 150 mm test tube. The components were heated with a heat gun until no solid remained. The melt was allowed to cool to room temperature, and the resulting solid was examined using IR spectroscopy. The results on solids obtained from melts were the same as the results obtained on solids produced from solution-phase reactions: cyanophenyloximes consistently formed cocrystals, whereas neither acetophenoneoximes nor benzaldoximes were capable of forming sufficiently strong heteromeric interactions to produce binary cocrystals to any appreciable extent. Molecular Electrostatic Potential Surface. The electrostatic maxima and minima as determined by AM1 for acetophenoneoxime, benzaldoxime, and cyanophenyloxime are shown in Scheme 5. X-ray Crystallography. Single-crystal structure determinations were carried out on five cyanophenyloxime-based cocrystals as well as on one of the three cocrystals that were produced from attempted reactions between an N-heterocycle and acetophenonoximes/benzaldoximes. The relevant crystal-
Cyanophenyloximes
Crystal Growth & Design, Vol. 6, No. 4, 2006 1039 Table 3. Crystallographic Data for 1a-d, 2a, and 4a
systematic name formula moiety empirical formula molecular weight color, habit crystal system space group, Z a, Å b, Å c, Å R, ° β, ° γ, ° volume, Å3 density, g/cm3 temperature, K X-ray wavelength µ, mm-1 Θmin, ° Θmax, ° reflections collected independent observed threshold expression R1 (observed) wR2 (all)
systematic name formula moiety empirical formula molecular weight color, habit crystal system space group, Z a, Å b, Å c, Å R, ° β, ° γ, ° volume, Å3 density, g/cm3 temperature, K X-ray wavelength µ, mm-1 Θmin, ° Θmax, ° reflections collected independent observed threshold expression R1 (observed) wR2 (all)
1a
1b
1c
1,4-bis[(benzimidazol-1-yl)methyl]benzene (4-bromophenylacetonitrile oxime)2, (C22H18N4) (C8H5BrN2O)2 C38H28Br2N8O2 788.50 colorless plate monoclinic P2(1)/n, 2 11.436(4) 5.640(2) 26.449(9) 90.00 99.252(5) 90.00 1683.7(10) 1.555 100(2) 0.71073 2.456 2.72 25.94
1,4-bis[(1-imidazolyl)methyl]benzene, (4-bromophenylacetonitrile oxime)2 (C14H14N4) (C8H5BrN2O)2 C30H24Br2N8O2 688.39 colorless plate monoclinic P2(1)/c, 2 12.9436(5) 5.1863(2) 21.6419(9) 90.00 93.4500(10) 90.00 1450.17(10) 1.577 100(2) 0.71073 2.839 2.38 30.04
1,4-bis[(2-methyl-1-benzimidazolyl)methyl]benzene, (4-bromophenylacetonitrile oxime)2 (C24H22N4) (C8H5BrN2O)2 C40H32Br2N8O2 816.56 colorless prism monoclinic P2(1)/c, 2 7.4360(9) 19.613(2) 12.5107(2) 90.00 107.063(2) 90.00 1744.3(4) 1.555 100(2) 0.71073 2.374 2.69 30.00
10160 3059 2216 >2σ(I) 0.0583 0.1462
15907 4257 3913 >2σ(I) 0.0245 0.0703
19921 5084 4704 >2σ(I) 0.0253 0.0683
1d
2a
4a
1,4-bis[(2-methyl-1-imidazolyl)methyl]benzene, (4-bromophenylacetonitrile oxime)2 (C16H18N4) (C8H5BrN2O)2 C32H28Br2N8O2 716.44 colorless prism triclinic P1h, 1 7.0034(8) 10.6013(1) 11.1605(1) 77.000(2) 75.995(2) 84.920(2) 782.87(2) 1.520 100(2) 0.71073 2.632 2.45 30.00
1,4-bis[(1-imidazolyl)methyl]benzene, (3-chloro-phenylacetonitrile oxime)2 (C14H14N4) (C8H5ClN2O)2 C30H24Cl2N8O2 599.47 colorless plate triclinic P1h, 1 5.9000(1) 7.2231(1) 17.088(3) 86.114(3) 89.633(4) 73.472(3) 696.5(2) 1.429 100(2) 0.71073 0.278 2.39 30.02
1,4-bis[(2-methylbenzimidazol-1-yl)methyl]benzene, (4-bromoacetophenone oxime)2 (C24H22N4) (C8H8BrNO)2 C40H38Br2N6O2 794.58 colorless plate monoclinic P2(1)/c, 2 10.9286(1) 14.1612(2) 11.3704(1) 90.00 92.619(2) 90.00 1757.9(3) 1.501 100(2) 0.71073 2.351 1.87 29.95
8981 4458 4157 >2σ(I) 0.0281 0.0784
8022 3973 3427 >2σ(I) 0.0453 0.1183
16193 5087 4394 >2σ(I) 0.0292 0.0775
Table 4. Hydrogen-Bond Geometries for 1a-d, 2a, and 4a cocrystal
D-H‚‚‚A
d(D-H), Å
d(H‚‚‚A), Å
d(D‚‚‚A), Å
