CRYSTAL GROWTH & DESIGN
Supramolecular Stabilization of Hemiacetals of N-Alkyl(Benz)Imidazole Aldehydes Alexander Solchinger, Klaus Wurst, Holger Kopacka, and Benno Bildstein* UniVersity of Innsbruck, Faculty of Chemistry and Pharmacy, Institute of General, Inorganic and Theoretical Chemistry, Innrain 52a, 6020 Innsbruck, Austria
2007 VOL. 7, NO. 12 2380–2381
ReceiVed April 19, 2007
ABSTRACT: In contrast to common textbook chemistry, aldehydes of N-alkyl(benz)imidazoles do not exist in their carbonyl structure; unexpectedly, under ambient conditions, they form isolable hemiacetals stabilized by strong intermolecular O–H–N hydrogen bonds, both in solution and in the solid state. The carbonyl functionality of aldehydes or ketones is one of the most important and versatile functional groups in synthetic organic chemistry. The mechanism of simple condensation reactions of their carbonyl moiety involves usually an unstable, nonisolable hemiacetal/ketal intermediate that reacts further to the condensation product under extrusion of one equivalent of water. Only very few types of stable hemiacetal/ketals are known, most prominently cyclic representatives (carbohydrates A, dimer of glyoxal B) and some scattered acyclic examples,1 (chloral hemiacetals2 C, cyclopropanone hemiketal3 D, R-pyridinium hemiacetal4 E and dodecanyl dodecanal hemiacetal5 F) (Chart 1). The obvious reasons for the high stability of these hemiacetals are either the formation of strong O–H–O hydrogen bonds (A, B) or the increased reactivity of the carbonyl functionality (C, D, E) or strong van der Waals interactions (F). In this communication, we report on a new structural motif for stable hemiacetals based on strong intermolecular O–H–N hydrogen bonding between the hemiacetal-hydroxyl group and the unsubstituted nitrogen of a (benz)imidazolyl heterocyclic substituent. From a general point of view, one might expect that the same structural motif will also stabilize analogous hemiacetals with other basic N-heterocyclic groups capable of forming O–H–N bonds, for example, pyrazole, triazole, tetrazole, pyridazine, pyrimidine, and others. This might be relevant for the general reactivity of such heterocyclic aldehydes as well as for polymorphism of N-heterocyclic pharmaceuticals. In the course of designing new late transition metal olefin polymerization catalysts, we searched for synthetic approaches to chelating cyclopentadienyl-N-heterocyclic carbene ligands.6 Key synthons in our reaction sequence were (benz)imidazoles substituted with a N-(formyl-C1-alkyl) group. Interestingly, such simple functional molecules have never been synthesized.7 Possible approaches to such N-(formyl-C1-alkyl)-(benz)imidazoles include either deprotection of the corresponding acetals, or selective oxidation of the corresponding alcohols, or reduction of suitable carboxylic acid derivatives. In the first case, the corresponding heterocyclic acetals are easily accessible; however, deprotection under a variety of increasingly harsh conditions8 proved unsuccessful, indicating an unexpectedly high stability of these acetals. In the second case, the corresponding heterocyclic alcohols are also easily accessible, but no selective oxidation could be achieved employing various common reagents.9 In the third case, the corresponding heterocyclic nitriles or carboxylic esters are also synthetically accessible without difficulties, but their attempted reduction with diisobutylaluminum hydride (DIBAL) under standard reaction conditions10 to the target N-(formyl-C1-alkyl)-(benz)imidazoles met only with limited success. Whereas N-(cyano-C1-alkyl)(benz)imidazoles failed to react in a chemoselective manner, * To whom correspondence
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Chart 1. Literature-Known Stable Hemiacetals 1
Scheme 1. Reduction of 1a,b with DIBAL10
N-(alkoxycarbonyl-C1-alkyl)-(benz)imidazoles 1a,b were indeed reducable to the desired aldehyde oxidation state (Scheme 1). However, in contrast to expectations and against all chemical intuition, the desired aldehydes 2a,b exist only in the form of their hemiacetals in solution as well as in the solid state. Interestingly, 3a,b as the primary and isolable products of the DIBAL-reduction of 1a,b were characterized by NMR spectroscopy in solution, but in the solid state single crystal structures of 3a and 4b were obtained. The formation of 4b involved clearly hydrolysis of 3b to the corresponding hydrate, which reacted further to 4b as the monocondensation product of two aldehyde hydrates, formally a bishemiacetal or, more precisely, a bis-hemialdal.1 Diagnostic NMR spectroscopic properties of hemiacetals 3a11 and 3b12 are the chemical shifts of the hemiacetal moiety (3a: 1H: δ 4.78 (s, 1H, HO-CH-OCH3), 6.67 (br s, 1H, OH); 13C: δ95.07 (HO-CH-OCH3); 3b: 1H: 4.41 (s, 1H, HO-CH-OCH3), 6.65 (br s, 1H, OH); 13C:
10.1021/cg070377h CCC: $37.00 2007 American Chemical Society Published on Web 11/15/2007
Communications
Crystal Growth & Design, Vol. 7, No. 12, 2007 2381 cycles with an additional basic nitrogen in their heterocyclic core. This finding might be relevant for polymorphism and/or unusual reactivity of such formyl heterocycles.
Acknowledgment. We thank the R&D department of Basell Polyolefine GmbH, Frankfurt, Germany, for financial support. Supporting Information Available: Crystallographic data of 3a and 4b in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org.
References
Figure 1. ORTEP view of 3a showing the intermolecular O–H–N hydrogen bonded chain structure and the π-π-stacking interactions between the imidazole moieties. Hydrogen atoms, except for the hydroxyl and hemiacetal hydrogens, have been omitted for clarity. Selected distances (pm): O(1)-N(2) ) 277.0(2), distance of benzimidazole centroids ) 339.
Figure 2. ORTEP view of 4b showing the intermolecular O–H–N hydrogen bonded ribbon structure. Hydrogen atoms, except for the hydroxyl and hemiacetal hydrogens, have been omitted for clarity. Selected distance (pm): O(1)-N(2) ) 270.6(3).
100.20 (HO-CH-OCH3)). In accordance with these data, 3a exhibits in the crystalline state13 a hemiacetal molecular structure with unexceptional bond distances and angles (Figure 1). Most significant, however, is the intermolecular supramolecular assembly of the molecular units through O–H–N hydrogen bonds and rather short π-π-stacking14 of the imidazole units of the benzimidazole moieties, resulting in a linear chiral chain structure. It seems obvious that these intermolecular hydrogen bonds are mainly responsible for the high stability of hemiacetal 3a. The chirality of a chain at the semiacetal carbons with their four different substituents is either all S or R, most likely due to steric reasons. In contrast to this simple semiacetal structure of 3a, compound 4b is a bis-hemialdal generated by condensation of two aldehyde hydrates (Figure 2).15 The molecular structure is again rather unexceptional, but the crystal packing is once more dominated by O–H–N hydrogen bonds, in this case with two hydrogen bonds between the molecules but without π-π-stacking interactions, resulting in a linear ribbon structure composed of either all R/R or S/S repeat units. In summary, new stable hemiacetals have been prepared and structurally characterized by X-ray single structure analysis. The unique stability of these heterocyclic hemiacetals is due to their strong intermolecular O–H–N hydrogen bonding, demonstrating a new motif for stabilizing the otherwise elusive hemiacetal functionality in compounds containing formyl-functionalized hetero-
(1) Hurd, C. D. J. Chem. Educ. 1966, 43, 527. (2) Hashimoto, M.; Isono, T.; Mano, K. Ber. Bunsenges. Phys. Chem. 1994, 98, 793. (3) Salaun, J. Chem. ReV. 1983, 83, 619. (4) Steinberg, G. M.; Poziomek, E. J.; Hackley, B. E., Jr J. Org. Chem. 1961, 26, 368. (5) Erickson, J. L. E.; Campbell, C. R., Jr J. Am. Chem. Soc. 1954, 76, 4472. (6) Solchinger, A. Ph.D. Dissertation, University of Innsbruck, Innsbruck, Austria, 2006. (7) A patent claim, although without any experimental proof, has been published: Hayashi, M.; Tanouchi, T.; Takatsuki; Kawamura, M. I.; Kajiwara, I.; Iguchi, Y.; Takatsuki. German Patent 2917456, 1979. (8) Common acidic acetal deprotection reagents in various concentrations were used: (a) HCl/THF, (b) H2SO4/THF, (c) HBF4/Et2O, (d) HCl/ H2O, (e) amberlyst/acetone. (9) Standard–CH2–OH/–CHO oxidizing reagents were used: (a) pyridinium dichromate (Corey’s reagent), (b) BaMnO4, (c) CrO3/pyridine (Collin’s reagent), (d) DMSO/oxalyl chloride (Swern’s reagent), (e) periodinane (Dess-Martin-reagent), (f) KMnO4/MnO2, (g) microwave-activated MnO2. (10) Reaction conditions: 4 equiv of DIBAL in hexane solution, 3 h stirring at -70 °C, hydrolysis by dropwise addition of dry methanol at -70 °C. (11) Spectroscopic data for 3a: 1H NMR (300 MHz, CD3SOCD3): δ 3.24 (s, 3H, H3C-O), 4.16–4.32 (m, 2H, CH2-N), 4.78 (s, 1H, HO-CHOCH3), 6.67 (br s, 1H, OH), 7.15–7.27 (m, 2H, benzimidazole), 7.59– 7.64 (m, 2H, benzimidazole), 8.15 (s, 1H, benzimidazole); 13C NMR (300 MHz, CD3SOCD3): δ 48.97 (CH2-N), 53.81 (H3C-O), 95.07 (HOCH-OCH3), 110.76, 119.23, 121.36, 122.20, 134.31, 143.17, 144.72 (benzimidazole); IR (ATR): 3088w, 1499s, 1461m, 1376m, 1260m, 1098m, 1116s, 968m, 883m, 873m, 752s, 636m, 551m cm-1. (12) Spectroscopic data for 3b: 1H NMR (300 MHz, CD3SOCD3): δ 1.43 (s, 6H, H3C-C), 3.18 (s, 3H, H3C-O), 4.41 (s, 1H, HO-CH-OCH3), 6.65 (br s, 1H, OH), 6.82 (s, 1H, imidazole), 7.22 (s, 1H, imidazole), 7.66 (s, 1H, imidazole); 13C NMR (300 MHz, CD3SOCD3): δ 23.06 H3C-C), 54.57 (H3C-O), 60.24 (H3C-C), 100.20 (HO-CH-OCH3), 117.91, 127.28, 135.57 (imidazole); IR (ATR): 2996w, 1497s, 1389m, 1271s, 1231s, 1124s, 1077s, 1058s, 1027m, 1008s, 921m, 825s, 754s, 664s cm-1. (13) Crystal data for 3a: C10H12N2O2 (192.22), monoclinic, space group P21/c, a ) 884.72(6), b ) 1169.62(9), c ) 978.39(4) pm, β°, V ) 0.96814(11) nm3, Z ) 4, Dc ) 1.319 Mg/m3, µ(Mo-KR) ) 0.094 mm-1, T ) 233(2) K, 1517 independent reflexes [Rint ) 0.0355], final R indices (133 parameters) for 1187 independent reflections [I < 2σ(I)] are R1 ) 0.0393, wR2 ) 0.0917, GOF ) 1.054. (14) Chen, C.-L.; Su, C.-Y.; Cai, Y.-P.; Zhang, H.-X.; Xu, A.-W.; Kang, B.-S.; zur Loye, H.-C. Inorg. Chem. 2003, 42, 3738. (15) Crystal data for 4b: C14H22N4O3 × 2 CH2Cl2 (464.21), orthorhombic, space group Pbcn, a ) 1782.14(7), b ) 727.22(4), c ) 1738.81(9) pm, V ) 2.25351(19) nm3, Z ) 4, Dc ) 1.368 Mg/m3, µ(Mo-KR) ) 0.548 mm-1, T ) 233(2) K, 1767 independent reflexes [Rint ) 0.0368], final R indices (132 parameters) for 1397 independent reflections [I < 2σ(I)] are R1 ) 0.0509, wR2 ) 0.1293, GOF ) 1.061.
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