pubs.acs.org/joc - - Reaction of Dichloromethane with Pyridine and acylation,1 10 Dess-Martin oxidation,11 13 and ozono- 14 Derivatives under Ambient Conditions lysis. Typically DCM is chosen for its versatility as a solvent, while the pyridine acts as a nucleophilic catalyst or a proton acceptor.15 While using DCM as a solvent and pyridine as an Alexander B. Rudine, Michael G. Walter, and acid scavenger in electrochemistry experiments,16 we noticed Carl C. Wamser* that the stock electrochemistry solutions slowly formed fine 0 Department of Chemistry, Portland State University, white crystals, identified as 1,1 -methylenebispyridinium Portland, Oregon 97207-0751 dichloride (Scheme 1). SCHEME 1. Reaction of Pyridine with DCM [email protected] Received February 13, 2010 While the literature reports that DCM reacts with primary, secondary, and tertiary aliphatic amines,17-20 the analogous reaction with pyridine derivatives under ambient conditions has not been reported. However, it was reported that DCM and pyridine formed compound 3a under increased tempera- ture and pressure; the reaction was not observed at atmos- pheric pressure or room temperature, and an intermediate pyridinium adduct was never isolated.21 As might be expec- ted, dibromomethane and diiodomethane show higher re- activity toward pyridine and its derivatives, and adducts from those have been reported.21-23 In addition, unsymme- Pyridine derivatives and dichloromethane (DCM) are trical bispyridinium derivatives have been synthesized by commonly used together in a variety of different applica- independently reacting a halomethyl pyridinium derivative tions. However, DCM slowly reacts with pyridine and a with a dissimilar pyridine.24 variety of other representative pyridine derivatives to Since so little is known about the reaction of DCM with form methylenebispyridinium dichloride compounds un- pyridines under ambient conditions we investigated a series of der ambient conditions. The proposed mechanism (two pyridine derivatives in order to determine the generality of the consecutive SN2 reactions) was studied by evaluating the reaction and reactivity patterns. We also studied the kinetics kinetics of the reaction between 4-(dimethylamino)pyri- of the reaction of DCM with 4-(dimethylamino)pyridine dine and DCM. The second-order rate constants for the (DMAP) in order to elucidate the time course of the reaction, first (k1) and second (k2) substitutions were found to be shed light on the reaction mechanism, and explain why the 2.56((0.06) Â 10-8 and 4.29((0.01) Â 10-4 M-1 s-1, res- intermediate pyridinium adduct is not isolated or observed. pectively. Because the second substitution is so much faster Thirteen different pyridine derivatives were dissolved in than the first, the monosubstitution product could not be DCM and monitored for reaction with 1H NMR spectro- isolated or detected during the reaction; it was synthe- scopy, looking for new downfield aromatic proton signals 25 sized independently in order to observe its kinetics. and the appearance of the distinctive methylene signal. The NMR samples were also inspected for the appearance of a (13) Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. Dichloromethane (DCM) and pyridine derivatives are fre- 2004, 69, 4626–4647. (14) Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74, 3066–3072. quently used together in reactions such as alcohol protection (15) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129–161. (16) Walter, M. G.; Wamser, C. C. J. Phys. Chem. C 2010, 114, 7563– (1) Piers, E.; Oballa, R. M. J. Org. Chem. 1996, 61, 8439–8447. 7574. (2) Lepage, O.; Deslongchamps, P. J. Org. Chem. 2003, 68, 2183–2186. (17) Hansen, S. H.; Nordholm, L. J. Chromatogr., A 1981, 204, 97–101. (3) Kumar, P.; Bodas, M. S. J. Org. Chem. 2004, 70, 360–363. (18) Beckett, A. H.; Ali, H. M. J. Chromatogr., A 1979, 177, 255262. (4) Lanman, B. A.; Myers, A. G. Org. Lett. 2004, 6, 1045–1047. (19) Wright, D.; Wulff, C. J. Org. Chem. 1970, 35, 4252–4252. (5) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1993, 58, (20) Mills, J. E.; Maryanoff, C. A.; McComsey, D. F.; Stanzione, R. C.; 3791–3793. Scott, L. J. Org. Chem. 1987, 52, 1857–1859. (6) Ruecker, C. Chem. Rev. 2002, 95, 1009–1064. (21) Almarzoqi, B.; George, A. V.; Isaacs, N. S. Tetrahedron 1986, 42, (7) Barton, D. H. R.; Buschmann, E.; Hausler, J.; Holzapfel, C. W.; 601–607. Sheradsky, T.; Taylor, D. A. J. Chem. Soc., Perkin Trans. 1 1977, 1107–1114. (22) Munavalli, S.; Poziomek, E. J.; Landis, W. G. Heterocycles 1986, 24, (8) Hernandez, O.; Chaudhary, S. K.; Cox, R. H.; Porter, J. Tetrahedron 1883–1892. Lett. 1981, 22, 1491–1494. (23) Katritzky, A. R.; Nowakwydra, B.; Rubio, O. Chem. Scr. 1984, 24, (9) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 95–98. 7–10. (10) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99–102. (24) Anders, E.; Opitz, A.; Wermann, K.; Wiedel, B.; Walther, M.; Imhof, (11) Ratcliffe, R.; Rodehorst, R. J. Org. Chem. 2002, 35, 4000–4002. W.; Gorls, H. J. Org. Chem. 1999, 64, 3113–3121. (12) Shi, B.; Hawryluk, N. A.; Snider, B. B. J. Org. Chem. 2003, 68, 1030– (25) Munavalli, S.; Szafraniec, L. L.; Beaudry, W.; Poziomek, E. J. Magn. 1042. Reson. Chem. 1986, 24, 743–747. 4292 J. Org. Chem. 2010, 75, 4292–4295 Published on Web 05/14/2010 DOI: 10.1021/jo100276m r 2010 American Chemical Society Rudine et al. JOCNote TABLE 1. Reactivity of Pyridine Derivatives toward DCM SCHEME 2. Proposed Mechanism for the Reaction of Pyridine pyridine derivative reaction Derivatives with DCM pyridine (1a) yes 4-N(CH3)2 (1b) yes 4-tBu (1c) yes 4-NH2 (1d) yes 3-NH2 (1e) yes 4-(40-pyridyl) (1f) yes 2-Cl no 3-Cl no 2-NH2 no 2-CH3 no 2-(CH ) OH no 2 2 the lack of any detectable exchange of the methylene (or any) 2-(CH2)3OH no a - 2-CH2SH no C H bonds when 2a, 2b, 3a,or3b were allowed to stand in aThiols react with DCM. D2O solution for five days. Given the favorable solubility of product 3b, we moni- precipitate, and in the case of a positive result from either tored the reaction kinetics of DCM with DMAP (1b) using a method of detection, a scaled up solution of the pyridine in 0.7 M solution of DMAP in 1:1 (v/v) DCM/DMSO-d6, moni- DCM was made and the product isolated and characterized. tored in quadruplicate for 31 days. Figure 1 shows three 1H Table 1 highlights the pyridines that were tested and the six NMR spectra of the reaction mixture taken at the time points pyridine derivatives that were observed to react under ambient (in days) indicated on the right side of the spectra, with all the conditions within a reasonable time period (two months) to NMR signals assigned to specific protons on 1b or 3b. Several form bispyridinium compounds. Of the six products, only parts of the spectrum were excised to conserve space so the 0 1,1 -methylenebis(4-dimethylamino)pyridinium dichloride (3b) DCM peak at 5.76 ppm is not shown (see the Supporting remained in solution, which made it amenable to monitoring Information for the full spectra). On the basis of the spectra by NMR. The other five were extremely insoluble and began shown it is interesting to note the large downfield shift of all to precipitate soon after mixing. For example, 3 and 0.1 M the protons in 3b due to the presence of the positive ring nitro- solutions of pyridine in DCM showed precipitation within gen, especially the methyl protons [(3b)Me], indicating signi- 2 and 11 h of combination, respectively. The reason for the ficant charge transfer from the ring nitrogen to the p-dimethyl- favorable solubility of 3b may be based on its ability to de- amino moiety. Also notable is the lack of any signal from the localize charge from the ring nitrogen to the dimethylamino intermediate (2b), which corroborates other reports and our group to enhance the solvation. The hydroxy and thiol deri- own observation that the intermediate is not isolatable or vatives were tested in an attempt to use an intramolecular observed during the course of the reaction. nucleophile to capture a potential monosubstituted pyridi- On the basis of the 1H NMR integrations and considering nium intermediate, but these failed to react, as did all of the DCM (5 M) to be in excess, a pseudo-first-order rate law was 2-substituted derivatives. Thus 2-substituted pyridines in gene- used to obtain the second-order rate constant (ko) for the ral may be more suitable for applications such as proton overall reaction of 2.56((0.06)Â10-8 M-1 s-1 (for kinetic plots scavenging in DCM solvent. It has been noted before that and calculations see the Supporting Information). Consider- 2- (and 2,6-) substitution provides steric hindrance that dimi- ing the lack of evidence for 2b, we made the assumption that nishes the nucleophilicity of pyridines while maintaining or the first step is rate determining (k ) and that 2b is consumed 26 1 increasing basicity. One of the 3- and all of the 4-substituted by the second substitution immediately upon formation (k2). pyridines studied reacted to form bispyridinium adducts; On the basis of the steady-state approximation with k1 , k2, thus in those cases caution is necessary whenever they are then ko ≈ k1. used with DCM. It was also notable that the 3- and 4-amino To monitor the kinetics of the second step, we synthesized derivatives (1d and 1e) did not react at the free amino group, 2b independently, starting with DMAP, thionyl chloride, and 0 and that 4,4 -bipyridyl (1f) did not produce polymer, pre- paraformaldehyde in acetonitrile as described by Anders sumably due to the insolubility of the initial bispyridinium et al.24 The kinetics of the second step were evaluated by using salt in DCM.