H−D Exchange between N-Heterocyclic Compounds and D2O with a

May 27, 2009 - Calf , G. E.; Garnett , J. L.; Pickles , V. A. Aust. J. Chem. 1968, 21 (4) 961– 72. [CAS]. 7. Catalytic deuterium exchange reactions ...
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Organometallics 2009, 28, 4020–4027 DOI: 10.1021/om9001796

H-D Exchange between N-Heterocyclic Compounds and D2O with a Pd/PVP Colloid Catalyst Kathryn A. Guy and John R. Shapley* Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 Received March 6, 2009

A polymer-protected palladium colloid (Pd/PVP, PVP = poly-N-vinylpyrrolidone) has been used to catalyze H-D exchange between the D2O solvent and pyridine, substituted pyridines, and related N-heterocycles. Within a few hours under ambient conditions, significant exchange at the positions adjacent (R) to the endocyclic nitrogen was observed for 4-dimethylaminopyridine, 4-methoxypyridine, 4-methylpyridine, pyridine, and quinoline. H-D exchange was observed also for the methyl group in 4-methylpyridine and for the fused-ring H8 position in quinoline. N-Methylimidazole was rapidly and selectively deuterated at the H2 position. Nonselective deuteration was observed at various ring positions (but not the methyl group) for 3-methylpyridine. The presence of a β substituent in 3-cyanopyridine and nicotinic acid hindered H-D exchange at the adjacent R (H2) site, but significant deuteration was observed for the second R position (H6). Portions of the 2- and 4-vinylpyridine samples underwent rapid hydrogenation to 2- and 4-ethylpyridine with residual hydrogen used to activate the catalyst. After an extended period, the 1H NMR spectrum of the remaining 2-vinylpyridine showed evidence for H-D exchange not only at the R position but also at both terminal sites in the vinyl group. These results suggest a variety of possible intermediates formed by interaction of the N-heterocycle with the Pd catalyst surface. Introduction H-D exchange in nitrogen-containing heterocycles has been achieved by using acid or base catalysts in liquid D2O,1,2 by heating in neutral D2O at elevated temperatures,3,4 and by using a solid metal catalyst with gaseous D25 or D2O.6-9 These methods often result in multiple exchange sites with varying amounts of deuterium incorporation. Increased selectivity for specific sites can be achieved through the use of a metal catalyst dispersed in a solvent. Selective deuteration of pyridine derivatives at the position R to the endocyclic nitrogen has been achieved at room temperature in methanol-d4 under a D2 atmosphere using a 5% Ru/C catalyst at room temperature,10 and similar results were achieved with Ru or Rh catalysts in THF under D2.11 Recently, 1H NMR studies of palladium nanoparticles stabilized by 4-N,N-dimethylaminopyridine (DMAP) and *Corresponding author. Phone: 217-333-0297. Fax: 217-244-3186. E-mail: [email protected]. (1) Kebede, N.; Pavlik, J. W. J. Heterocycl. Chem. 1997, 34 (2), 685–686. (2) Zoltewicz, J. A.; Meyer, J. D. Tetrahedron Lett. 1968, No. 4, 421–6. (3) Werstiuk, N. H.; Ju, C. Can. J. Chem. 1989, 67 (1), 5–10. (4) Werstiuk, N. H.; Timmins, G. Can. J. Chem. 1981, 59 (6), 1022–4. (5) Moyes, R. B.; Wells, P. B. J. Catal. 1971, 21 (1), 86–92. (6) Biddiscombe, D. P.; Herington, E. F. G.; Lawrenson, I. J.; Martin, J. F. J. Chem. Soc. 1963, 444–8. (7) Calf, G. E.; Garnett, J. L.; Pickles, V. A. Aust. J. Chem. 1968, 21 (4), 961–72. (8) Esaki, H.; Ito, N.; Sakai, S.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Tetrahedron 2006, 62 (47), 10954–10961. (9) Sajiki, H.; Ito, N.; Esaki, H.; Maesawa, T.; Maegawa, T.; Hirota, K. Tetrahedron Lett. 2005, 46 (41), 6995–6998. (10) Rubottom, G. M.; Evain, E. J. Tetrahedron 1990, 46 (15), 5055–64. (11) Alexakis, E.; Jones, J. R.; Lockley, W. J. S. Tetrahedron Lett. 2006, 47 (29), 5025–5028. pubs.acs.org/Organometallics

Published on Web 05/27/2009

dispersed in D2O revealed that complete deuteration of DMAP at the position R to the endocyclic nitrogen occurred overnight at room temperature.12 Monometallic Pd(DMAP)4(OH)2 was observed in some of the samples, but further studies showed that it did not catalyze H-D exchange, suggesting that surface Pd centers were necessary for deuteration to occur.12 In subsequent work, the DMAP-stabilized Pd nanoparticles were transferred to thiol-functionalized multiwalled carbon nanotubes, and the composite material was found to catalyze H-D exchange at 50 °C over 5 h predominantly, but not exclusively, at the R-position in 4aminopyridine and at the β-position in 4-hydroxypyridine.13 In contrast to the Pd/DMAP system, palladium nanoparticles stabilized by poly-N-vinylpyrrolidone (PVP) have a stabilizer that is distinct from possible substrates. Such Pd/ PVP colloids, synthesized by reduction14-17 or thermal decomposition18,19 methods, have been of interest as catalysts for a variety of reactions including hydrogenation,14,20 :: (12) Flanagan, K. A.; Sullivan, J. A.; Mueller-Bunz, H. Langmuir 2007, 23 (25), 12508–12520. (13) Sullivan, J. A.; Flanagan, K. A.; Hain, H. Catal. Today 2008, 139 (3), 154–160. (14) Hirai, H.; Chawanya, H.; Toshima, N. React. Polym., Ion Exchangers, Sorbents 1985, 3 (2), 127–141. (15) Bradley, J. S.; Millar, J. M.; Hill, E. W. J. Am. Chem. Soc. 1991, 113 (10), 4016–4017. (16) Teranishi, T.; Miyake, M. Chem. Mater. 1998, 10 (2), 594–600. (17) Gniewek, A.; Zi olkowski, J. J.; Trzeciak, A. M.; Kepinski, L. J. Catal. 2006, 239 (2), 272–281. (18) Esumi, K.; Tano, T.; Meguro, K. Langmuir 1989, 5 (1), 268–270. (19) Esumi, K.; Suzuki, M.; Tano, T.; Torigoe, K.; Meguro, K. Colloids Surf. 1991, 55, 9–14. (20) Nadgeri, J. M.; Telkar, M. M.; Rode, C. V. Catal. Commun. 2008, 9 (3), 441–446. r 2009 American Chemical Society

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Suzuki-Miyaura and Heck coupling,21-24 alcohol oxidation,25 methoxycarbonylation,17,22 and nitrite reduction.26 Since Pd/PVP colloids are dispersible in several solvents, including water, solution techniques, such as NMR spectroscopy,15 can be used to monitor reactions. Here we report that a Pd/PVP colloid can catalyze efficient H-D exchange at room temperature between D2O and various N-heterocyclic compounds. The patterns of exchange suggest multiple possible modes of interaction between these substrates and the Pd catalyst surface.

Experimental Section Chemicals. Palladium(II) acetate was purchased from SigmaAldrich. Poly(N-vinylpyrrolidone) (PVP, MW = 40 000) was purchased from Alfa Aesar. The solvents 2-ethoxyethanol (Sigma-Aldrich) and acetone (Fisher Scientific) were used as received. Nanopure water was collected from a Synergy 185 Millipore with a Simpak2 purifying system. Tanks of hydrogen (99.95%) were supplied by Linde Gas. D2O (99.9%) was purchased from Aldrich. The N-heterocycles DMAP (99%), 4-methoxypyridine (97%), 4-methylpyridine (99%), 3-methylpyridine (99%), 3-cyanopyridine (98%), N-methylimidazole (99%), quinoline (96%), 4-vinylpyridine (95%), and 2-vinylpyridine (97%) were purchased from Aldrich and were used as received. Pyridine (99.9%, Fisher) and nicotinic acid (98%, Sigma-Aldrich) also were used as received. Preparation of Pd/PVP Colloid. The procedure was based on that of Bradley and co-workers.15 Palladium(II) acetate (0.898 g, 4.00 mmol) and 1.700 g of PVP were transferred to a single-neck 100 mL round-bottom Schlenk flask with a Teflon-coated magnetic stir-bar. The flask was connected to a reflux condenser, and the system was put under a nitrogen atmosphere. With nitrogen flowing, the condenser was slightly lifted from the flask so that 50 mL of 2-ethoxyethanol could be added by syringe to the solids. The resulting palladium concentration was 80 mM. After reattaching the condenser, the flask was lowered into a 145 °C ((5 °C) oil bath, and the clear, golden brown solution was brought to reflux. An opaque dark brown/black color developed within 5 min of beginning heating, but the reaction was continued for 2 h to ensure complete reduction. Then the dark dispersion was cooled under nitrogen and maintained at room temperature. Under nitrogen, this material appeared stable for months, with no evidence for precipitation. Powder XRD data presented elsewhere indicated that the dried colloid contained ca. 4.5 nm fcc Pd nanoparticles.26 In order to remove excess PVP, 2-ethoxyethanol, and any residual reaction products, a dispersion of the colloid in water was prepared by the following procedure. A measured volume of the colloidal dispersion as prepared was filtered through a 0.2 μm nylon syringe filter (13 mm, Millex) and dried under vacuum at room temperature overnight. The residue was redispersed in a small amount of nanopure water, followed by the addition of a 4-fold excess of acetone to cause the colloid to aggregate. The aggregated colloid particles were filtered by passing the mixture through a bed of Celite (Fisher) on a glass frit. The colloid was then rinsed from the Celite into a clean flask by nanopure water until the water came through colorless, and (21) de Souza, A. L. F.; da Silva, L. C.; Oliveira, B. L.; Antunes, O. A. C. Tetrahedron Lett. 2008, 49 (24), 3895–3898. (22) Gniewek, A.; Trzeciak, A. M.; Zi olkowski, J. J.; Kepinski, L.; Wrzyszcz, J.; Tylus, W. J. Catal. 2005, 229 (2), 332–343. (23) Li, Y.; Hong, X. M.; Collard, D. M.; El-Sayed, M. A. Org. Lett. 2000, 2 (15), 2385–2388. (24) Narayanan, R.; El-Sayed, M. A. J. Am. Chem. Soc. 2003, 125 (27), 8340–8347. (25) Hou, W. B.; Dehm, N. A.; Scott, R. W. J. J. Catal. 2008, 253 (1), 22–27. (26) Guy, K. A. X., H.; Yang, J. C.; Werth, C. J.; Shapley, J. R. J. Phys. Chem. C 2009, 113, 8177–8185.

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the water was removed under vacuum at room temperature. Finally, the colloidal Pd/PVP material was redispersed in nanopure water to the original volume and stored under nitrogen. Prior to the NMR experiments, a 5 mL portion of the aqueous colloidal dispersion was dried under vacuum overnight. The dried material was then redispersed in 20 mL of D2O for a final Pd concentration of 20 mM. Exchange Experiments. For each experiment, 0.5 mL of the colloid in D2O was added to a standard 5 mm NMR tube. The tube was capped with a rubber septum. A syringe needle long enough to reach the bottom of the tube was inserted through the septum. A shorter needle was also inserted into the septum to maintain atmospheric pressure. Hydrogen was bubbled through the colloidal dispersion for 10 min to ensure that the Pd surface was fully reduced. (Note: No activity for H-D exchange was observed if this activation step was omitted.) Immediately prior to inserting the tube into the NMR instrument, 0.5 mL of a stock solution containing the N-heterocycle of interest was added to the tube. For DMAP, stock solutions of 104, 208, or 312 mM in D2O were used, resulting in final DMAP concentrations of 52, 104, and 156 mM, respectively. For the other N-heterocyclic compounds, stock solutions of 104 mM were prepared in D2O, resulting in concentrations of 52 mM in the NMR tube. The septum was quickly substituted with a colored NMR cap to allow quick identification of the contents of the tube when multiple experiments were carried out simultaneously. The concentration of Pd in all cases was 10 mM (10 μmol Pd in 1 mL solution). 1 H NMR spectra were collected periodically over the course of 3-4 h on a Varian Unity 500 instrument at 11.75 T. The temperature of the NMR probe was held at 20 ( 0.2 °C. The time recorded for each spectrum was the point at which acquisition was started. The chemical shifts are reported on the δ scale and referenced to the solvent peak at 4.63 ppm. Signals for the PVP polymer are observed in all samples in the 1-4 ppm region.27 Under the reaction conditions employed, no exchange of the PVP protons was observed. When possible, the ratio of peak areas was made to an internal standard within the substrate itself. Between measurements, the samples were kept at room temperature outside of the NMR instrument.

Results H-D Exchange in DMAP. The deuteration of DMAP was monitored over the course of several hours by 1H NMR spectroscopy. Figure 1 shows the changes in the NMR spectra as time progressed for the 52 mM DMAP sample. The signal at 7.88 ppm, corresponding to the hydrogens R to the endocyclic nitrogen (H2,6), decreased in intensity with time, but the signal at 6.48 ppm, corresponding to the hydrogens β to the endocyclic nitrogen (H3,5), did not decease. The peak at 2.80 ppm due to the methyl protons also remained unchanged. Thus, the R position is the only position for which H-D exchange was observed. Similar results were obtained for all three DMAP concentrations. No evidence for the formation of molecular Pd-DMAP compounds in these experiments was seen. In order to compare the rates of H-D exchange for the three DMAP reactions, relative areas were calculated by integrating the R-H and β-H peaks with respect to the N-methyl signal. The decrease in the R-H peak area with time was fit with a first-order rate equation (Figure 2). As was seen by visual inspection of the NMR spectra, no change in the β-H integrated signal area was measured. Also included in Figure 2 is a plot of the observed first-order rate constant, kex, as a function of the DMAP concentration. At higher concentrations of DMAP, the observed rate constant decreases. (27) Sesta, B.; Segre, A. L.; Daprano, A.; Proietti, N. J. Phys. Chem. B 1997, 101 (2), 198–204.

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Figure 1. 1H NMR spectra showing H-D exchange in 4-dimethylaminopyridine. The water peak at 4.63 ppm is truncated to allow expansion of the signals of interest. The broad signals from ca. 1.5-3.5 ppm are due to PVP.

Figure 2. Reaction profiles for the R-H and β-H signals for the three DMAP concentrations: (a) 52 mM (b) 104 mM (c) 156 mM. Integrals were normalized by the value for the N-CH3 signal. Plot (d) shows the inverse relationship of the observed first-order rate constant as a function of DMAP concentration.

The inverse dependence of H-D exchange rate with DMAP concentration is in agreement with expressions for the kinetics of isotope exchange reactions, where the substrate concentration (e.g., [DMAP]) is very much less than that of the isotope reservoir ([D2O]).28 For each instance of the exchange reaction (proceeding with a pseudo-first-order exchange rate kex),

LH þ D2 O f LD þ HDO an increased total [LH] means a decreased fractional change with each step and hence an apparent smaller rate. Similarly, for a substrate with two equivalent exchange sites (as in DMAP) each exchange step,

LH2 þ D2 O f LHD þ HDO (28) Frost, A. A.; Pearson, R. G., Kinetics and Mechanism: A Study of Homogeneous Chemical Reactions; Wiley: New York, 1953; p 343.

involves only one-half of the sites in the substrate molecule, so that (barring secondary effects) the true exchange rate (kex) is twice the apparent rate. The entries in Table 1 have been adjusted to reflect the number of equivalent exchange sites as needed. H-D Exchange in 4-Methoxypyridine. The changes in the 1 H NMR spectra of 4-methoxypyridine over time are shown in Figure S1, Supporting Information. A decrease in the signal for the protons R to the endocyclic nitrogen (H2,6) was observed. No other signal changes were seen. A plot of the peak areas for the R and β (H3,5) protons referenced to the methoxy (OCH3) proton signal is shown in Figure 3a. A first-order equation was fit to the decrease in the R signal, and the normalized kex value is listed in Table 1. H-D Exchange in Pyridine. The changes in the 1H NMR spectra for pyridine over time are shown in Figure S2, Supporting Information. Loss of the signal for the protons R to the endocyclic nitrogen (H2,6) was observed. A plot of the peak areas for the R and β (H3,5) protons referenced to that of the γ (H4) proton is shown in Figure 3b. A first-order equation was fit to the decrease in the R signal, and the normalized kex value is listed in Table 1. H-D Exchange in 4-Methylpyridine. The changes in the 1 H NMR spectra for 4-methylpyridine over time are shown in Figure 4. H-D exchange leading to decreased intensity of the signal for the protons R to the endocyclic nitrogen (H2,6) was again observed. In addition, there was a loss in intensity of the methyl proton signal at 2.21 ppm. The 4-methylpyridine signal intensities were integrated relative to the PVP proton signal at ca. δ1.85 and are shown plotted as a function of time in Figure 5a. First-order decay equations were used to fit these plots, and the normalized kex values are listed in Table 1. H-D Exchange in 3-Methylpyridine. The changes in the 1 H NMR spectra for 3-methylpyridine over time are shown in Figure S3, Supporting Information. Some loss of signal intensity was observed for all hydrogen positions on the ring (H2, H4, H5, H6). However, no decrease in the methyl signal was seen. The peak areas of the 3-methylpyridine hydrogen signals were integrated with respect to the PVP signal at ca. δ 1.85, and the results are shown in Figure 5b. Observed rate constants derived from first-order fits of each data set are listed in Table 1. Although H-D exchange was apparently

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Table 1. Selective H-D Exchange Rates Determined for N-Heterocyclic Compounds in D2Oa

Figure 3. Reaction profiles for the R-H and β-H signals for (a) 4-methoxypyridine normalized by the OMe signal intensity and (b) pyridine normalized by the γ-H signal intensity.

a Where needed, observed rates are multiplied by the number of symmetry-related exchange sites. All values given are for a substrate concentration of 52 mM and a Pd (in Pd/PVP) concentration of 10 mM.

more rapid at the R position H2 than it was at H6, we do not think that our assignments for the signals corresponding to these two sites should be reversed; the broader line width for the H6 signal matches the pattern also seen for 3-cyanopyridine (vide infra). H-D Exchange in 3-Cyanopyridine. The changes in the 1H NMR spectra for 3-cyanopyridine over time are shown in Figure S4, Supporting Information. Measurable loss of proton signal in the time frame monitored was only observed for H6, one of the positions R to the endocyclic nitrogen; see Figure 6a. A first-order equation was fit to the decrease in the

H6 signal referenced to H5, and the resulting kex value is listed Table 1. H-D Exchange in Nicotinic Acid. The changes in the 1H NMR spectra for nicotinic acid over time are shown in Figure S5, Supporting Information. Our assignments for the proton signals as shown in Figure S5 are based on comparing splitting patterns with those seen in the spectrum of 3-cyanopyridine (see Figure S4). Literature assignments for nicotinic acid in DMSO29 reverse the order for H4 and H6; however, we believe that in D2O the H6 signal is shifted to appear upfield of the H4 signal. On the basis of our assignments, nicotinic acid underwent H-D exchange at one of the positions R (H6) to the endocyclic nitrogen in a similar fashion to 3-cyanopyridine. The second R position (H2) showed no evidence of exchange during the reaction time frame (Figure 6b). Table 1 shows the kex value obtained from fitting the decrease in the H6 signal, normalized to H5. H-D Exchange in N-Methylimidazole. The changes in the 1 H NMR spectra for N-methylimidazole over time are shown in Figure S6, Supporting Information. Rapid loss of the signal for the H2 proton located between the two endocyclic nitrogens was observed. No evidence of exchange at either of the two other ring protons (H4, H5) was seen. The peak areas for the three ring proton signals were normalized to the area of the methyl signal and were plotted as a function of time (Figure 7a). A first-order equation was fit to the decrease in the H2 signal, and the kex value determined is listed in Table 1. H-D Exchange in Quinoline. H-D exchange in quinoline occurred at the R-H position (H2) in a similar fashion to the majority of the pyridine compounds studied (Figure S7, Supporting Information). In addition, the H8 hydrogen was also partially deuterated over the course of 4 h. The peak areas for these two signals were normalized with respect to H7, which was chosen as the reference since it had the clearest baseline resolution. The changes with time are shown in Figure 7b. Exchange at the H2 and H8 positions occurred at nearly the same rate (Table 1). The slow rate may be due in part to the low solubility of quinoline in water. Signs of phase separation were observed as the sample sat between measurements, so the sample was remixed prior to each acquisition. (29) National Institute of Advanced Industrial Science and Technology (AIST) Spectral Database for Organic Compounds (SDBS), http:// riodb01.ibase.aist.go.jp/sdbs/cgi-bin/direct_frame_top.cgi.

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Figure 4. 1H NMR spectra showing H-D exchange in 4-methylpyridine. The water peak at 4.63 ppm is truncated to allow expansion of the signals of interest. The broad signals from ca. 1.5-3.5 ppm are due to PVP.

Figure 5. Reaction profiles for (a) the R-H, β-H, and CH3 signals for 4-methylpyridine and (b) the H2, H4, H5, H6, and CH3 signals for 3-methylpyridine normalized by the PVP signal intensity at ∼1.85 ppm.

Figure 6. Reaction profiles for the H2, H4, and H6 signals normalized by the H5 signal intensity for (a) 3-cyanopyridine and (b) nicotinic acid.

Hydrogenation and H-D Exchange in 4-Vinylpyridine. The initial 1H NMR spectrum for a sample prepared with 4-vinylpyridine is shown in Figure 8. No change in the relative intensities of any signals was seen over a 3.5 h period (see Figure S8, Supporting Information). However, close inspection of Figure 8 shows that in addition to the signals due to 4-vinylpyridine (vinyl Ha, Hb, Hc at δ 6.61, 5.42, 5.96, respectively; ring H2,6 and H3,5 at δ 8.30 and 7.33) there is

Figure 7. Reaction profiles for (a) the H2, H4, and H5 signals for N-methylimidazole normalized by the N-CH3 signal intensity and (b) the H2, H4, and H8 signals for quinoline normalized to the H7 signal intensity.

a second pair of ring signals (H0 2,6 and H0 3,5 at δ 8.23 and 7.18) as well as a pair of signals in the aliphatic region (H0 a, 2.52 and H0 b, 1.05). These new signals are attributed to the presence of 4-ethylpyridine, which was apparently formed very rapidly upon adding 4-vinylpyridine to the hydrogen-saturated dispersion of the Pd/PVP colloid. Note that ca. 40% of the 52 μmol of 4-vinylpyridine was converted to 4-ethylpyridine. Although 20 μmol of H2 is more than the 10 μmol of Pd present in the tube, there should easily have been enough residual H2 in solution and in the headspace to make up the difference. The sample was removed from the spectrometer and allowed to stand for an extended period (38 days). Examination of the sample revealed a 67% loss in the total intensity of the partially overlapping H2,6 and H0 2,6 signals. No other changes were evident. Finally, after a brief (10 min) further exposure to H2, all signals for 4-vinylpyridine were gone and only those for 4-ethylpyridine were seen. The ratio H0 b:H0 a was 1.0:0.7, indicating no selective deuteration into the ethyl group. Hydrogenation and H-D Exchange in 2-Vinylpyridine. The initial 1H NMR spectrum obtained for the 2-vinylpyridine sample is shown in Figure 9. Signals for both 2-vinylpyridine (vinyl Ha, Hb, Hc at δ 6.70, 5.41, 5.97, respectively; ring H6, H5, H4, H3 at δ 8.29, 7.19, 7.69, 7.41) and 2-ethylpyridine (H0 6, H0 5, H0 4, H0 3, H0 a, H0 b at δ 8.26, 7.10, 7.63, 7.19, 2.61, 1.08) were seen. Approximately one-half of the original 2-vinylpyridine

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Figure 8. 1H NMR spectrum of sample with 4-vinylpyridine after 8 min.

Figure 9. 1H NMR spectrum of sample with 2-vinylpyridine after 3 min.

was hydrogenated to 2-ethylpyridine. No changes in the relative intensities of these signals were observed over a 3 h period (see Figure S9, Supporting Information). A separate sharp signal in the aliphatic region at δ 2.08 was present in all spectra, but this signal also appeared as a minor component in the 2-vinylpyridine starting material; it is tentatively assigned as due to 2-methylpyridine. An NMR spectrum taken after the sample had sat for 38 days revealed a nearly complete loss of signal intensity for Hb and Hc (Figure 10). Since the signal intensity due to Ha remained unchanged, the loss of signal intensity was attributed to H-D exchange at these positions rather than further hydrogenation of 2-vinylpyridine. No signal at δ 2.08 was discernible separately from the signals for PVP. In addition, the intensity of the H6, H0 6 signal pair was reduced by 32%. Additional treatment with hydrogen (10 min) led to complete loss of signals due to 2-vinylpyridine, and only those for 2-ethylpyridine remained. The final ratio of H0 b:H0 a was 0.9:1.0, which reflects the selective deuteration at the vinylic Hb and Hc sites prior to hydrogen addition to form the ethyl group.

Discussion We have examined a set of nitrogen-containing heterocyclic aromatic compounds for H-D exchange in D2O using

Figure 10. Partial 1H NMR spectrum of 2-vinylpyridine sample after an extended period.

a colloidal Pd/PVP catalyst formed by the reduction of Pd (OAc)2 by 2-ethoxyethanol in the presence of PVP. Due to oxidation of the Pd surface from exposure to air, activation of the Pd/PVP catalyst with hydrogen13 was necessary prior to running the experiments. Evidence for H-D exchange was generally observed over the course of a few hours at

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room temperature. The substitution on the ring and overall structure of the heterocycle had a significant impact on which position was deuterated. The 4-substituted pyridine compounds primarily underwent H-D exchange at the carbon R to the endocyclic nitrogen. This is in agreement with previously published results for Ru- and Rh-catalyzed reactions of DMAP and 4-methylpyridine with D2 in THF11 and for Ru-catalyzed exchange in pyridine with D2 in CD3OD.10 DMAP-stabilized Pd nanoparticle catalysts also demonstrated selective H-D exchange only at the R position of DMAP.12,13 However, when Pd was used as a catalyst at elevated temperatures (110-130 °C) under pressurized conditions7,8 or in the gas phase,6 complete deuteration of pyridine and 4-methylpyridine was reported. Selective exchange at the R position is readily interpreted in terms of the mechanism suggested for pyridine reactions on a nickel surface.30 Coordination through the lone pair on the endocyclic nitrogen places the neighboring C-H bonds close to the metal surface, promoting cleavage of one of these bonds to form a metal R-pyridyl intermediate (Scheme 1). If the reverse reaction takes place with deuterium atoms on the palladium surface (formed by exchange with D2O), the R-Dsubstituted pyridine results. Triosmium carbonyl clusters are also known to react with pyridine to form complexes involving donation from the nitrogen atom as well as oxidative addition of a C-H bond R to the nitrogen atom.31,32 In 4-methylpyridine, the methyl group was deuterated in addition to the R ring positions. Binding of the endocyclic nitrogen to the palladium surface may allow for resonance stabilization of a deprotonated methyl group, with subsequent deuteration by reversal (Scheme 2). This stabilization would only be expected for methyl groups at the 2 and 4 positions on the pyridine ring, and indeed, we saw no H-D exchange for the methyl group in 3-methylpyridine. Similar results have been seen for base-catalyzed H-D exchange of methyl-substituted pyridines; deuteration of methyl groups occurred at the 2, 4, and 6 positions, but not at the 3 and 5 positions.1 The presence of an alternative exchange pathway may account for the observed rate of exchange at the R sites in 4-methylpyridine being slower compared to those for pyridine and the other 4-substituted pyridines. The only compound in our study that exhibited deuterium substitution at all sites on the pyridine ring was 3-methylpyridine. The R positions were still favored, but it is interesting to note that exchange at the more sterically hindered H2 position was marginally faster overall than exchange at the less hindered H6 position. This may be the result of the electron-donating ability of the methyl group increasing the stability of the C-Pd bond at the C2 position. Partial deuteration of the H4 and H5 sites suggests that there was a competing interaction between the Pd surface and the π electrons of the ring. Coordination in this manner would allow a carbon-metal bond and subsequent H extraction at any site on the ring. Although all of the compounds studied could in principle also undergo nonselective deuteration by bonding through the aromatic ring, if given enough time, 3-methylpyridine is the only compound for which such (30) Wexler, R. M.; Muetterties, E. L. J. Am. Chem. Soc. 1984, 106 (17), 4810–14. (31) Coffer, J. L.; Drickamer, H. G.; Shapley, J. R. J. Phys. Chem. 1990, 94 (13), 5208–5210. (32) Johnson, B. F. G.; Lewis, J.; Pippard, D. A. J. Chem. Soc., Dalton Trans. 1981, 2, 407–412.

Guy and Shapley Scheme 1. Cleavage of the C-H Bond r to the Endocyclic Nitrogen of Pyridine

Scheme 2. H-D Exchange in the Methyl Group of 4-Methylpyridine

Scheme 3. Formation of the Proposed Intermediate for H-D Exchange in N-Methylimidazole

exchange was observed in the 4 h period that these reactions were monitored. Under these circumstances, the H-D exchange at H4 and H5 amounted to an 11% loss in peak area. Although 3-cyanopyridine and nicotinic acid have two sites R to the nitrogen, we observed H-D exchange only at the less-hindered H6 position. This exchange was markedly slower than for the 4-substituted pyridines. Presumably the same type of R-pyridyl intermediate shown in Scheme 1 is involved; however, the electronic effects of the strong electron-withdrawing groups may decrease the stability of the R-C-Pd bond, thereby increasing the kinetic barrier to exchange. It would also be possible for the cyano and carboxylic acid groups to coordinate to the palladium surface, thereby limiting the number of sites available for the endocyclic nitrogen to bind. However, such coordination, if it is competitive, did not appear to promote an alternative H-D exchange pathway. Our results on H-D exchange in nicotinic acid are in partial agreement with those obtained by Esaki and co-workers with Pd/C in neutral D2O at 160 °C; deuteration occurred predominantly at the H6 position; however, at the elevated temperature, significant exchange at H2 was also seen.8 In 1-methylimidazole, H-D exchange occurred rapidly at the carbon R to both of the endocyclic nitrogens (H2). The rate of exchange measured is comparable to those of R exchange in pyridine, 4-methoxypyridine, and 4-N,N-dimethylaminopyridine. The proposed intermediate is shown in Scheme 3. The stability of the C-Pd bond following C-H bond cleavage apparently results in exclusive H-D exchange at this site. Similar selectivity of H-D exchange at the H2 position was reported in the literature for the complex

Article Scheme 4. Binding of the H8 Position in Quinoline to the Palladium Surface

Scheme 5. Interactions of 2-Vinylpyridine with the Catalyst Surface

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the endocyclic nitrogens likely indicates that the vinyl group binds preferentially or at least competitively to the palladium surface. This is supported by the rapid uptake of available surface hydrogen to form the ethyl group. However, in 2-vinylpyridine, as shown in Scheme 5, an intermediate may be formed where both the nitrogen and vinyl group are involved. If the formation of the M-C bond is reversible, H-D exchange of the β protons on the vinyl group occurs. Since no deuteration of the vinyl group was observed in 4-vinylpyridine even after 38 days, H-D exchange in the vinyl group does not proceed in the absence of nitrogen coordination. Oxidative addition of the C-H bond on the vinyl group in addition to binding through the endocyclic nitrogen has been reported for multinuclear osmium, ruthenium, and rhenium complexes of 2-vinylpyridine.37,38 The structure following oxidative addition of the C-H bond R to the endocyclic nitrogen is reported only as a minor product in these reactions.37

Conclusion

[Pt(MeIm)4](ClO4)2 in D2O/NaOD at 60 °C.33 Under neutral conditions in D2O, H-D exchange at the H2 position was also favored, apparently due to stabilization of an intermediate anion located between the two endocyclic nitrogens.34 The nitrogen in quinoline is expected to bind to the palladium surface in a fashion similar to the 4-substituted pyridines discussed above. In addition to seeing deuteration R to the nitrogen atom, H-D exchange was observed also at the H8 position. When quinoline binds, the C-H8 bond would be held close to the surface. Formation of a Pd-C bond at this site provides a path for selective exchange (Scheme 4). Triosmium complexes with quinoline and related heterocycles show similar results with binding through the nitrogen atom and oxidative addition of the C-H bond at C8 across two osmium centers.35,36 Both 4-vinylpyridine and 2-vinylpyridine samples showed, in part, hydrogenation of the double bond early in the reaction. This reaction is likely the result of hydrogen activated at the palladium nanoparticle surface following reduction of the catalyst. When additional hydrogen was bubbled through the mixed vinylpyridine/colloid samples for 10 min, complete loss of any signals due to the vinylpyridine was achieved, and the corresponding ethylpyridine signals were observed. The slow loss of signal due to the protons R to (33) Clement, O.; Roszak, A. W.; Buncel, E. J. Am. Chem. Soc. 1996, 118 (3), 612–620. (34) Takeuchi, Y.; Kirk, K. L.; Cohen, L. A. J. Org. Chem. 1978, 43 (18), 3570–8. (35) Akther, J.; Azam, K. A.; Das, A. R.; Hursthouse, M. B.; Kabir, S. E.; Abdul Malik, K. M.; Rosenberg, E.; Tesmer, M.; Vahrenkamp, H. J. Organomet. Chem. 1999, 588 (2), 211–221. (36) Sadimenko, A. P. Organometallic Complexes of the η2(N,C)Coordinated Derivatives of Pyridine. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 2005; Vol. 88.

We have studied H-D exchange in D2O under ambient conditions using a Pd/PVP catalyst for a set of nitrogencontaining heterocyclic compounds. Deuteration was primarily observed at R sites, which is proposed to occur through the formation of an intermediate with a Pd-C(R) bond. However, exchange was also observed in the methyl group of 4-methylpyridine, which may be due to a deprotonated intermediate stabilized by resonance delocalization with the surface. The presence of an electron-withdrawing substituent at the 3-position on the pyridine ring directed deuteration to the H6 position and reduced the rate at which H-D exchange occurred. Vinylpyridines were rapidly hydrogenated to ethylpyridines by residual hydrogen on the catalyst surface. Very slow exchange at the position R to the endocyclic nitrogen was observed; however, 2-vinylpyridine, but not 4-vinylpyridine, also showed H-D exchange at the β hydrogen sites of the vinyl group. Even under the very mild conditions of these experiments, activation of different types of substrate C-H bonds, apparently promoted by coordination of the N-heterocycle to the Pd nanoparticle surface, has been demonstrated.

Acknowledgment. This work was supported in part by the Center of Advanced Materials for Purification of Water with Systems (WaterCAMPWS), which is funded by the National Science Foundation under the agreement number CTS-0120978. Additional funding was provided under the NSF grant CHE 07-18078. We also thank Dr. Vera Mainz of the SCS NMR Lab, UIUC, as well as Charles Spicer for their help in obtaining the NMR spectra. Supporting Information Available: Additional 1H NMR spectra are provided in Figures S1-S9. This material is available free of charge via the Internet at http://pubs.acs.org. (37) Burgess, K.; Holden, H. D.; Johnson, B. F. G.; Lewis, J.; Hursthouse, M. B.; Walker, N. P. C.; Deeming, A. J.; Manning, P. J.; Peters, R. J. Chem. Soc., Dalton Trans. 1985, No. 1, 85–90. (38) Azam, K. A.; Bennett, D. W.; Hassan, M. R.; Haworth, D. T.; Hogarth, G.; Kabir, S. E.; Lindeman, S. V.; Salassa, L.; Simi, S. R.; Siddiquee, T. A. Organometallics 2008, 27 (19), 5163–5166.