The 13C n.m.r. spectra of the N-methylated mono- and diazanaphthalenes have been recorded and analysed. It has been shown that N-methylation as well as N-protonation in cinnoline occur predominantly at the -nitrogen atom. N-methylation and N-protonation show a similar effect on the 13C chemical shift

Ham, Dirk M.W. van den

Mohan, Chandra

Weijer, Peter van de

English

van de Weijer, Peter

van den Ham, Dirk M.W.

University of Twente Research Information

Carbon-13 N*rn.r* Investigation on the Nitrogen Methylation of the Mono- and Diazanaphthalenes Peter van de Weijer,* (the late) Chandra Mohan and Dirk M. W. van den Ham Chemical Physics Laboratory, Twente University of Technology, P.O. Box 217, Enschede, The Netherlands The ''C n.m.r. spectra of the N-methylated mono- and diazanaphthalenes have been recorded and analysed. It has been shown that N-methylation as well as N-protonation in cinnoline occur predominantly at the P-nitrogen atom. N-methylation and N-protonation show a similar effect on the '% chemical shifts. INTROD WCTION Pugmire and Grant' have investigated the N- protonation behaviour of the azabenzenes by means of 13C n.m.r. These authors have shown that the changes in 13C chemical shifts under the influence of N- protonation (A6,)  in the diazabenzenes could be pre- dicted by using the values of pyridine as protona- tion parameters. (Additivity rules). In a previous contribution* we have shown that a similar relationship exists between the A6,  values of the diazanaphthalenes and those of quinoline and of isoquinoline. The high reliability of this relationship permitted us to establish the site of protonation in some asymmetric diazanaphthalenes. The analysis of the 13C n.m.r. spectra of protonated aza-aromatics is facilitated by the fact that the proton is in rapid exchange between the aza-aromatic molecule and the solvent (water). Once the assignment of the I3C n.m.r. spectrum of the neutral molecule is known, the spectrum of the protonated species can be analysed by recording a titration curve of the n.m.r. resonance line of each individual carbon atom. In contrast to the behaviour of protonated aza- aromatics, their N-methylated counterparts are stable ions; hence analysis of spectra that belong to the latter type of ion must be carried out in a different way. Recently we reported a 13C n.m.r. investigation on the N-methylation of some a~abenzenes .~  The analysis of the spectra was based on selective proton- decoupled 13C experiments. From these experimental data it has been shown that, by analogy with N- protonation, the changes in  "C chemical shifts under the influence of N-methylation (A6,) in the diazaben- zenes could be predicted well by the A6M values in pyridine. Moreover it appeared that, despite their different thermodynamic behaviour, N-methylation and N-protonation have a very similar effect on the 13C chemical shifts. The observations mentioned above suggest that the * Author to whom correspondence should be addressed @ Heyden & Son Ltd, 1977 C n.m.r. spectra of the N-methylated azanaph- thalenes can be analysed in two ways. First the assignment of the spectra can be performed by a direct comparison with the I3C n.m.r. spectra of the corres- ponding N-protonated species. Secondly, once the spectra of N-methylated quinoline and isoquinoline have been analysed by the first procedure, the spectra of the N-methylated diazanaphthalenes can be as- signed using the A6M values in quinoline and iso- quinoline as the a -  and P-methylation parameter sets respectively. Because of the rapid tautomeric proton exchange between equivalent nitrogen atoms, monoprotonation, as opposed to monomethylation, does not alter the symmetry of a symmetric diazacompound. Therefore the spectra of the N-methylated products of symmet- ric diazanaphthalenes can only be analysed on the basis of the methylation parameters. The compounds that have been studied are the mono-N-methyl de- rivatives of cinnoline (1,2-diazanaphthalene, 1) quinazoline (1,3-diazanaph thalene,2), quinoxaline ( 174-diazanaphthalene, 3), 1,5 naphthyridine ( 1 3 -  diazanaphthalene, 4), 1,6-naphthyridine (1,6-diaza- naphthalene, 5), 1,7-naphthyridine (1,7-diazanaph- thalene, 6), 1,s-naphthyridine (1,s-diazanaph- thalene, 7), phthalazine (2,3-diazanaphthalene, 8), 2,6- naphthyridine (2,6-diazanaphthalene, 9) ,  2,7-naph- thyridine (2,7-diazanaphthalene, lo), quinoline (l-aza- naphthalene, 11) and isoquinoline (2-azanaph- thalene, 12), all counter ions being FSO;.. 13 RESULTS A N D  DISCUSSION Analysis of the spectra The spectral data of quinoline and isoquinoline have been collected in Table 1. Assignments of the reso- nance lines to the respective carbon atoms have been made by comparison with the data derived for the corresponding N-protonated product. From Table 1 it can be seen that the correspondence between the A 6 ,  and A6M values is good. The correlation coefficient c = 0.949. The largest differences between methylation ORGANIC MAGNETIC RESONANCE, VOL. 10, 1977 165 P. VAN DE WEIJER, C. MOHAN AND D. M. W. VAN DEN HAM Table 1. Carbon-13 chemical shifts in quinoline and iso- quinoline CB 11-2 11-3 11-4 11-5 11-6 11-7 11-8 11-9 11-10 12-1 12-3 12-4 12-5 12-6 12-7 12-8 12-9 12-1 0 anb 150.79 122.28 137.91 128.87 127.69 130.87 128.59 1 47.49 128.87 152.41 142.03 122.03 127.15 131.96 128.57 128.57 129.16 136.42 aRn+c 145.49 122.99 148.46 130.17 131.26 136.35 121.14 137.90 129.50 147.42 131.98 126.57 128.33 138.11 132.25 131.22 127.62 139.29 SRcnJ+d 150.47 122.88 148.60 131.29 131.44 137.05 119.28 139.45 130.50 150.66 136.10 127.26 128.19 138.05 132.46 130.97 731.66 139.39 -5.30 +0.71 +10.55 +1.30 +3.57 +5.48 -7.45 -9.59 +0.63 -4.99 -10.05 +4.54 +1.18 +6.15 +3.68 +2.65 +2.87 -1.54 As,' -0.32 +0.60 +10.69 +2.42 +3.75 +6.18 -9.31 -8.04 +1.63 -1.75 -5.93 +5.23 +1.04 +6.09 +3.89 +2.40 +2.50 +2.97 ~ a Compound and carbon atom number. Chemical shifts of the neutral molecule R, (Ref. 4). Chemical shifts of the protonated molecule RH+ (Fef. 4). Chemical shifts of the methylated molecule RCH, . Protonation shifts. Methylation shifts. and protonation shifts are found for carbon atoms in ortho position with respect to the methylated nitrogen atom. The ASM value of quinoline and isoquinoline have been subsequently used to analyse the spectra of com- pounds 1-10. With the exception of 2, the analysis of these spectra was straightforward. The results have been collected in Table 2. The failure to analyse the spectrum of the N- methylquinazolinium ion must be attributed to its rapid pseudo-base f ~ r m a t i o n . ~  In the spectrum of N-methytated 2,6-naphthyridine only one resonance line was found for the bridge atoms. The analytical procedure allows two explana- tions. Either both bridge atoms have the same chemi- cal shift or one resonance line coincides with that of C-4. In the spectrum of N-methylated 2,7- naphthyridine, the signals of C-9 and C-4 probably coincide. From Table 2 it can be concluded that there is a satisfactory correspondence between the observed and expected methylation shifts (correlation coefficient c = 0.951). The spectra of N-methylated 1,6- and 1,7- naphthyridine yield additional support for the reliabil- ity of the analytical procedure used. Paudler and Kress6 have proven that N-methylation in these two compounds occurs on the p-nitrogen only. If we use the a-methylation parameter set to predict the shifts, there is no correlation at  all between expected and' observed data ( c  = 0.439 and 0.015 respectively), whereas the p-parameter set works very well for both compounds (c = 0.979 and 0.955). The interpretaton of the spectrum of N-methylated cinnoline needs further comment. Conflicting results are reported on the site of protonation and methyla- tion."" Theoretical studies (e.g. Ref. 9) indicate that there is hardly any difference in the electron-densities on the two nitrogen atoms. Molecular potential calcu- lations" show a slight preference for a-nitrogen pro- tonation (0.69 kcal mole-')ll whereas our previous ex- periments led to the conclusion that a-  and p-nitrogen protonation occur in a 2:3 ratio. Palmer and McIn- tyre12 suggested that the preferential p-nitrogen pro- tonation is simply the result of steric hindrance exerted by the peri-%proton. They substantiated this suggestion by N-methylation experiments on substi- tuted 4-methylcinnolines. N-methylation of 4-methyl- cinnoline yielded two isomeric products in a 9:  1 ratio. N-methylation of 3,4-dimethylcinnoline, however, yielded two isomers in a 1:l ratio. Substitution in the 3 position clearly balances the steric hindrance exerted by the peri-8-proton. The 'H n.m.r. spectrum of mono-N-methylated cin- noline revealed the existence of two methylated pro- ducts. If we take the resonance signals of the N- methyl protons as a gauge, a ratio of 1 O : l  is found. In a similar experiment Zoltewicz and Deady13 found a 9: 1 ratio. The 13C spectrum of the more abundant compound could be accounted for only with the 0- methylation parameter set. Of the other, less concen- trated, compound only four lines were found. The absence of the other lines must be attributed to the lack of a nuclear Overhauser effect for the bridge atoms and to the accidental coincidence with the reso- nance lines of the more abundant isomer. The four observed lines, however, could be well correlated with the a-methylation parameter set ( c  = 0.998). Two resonance lines show considerable line- broadening in the spectra of all the compounds. From the analytical procedure followed, it appeared that these are the resonance lines of the ortho carbon atoms except in N-methylated quinoline and 13- naphthyridine. Assuming this phenomenon to be gen- eral the assignments of C-2 and C-4 in N-methylated quinoline and 1 ,Snaphthyridine are reversed with respect to the analytical procedure followed. Comparison of N-methylation and N-protonation In solutions of monoprotonated symmetric diaza com- pounds a rapid tautomeric exchange exists between the two equivalent nitrogen atoms. Mono-N- methylated aza-compounds form stable ions in solu- tion. The spectrum of a monoprotonated symmetric diazanaphthalene, therefore, shows only four reso- nance lines, whereas the spectrum of the correspond- ing monomethylated species shows eight lines. Thus, in comparing the methylation with the protonation shifts, the methylation shifts of those carbon atoms that remain equivalent in the monoprotonated sym- metric diazanaphthalenes must be averaged. For the asymmetric diazanaphthalenes, a direct comparison is possible. The results (Table 3) show that the methyla- tion shifts are similar to the protonation shifts ( c  = 0.943). Figure 1 is a pictorial representation of these results. It can be seen that the absolute values of the negative Ah6 values for the ortho carbons are smaller 166 ORGANIC MAGNETIC RESONANCE, VOL. 10, 1977 I3C N.M.R. INVESTIGATION ON NITROGEN METHYLATION OF MONO AND DIAZANAPHTHALENES Table 2. Influence of N-methylation on 13C chemical shifts in the diazanaphthalenes Cd 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-1 0 3-2 3-3 3-5 3-6 3-7 3-8 3-9 3-10 4-2 4-3 4-4 4-6 4-7 4-8 4-9 4-10 5-2 5-3 5-4 5-5 5-7 5-8 5-9 5-1 0 6-2 6-3 6-4 6-5 6n 144.93 125.87 127.36 132.75 132.68 127.75 149.33 126.86 145.19 145.19 128.42 131.58 131.58 128.42 141.17 141.17 151.31 125.72 136.99 151.31 125.72 136.99 141.78 141.78 155.66 124.16 137.80 152.95 145.91 121.64 148.67 123.48 152.53 126.74 136.50 121.70 6 R C H i  141.89 135.85 128.46 139.51 137.51 130.41 150.47 131.37 141.93 148.16 132.10 135.58 138.04 119.98 132.78 146.74 151.60 126.88 148.48 155.72 130.76 129.48 137.94 144.20 161.71 127.64 140.47 153.04 141.09 127.64 151.11 125.34 157.70 131.70 137.49 128.02 -3.04 +9.98 +1.10 +6.76 +4.83 +2.66 +1.14 +4.51 +2.97 +3.68 +4.00 +6.46 -3.26 -8.44 -8.39 +5.57 +0.29 +1.16 +11.49 +4.41 +5.04 -7.51 -3.84 +2.42 +6.05 +3.48 +2.67 +0.09 -4.82 +6.00 +2.44 +1.86 +5.17 +4.96 +0.99 +6.32 AS.,; -5.93 +5.23 +1.04 +6.09 +3.89 +2.40 +2.50 +2.97 +0.60 +2.42 +3.75 +6.18 -9.31 -8.04 -0.32 +1.63 +0.60 +10.69 +3.75 +6.18 -9.31 -8.04 -0.30 +1.63 +6.09 +3.89 +2.40 -1.75 -5.93 +5.23 +2.97 +2.50 +3.89 +6.09 +1.04 +5.23 Cd 6-6 6-8 6-9 6-1 0 7-2 7-3 7-4 7-5 7-6 7-7 7-9 7-1 0 8-4 8-5 8-6 a-7 8-8 8-9 8-1 0 9-1 9-3 9-4 9-5 9-7 9-8 9-9 9-1 0 10-1 10-3 10-4 10-5 10-6 10-8 10-9 10-10 8-1 6n 142.63 151.35 141.03 131.37 153.85 123.54 139.27 139.27 123.54 153.85 153.37 123.15 152.01 152.01 127.23 134.67 134.67 127.23 126.73 126.73 151.53 143.87 120.73 151.53 143.87 120.73 129.82 129.82 152.61 146.24 120.58 120.58 146.24 152.61 123.27 138.57 G R C H ~  138.23 151.27 142.91 136.48 152.58 124.13 150.20 141.31 127.52 158.58 145.44 124.13 152.43 156.06 129.48 140.62 137.74 131.26 128.82 129.11 152.12 139.12 127.75 153.27 147.70 122.68 131.63' 131.63' 153.17 140.95 126.84 121.45 151.94 155.79 126.84' 141.71 A6obc -4.40 -0.08 +1.88 +5.11 +0.59 +10.93 +2.04 +3.98 +4.73 -7.93 +0.98 +0.42 +4.05 +2.25 +5.95 +3.07 +4.03 +2.09 +2.38 +0.59 -4.75 +7.02 +1.74 +3.83 +1.95 +1.81 +1.81 +0.56 +6.26 +0.87 +5.70 +3.18 +3.57 +3.14 -1.27 -5.29 A6.,,' -5.93 -1.75 +2.50 +2.97 +0.60 +10.69 +2.42 +3.75 +6.18 -8.04 +1.63 +5.23 +1.04 +6.09 +3.89 +2.40 +2.50 +2.97 -1 -75 -5.93 +5.23 +1.04 +3.89 +2.40 +2.50 +2.97 -1.75 -5.93 +5.23 + 1.04 +6.09 +2.40 +2.50 +2.97 -0.32 -1.75 a Observed methylation shift. Expected methylation shift. Uncertain assignment (see text). Compound and carbon atom number. ASP t -10 -5 -5 -10 Figure 1. Comparison of A 6  values for N-protonation with those for N-methylation. x = ortho carbon atoms. for methylation than for protonation. This was noticed before in the series of the a~a-benzenes.~ For p -N-methylated cinnoline the correlation be- tween expected and observed shifts was considerably lower (c = 0.883) than that for N-methylated 1,6- and 1,7-naphthyridine (c = 0.979 and 0.955 respectively). The same was observed for the protonation shifts.2 As, in contrast to N-methylation, a dynamic protonation equilibrium between both nitrogen atoms is possible, a linear combination of the a-  and p-protonation parameter set was chosen in order to obtain a better correlation between experimental and expected proto- nation shifts. The optimal combination corresponded to a 2:3 ratio of a-  and p-protonation. Since no dynamic equilibrium exists in the methylated com- pound the low correlation must simply be attributed to the lack of additivity when two nitrogen atoms are adjacent to each other. The present work shows that the methylation shifts in cinnoline are in excellent agreement with the proto- nation shifts (Table 3). In view of this observation we may conclude that in ORGANIC MAGNETIC RESONANCE, VOL. 10, 1977 167 P. VAN DE WEIJER, C. MOHAN AND D. M. W. VAN DEN HAM Table 3. Comparison of protonation shifts with methy- lation shifts C" 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-10 3-213 3-518 3-617 3-9/10 4-216 4-317 4-418 4-9/10 5-2 5-3 5-4 5-5 5-7 5-8 5-9 5-1 0 6-2 ASP -3.78 +9.59 + 1.42 +6.08 +5.17 +0.75 +6.10 - 0.60 -1.97 -1.74 +5.04 +0.08 +2.96 +2.61 -2.18 +5.48 +3.14 +3.80 -2.44 -2.71 -7.81 +4.75 +3.05 +1.53 +4.80 ASM -3.04 +9.98 +1.10 +6.76 +4.83 +2.66 +1.14 +4.51 -0.15 -2.88 +5.73 -1.41 +2.35 +3.10 +1.99 -0.71 +6.05 +3.48 +2.67 +0.09 -4.82 +6.00 +2.44 +1.86 +5.17 CS 6-3 6-4 6-5 6-6 6-8 6-9 6-1 0 7-217 7-316 7-4f 5 7-9 7-1 0 8-1 I 4  8-518 8-617 8-9/10 9-115 9-317 9-418 9-9/10 10-118 10-316 10-415 10-9 10-10 ASP +4.77 +1.55 +5.80 -7.96 -3.58 +0.89 +6.14 +0.15 +2.52 +6.23 -6.12 +2.45 +1.22 +3.29 +4.49 -1-2.26 -0.29 -2.67 +4.50 +2.25 +0.53 +3.66 +0.59 +4.44 -1.95 ASM +4.96 +0.99 +6.32 -4.40 -0.08 +1.88 +5.11 +1.73 +2.29 +6.49 -7.93 +0.98 +2.24 +3.14 +4.51 +2.24 +1.17 -0.46 +4.49 +1.81 +1.87 +0.20 +3.57 +3.75 +3.14 a Compound and carbon atom number. the previous study the effect of the tautomeric ex- change was overrated and that the protonation equilibrium is shifted much more to the P-protonated product. EXPERIMENTAL Compounds 1-12 were prepared by the addition of a 10% solution of methylfluorosulphate14 in dichloro- methane to solutions of the parent compound in a dichloromethanelether (1 : 1) mixture. The amount of methylating agent used was always smaller than that calculated for complete N-methylation. This proce- dure was necessary to prevent formation of dimethy- lated products. The parent compounds of 1-4, 8 and 11-12 were commercial products (Aldrich). The other parent com- pounds were synthesized according to Refs. 15-19. The spectra were recorded on a Varian XL-100 spectrometer (25.2 MHz for 13C and 15.4 MHz for 'H lock). The data acquisition of the free induction decays (pulse width 22 ps; acquisition time 0.8 s; pulse delay 0.5 s) and Fourier transformation were performed with a Varian 620/L data instrument (16 k). With a spectral width of 5120 Hz and 4096 memory points the resolu- tion is 0.05 ppm. Using water as a solvent and 1.0 M concentrations, 500 transients were required to obtain an acceptable signal to noise ratio. The probe temper- ature was 20°C. A capillary was centred with the aid of three Teflon@ rings in the tube (outer diameter 10 mm) containing the aqueous solution. This capillary contained deuterated acetone to provide a signal for the deuterium field-frequency lock and TMS as an internal standard. Acknowledgements The investigations were supported in part by the Netherlands Foun- dation for Chemical Research (SON) with financial aid from the Netherlands Organization for the Advancement of Pure Research (ZWO). REFERENCES 1. R. J. Pugmire and D. M. Grant, J. Am. Chem. SOC. 90, 697 2. P. van de Weijer, H. Thijsse and D. van der Meer, Org. 3. P. van de Weijer and C. Mohan, Org. Magn. Reson. 9, 53 4. P. van de Weijer, D. M. W. van den Ham and D. van der 5. A. R. Osborn and K. Schofield, J. Chem. SOC. 4191 (1956). 6. W. W. Paudler and T. J. Kress, J. HeterocycI. Chem. 5, 7. D. E. Ames, G. V. Boyd, A. W. Ellis and A. C. Lovesey, 8. M. H. Falmer and B. Semple, Chem. Ind. 1766 (1965). 9. M. H. Palmer, A. J. Gaskell, P. S. Mclntyre and D. W. W. (1968). Magn. Reson. 8, 187 (1976). (1977). Meer, Org. Magn. Reson. 9, 281 (1977). 561 (1968). Chem. Ind. 458 (1966). Anderson, Tetrahedron 27, 2921 (1971). 12. 13. 7 4. 15. 16. 17. 18. 19. M. H. Palmer and P. S. Mclntyre, Tetrahedron 27, 2913 (1 97 1 ). J. A. Zoltewicz and L. W. Deady, J. Am. Chem. SOC. 94, 2765 (1972). R. W. Alder, Chem. Ind. 983 (1973). T. J. Kress and W. W. Paudler, Chem. Commun. 3 (1967); 1 .g-naphthyridine. H. Rapoport and A. Batcho, J. Org. Chem. 28,1753 (1963); 1,7-naphthyridine. T. J. Kress and W. W. Paudler, J. Org. Chem. 32, 832 (1 967); 1,8-naphthyridine. A. Taurins and R. Tanli, Can. J. Chem. 52, 843 (1974); 2.6-naphthyridine. W. W. Paudler and S. J. Cornich, J. HeterocycI. Chem. 7, 41 9 (1 970); 2,7-naphthyridine. 10. R. Bonaccorsi, E. Scrocco and J. Tomasi, J. Chem. Phys. 52, 11. P. van de Weijer, D. van der Meer and J. L. Koster, Theor. Received 16 April 1977; accepted 3 June 1977 5270 (1970). Chim. Acta 381 223 (1975). @ Heyden & Son Ltd, 1977 168 ORGANIC MAGNETIC RESONANCE, VOL. 10, 1977 

Carbon-<sup>13</sup>n.m.r. investigation on the nitrogen methylation of the mono- and diazanaphthalenes

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Carbon-13 n.m.r. investigation on the nitrogen methylation of the mono- and diazanaphthalenes

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