Reactions ofN-heteroaromatic bases with nitrous acid. Part 7. Kinetics of the nitrosation of secondary and of the diazotisation of primary beta;-aminopyridines

摘要

J.C.S. Perkin I1 Reactions of N-Heteroaromatic Bases with Nitrous Acid. Part 7.1 Kinetics of the Nitrosation of Secondary and of the Diazotisation of Primary P-Aminopyridines By Evangelos Kalatzis and Panayiotis Papadopoulos, The National Hellenic Research Foundation, 48 Vassileos Konstantinou, Athens, Greece The nitrosation of 3-methylaminopyridine and 3-methylaminopyridine 1-oxide and the diazotisation of 3-amino-, 3-amino-2-chloro-, and 3-amino-6-methoxy-pyridine in 0.002-0.50M-perchloric acid are first-order in both the amine and nitrous acid. The rate coefficients of these reactions increase with an increase in the concentration of perchloric acid and of sodium perchlorate. In perchloric acid solutions whose ionic strength is maintained constant by the addition of sodium perchlorate the rate coefficients of the nitrosation of 3-methylaminopyridine and of the diazotisation of 3-aminopyridine show only a rectilinear dependence on the H+of the medium.The nitrosation of 3-methylaminopyridine and the diazotisation of 3-amino- and 3-amino-6-methoxy-pyridine proceed mainly by the interaction of the nitrous acidium ion with the monoprotonated form of these amines whilst the nitrosation of 3-methylaminopyridine 1-oxide and the diazotisation of 3-amino-2-chloropyridine proceed by the simultaneous interaction of the nitrous acidium ion with the protonated and the free form of both amines. The nitrosation and diazotisation of the free P-aminopyridines involve an initial interaction between the nitrous acidium ion and the heteroaromatic nucleus whilst the nitrosation and diazotisation of the monoprotonated P-aminopyridines proceed by direct interaction between the nitrous acidium ion and the amino-group.These results are contrary to those of the nitrosation and diazotisation of the free and the protonated aromatic amines. Furthermore the nitrous acidium ion seems to show a distinct discrimination in its reaction with the free P-aminopyridines as is evident from a rectilinear relationship between the rate coefficients of their nitrosation and diazotisation and their Kp, values. The similarity between the nitrosation and the diazotisation results shows that the formation of the nitrosamine is the rate-determining stage of the diazotisation of the P-aminopyridines in the acid range examined.pK, Values are recorded. DIAZOTISATIONof p-aminopyridines is considered to be initial interaction of the nitrous acidium ion with the similar to that of the aromatic amines because of the heteroaromatic nucleus of the free p-aminopyridines or formation of rather stable diazonium ions.2 However, by a direct attack of the nitrous acidium ion on the no detailed studies on the mechanism of the nitrosation amino-group of their monoprotonated form. and the diazotisation of p-aminopyridines have been reported. RESULTS AND DISCUSSION This paper presents a study of the kinetics of the In 0.002--0.50~-perchloric acid solutions the nitros- nitrosation of 3-methylaminopyridine and 3-methyl-at ion of 3-methylaminopyridine and 3-methylamino- aminopyridine 1-oxide and of the diazotisation of 3-pyridine 1-oxide and the diazotisation of 3-amino-, TABLE1 Nitrosation of 3-methylaminopyridine and diazotisation of 3-amino-, 3-amino-2-cliloro-, and 3-amino-6-methoxy-pyridine at 2.0"; constancy of K, equation (1) at a given acidity 3-Methylaminop yridine 3-Aminop yridine* r 7 r 7 0.01 0.50 0.05 0.20 HC104IIM I -7 r--------h----1 -7-lr---1O4Amine /M 1.4 2.8 2.8 0.1 0.1 0.2 1.0 2.0 2.0 0.2 0.4 0.4 104Nitrous acid,/^ 2.8 1.4 2.8 0.1 0.2 0.1 2.0 1 .0 2.0 0.4 0.2 0.4 h2/1mol-1 s-1 0.597 0.582 0.579 108 117 105 4.55 4.54 4.38 35.9 33.8 34.1 Mean fi2/l mo1-I s-' 0.586 f0.010 110 f6 4.49 f0.10 34.6 1.1 3-Amino-2-chlorop yridine 3-Amino-6-methoxypyridine A Ar 7 0.025 0.100 0.05 0.25 HClO,I/M 7r ---A-r___h-__-7 -A__--7 r-7 lo4 Aminei/~ 1.5 1.5 3.0 1.o 1.0 2.0 0.5 0.5 1.0 0.25 0.25 0.50 104Nitrous acid,/^ 1.5 3.0 3.0 1.0 2.0 2.0 1.o 1.0 1.0 0.50 1.0 0.50 R,/l mol-1 s-1 2.59 2.79 2.54 8.93 9.46 9.36 1.50 1.54 1.44 11.4 11.4 10.3 Mean k,/l mol-l s-' 2.64 f0.13 9.25 f0.28 1.49 f0.05 11.0 f0.6 amino-, 3-amino-Z-chloro-, and 3-amino-6-methoxy-3-arnino-Z-chloro-, and 3-amino-6-methoxy-pyridine pyridine in 0.002-0.50~-perchloric acid.The results follow rate expression (1). Thus the stoicheiometric indicate that formation of the nitrosamine is the rate- Rate = h,Amine Nitrous acid determining step in both reactions and that contrary to the results of-the nitrosation and diazotisation of the second-order rate coefficients (k2) obtained by using aromatic amines 394 the reactions take place either by an rate expression (2) and various initial concentrations of the reactants remained constant (Table 1) for more than 70yL reaction (Table 2).Moreover, the validity of rate expression (1) was confirmed by the observation TABLE2 Nitrosation of 3-methylaminopyridille ancl diazotisation of 3-amino-~-chloropyridine at 8.0"; constancy of K, equation (I) during the reaction 3-Methylaminopyridinc HCIO,1 0.14~ NaClO, 0.36~ Arnineli 5.0 x 10-5~w Nitrous acidJi 2.5 x lW5~ t/min I0sProtluct/M 10amp;/1 mo1-1 s-1 3 0.550 29.3 4 0.714 30.4 5 0.843 30.2 7 3.08 30.6 10 1.35 30.6 13 1.56 30.9 17 1.78 31.1 22 1.96 31.1 3-Amino-2-chlorop yridine HC10*1 0.10111 Amineli 1.0 x 1W4h1 LNitroLis acidji 2.0 x lo- t /inin 1O" I'rod uct/ M amp;,/I mol-1 s-1 2 1.94 8.48 4 3.50 9.93 ti 4.69 9.82 8 5.86 9.52 10 6.08 9.57 13 6.83 Y.37 19 7.95 9.45 25 8.70 9.78 that for a number of acidities a two-fold increase in the concentration of either reactant caused a two-fold increase in the initial rate of the reaction, whilst a two-with slopes of 1.24 and 1.25, respectively, However, similar plots for the diazotisation of 3-amino-2-chloro- and 3-aniino-6-methoxy-pyridineare curves with rising slopes.The values of k, (Table 4) of the nitrosation of 3-methylaniinopyridine and the diazotisation of 3-aminopyridine in 0.01~-perchloric acid solutions contain- ing various concentrations of sodium perchlorate increase with an increase in the ionic strength of the medium (p) because a plot of log k, against dp (Table 4) gave straight lines with slopes of 1.06 and 0.91, respect- ively.These results, which show the similarity that exists between the nitrosation and the diazotisation of the (3-aminopyridines, suggest that these reactions involve charged species.5* In solutions of perchloric acid kept at constant ionic strength of 0.50 by the addition of sodium perchlorate the values of k, (Table 5) increase with an increase in the acidity of the medium. Thus a plot of log A2 against ---pH is a straight line for the nitrosation of 3-methylamino- pyridine and 3-methylaminopyridine 1-oxide with slopes of 1.00 and 0.93, respectively, and also for the diazol- tisation of 3-amino- and 3-amino-2-chloro-pyridine with slopes of 1.02 and 0.91, respectively.However, a similar plot for the diazotisation of 3-amino-6-methoxy- pyridine is a straight line only for low acidities whilst for higher acidities it becomes a curve with a decreasing slope (Figure). It is noteworthy that the second-order rate expression (1) was obeyed throughout the acid range studied in the present work without changing to a third-order rate expression. Thus it can be concluded that the nitrous anhydride mechanism, which follows third-order TABLE3 Nitrosation of 3-metliylaniinnpyritline and diazotisation of 3-amino-, 3-amino-2-chloro-, and 3-amino-8methoxy-pyricline at 2.0"; dependence of h, equation (l)on the concentration of an excess of perchloric acid 3-Methylamino-pyridine rp-7l-IClO*/M pH * k,/l ni01-l s-l 0.0086 2.53 0.124 f0.005 0.002 0.010 2.12 0.589 f0.011 0.020 1.75 1.42 f0.02 0.025 0.032 0.050 1.34 4.79 f0.18 0.075 0.100 1.00 12.6 f0 2 0.140 0 200 0.70 32.8 0.7 0.250 0.355 0.500 0.20 108 amp; 6 fold increase in the concentration of 3-Amino-2-chloro-3-Amino-6-mcthoxy-5-Aminop yridine pyricline pyridine 7 A 7 I * r A -7 pl-I * K,/1 mot1 s-1 pH * k2/1 mol-1 s-l 1 pH * R2/1 mol-1 s-1 2.69 0.100 f0.003 2.02 0.649 f0.014 2.13 0.521 amp; 0.027 1.70 2.82 f0.23 1.67 0.691 f0.050 1.60 4.04$.0.09 1.40 4.46 f0.10 1.33 5.23 f0.35 1.31 1.50 f0.05 1.17 6.76 f0.30 1.06 2.49 -amp; 0.11 1.00 10.6 f0.5 0.97 9.30 amp; 0.28 0.96 3 57 f0.12 0.82 12.5 0.6 0.81 5.32 5 0.1'3 0.70 34.0 f1.1 0.60 26.5 amp; 1.2 0.60 11.1 f0.6 0.40 47.9 f3.7 0.20 116 f1 0.20 92.5 40.9 0.20 23.4 f0.5 * Values determined by pH meter. both reactants caused a four-fold increase. The values of k, (Table 3) increase with an increase in the acidity of the medium and a plot of log A, against -pH is a straight line for the nitrosation of methyl- aminopyridine and thc diazotisation of 3-aminopyridine kinetics3'* (first-order with respect to the amine arid second-order with respect to nitrous acid) does not contribute to the nitrosation of 3-methylaminopyridine and 3-metliylaminopyridine 1-oxide and to the diazo- tisation of 3-amino-, 3-amino-2-chloro-, and 3-amino-B- methoxy-pyridine even when these reactions are carried out in the presence 'of excess of sodium perchlorate, which is known to catalyse the formation of nitrous anhydride (Table 6).These results are contrary to those of the nitrosation of N-methylaniline and the diazotisation of aniline in 0.5w-perchloric acid solu- tions because under these conditions the more basic aromatic amines are known to react mainly with nitrous anhydride.4 It follows from the present results that the nitrosation of 3-methylaminopyridine and 3-methylaminopyridine l-oxide and the diazotisation of 3-amino-, 3-amino-2- chloro-,and 3-amino-6-methoxy-pyridine can be examined together because these reactions show similar kinetic behaviour .Rate expression (1) can therefore be expanded to (2) for the nitrosation of 3-methylaminopyridine (pKa, 6.41 at 20" and pKa, -2.17 at 20") and the diazotisation TABLE 4 Nitrosation of 3-methylan1inopyridine and diazotisation of 3-aminopyridine in 0.OlM-perchloric acid and at 2.0"; dependence of h, equation (1) on the concentration of sodium perchlorate 3-Methylaminopyridine 3-Aminop yridine N;tClO,/hf amp;./1 mo1-l s-l K,/l mol-1 s-1 0.00 0.589 f0.011 0.649 amp; 0.014 0.01 0.721 f0.019 0.734 amp; 0,018 0.02 0.776 amp; 0.023 0.768 amp; 0.012 0.05 0.923 5 0.020 0 07 1.02 amp; 0.03 0.919 f0.020 0.954 * 0.020 0.10 1.12 j,0.03 1.11f0.04 0.15 1.38 f 0.04 1.24 f0.03 0.20 1.55 f0.04 1.40 f0.04 of 3-aminopyridine (pKa, 6.03 at 20" and pK,, -1.38 at 20") because these amines must be present almost Rate = k,Monoyrotonated amine HNO, H+ (2) entirely as the monocations under the present experi- mental conditions and in this case h, cc Hf.However, J.C.S. Perkin I1 diazotisation of the a-and y-aminopyridines,l.* the contribution to the overall rate of the reaction from a reaction path described by rate expression (3) cannot be neglected. Thus it is useful to determine separately (a) *N 1.5 U I* ~ (A1 * cn -0.5 0.0 1-1LI--2.0 -1.6 -1.2 -0.8 -0.4 -PH Plot of log A, (A) and log k, (H) against -pH for the diazotisation of 3-arnino-6-methoxypyridine in perchloric acid solutions kept at a constant ionic strength of 0.50 by the addition of sodium perchlorate the contribution of the two reaction paths described by rate expressions (2) and (3).Rate = k,'Free amineHNO,H+ (3) Equation (4) is, therefore, the result of a combination of equations (2) and (3) because Free amineH+ = Monoprotonated amineKal, where Ka, is the thermo- dynamic dissociation constant of the conjugate monoacid Rate = (k3'Ka,-t k3 H+)-Monoprotonated amine HNO, (4) K2 = k3'Ka1 + k3 H+ (5) of the amine. Equation (5)can be derived from equ- ations (1) and (4)for the nitrosation of 3-methylamino- pyridine and for the diazotisation of 3-aminopyridine at constant ionic strength because these amines are present TABLE5 Nitrosation of 3-methylaminopyridine and 3-inetliylaminopyridine l-oxide and diazotisation of 3-amino-, 3-amino-2-chloro-, ;~nd3-amino-6-methoxy-pyridine at 2.0"; dependence of h, equation ( l) on the concentration of pcrcliloric acid in solutions kept at a constant ionic strength of 0.50 by the addition of sodium perchlorate 3-Methylamino- 3-Methylaminopyridine 3-Amino-2-chloro-3-Amino-fi-methoxv-pyridinc I-oxide-3-Aminopyricline pyridine HCIO, /M PI1 K,/1 mol-1 s-1 Az/l mol-1 s-1 K,/1 nlol-' 5-1 Az/l mol-1 s-1 0.010 1.90 2.19 f 0.08 2.61 f0.12 0.026 1.50 5.71 amp; 0.12 6.01 f0.34 0.050 1.21 10.4 +-0.1 11.2 f 0.5 0.075 1.02 16.1 amp; 0.9 16.0 amp; 0.9 0.100 0.91 23.3 f 0.6 21.3 f0.5 0.140 0.76 30.8 amp; 0.4 29.4 f 0.8 0.250 0.50 54.6 f1.9 53.5 f2.5 0.500 0.20 108 amp; 6 98.4 amp; 3.5 the concentration of the free form of 3-methylamino-pyridine l-oxide (ph',, 1.67 at 2" and pKa, -2.42 at 25") or of 3-amino-2-chloropyridine (pKa, 1.96 at 2" and pKa, -3.64 at 25") is comparable to that of the monoprotonated form and therefore the overall rate of the nitrosation of the former or of the diazotisation of the latter amine cannot be described by rate expression (2) only, because, as in the case of the nitrosation or the 2.54 f0.04 1.19 + 0.08 6.35 * 0.12 6.14 4: 0.16 2.62 f0.05 12.5 f0.5 11.1 f0.2 4.74 f0.05 17.5 0.1 14.5 f0.6 6.42 If 0.28 24.8 f0.9 21.5 amp; 1.2 8.71 f0.42 23.8 f0.5 11.2 f 0.3 68.4 f0.8 51.9 rf_ 1.2 15.7 If.0.2 116amp; 1 92.5 f0.8 23.4 f0.5 almost entirely as the conjugate monoacids under the present experimental conditions. However, for the case of the nitrosation of 3-methylaminopyridine 1-oxide and the diazot isation of 3-amino-2-chloropyridine equation (6) can be derived from equations (1) and (4) because under the present experimental conditions the concentration of the free form of these amines is com- parable to that of the monoprotonated form which is 1981 251 given by equation (7). Values of k,' and K, (Table 7) write rate expression (1)as rate expression (8) in which were, therefore, evaluated by plotting either k, against the value of k, is given by equation (9) because the con- H+ or k,/H+ against l/E+ + KaIequations (5)and centration of the monoprotonated amine can be obtained -from equation (10).When the values of log k, were, H+l = k, + (k,' -k,)Kal1H+I 1 x (6) Rate = k,Monoprotonated amine jHNO, (8) Monoprotonated amine = k, = R,(1 (9) H+l Stoicheionietric aminej (7) Monoprotonated amine = (1 + H+I/rn (10)H++-KL, Amine (6), respectively and then calculating the slopes and therefore, plotted against -pH a straight line was ob- intercepts of the straight lines obtained. tained with a slope of 0.95 (Figure) thus showing that TABLE6 Nitrosation of 3-methylarninopyridinc and 3-methylaminopyridine l-oxide and diazotisation of 3-smi1io-, 3-amino-2-chloro-, and 3-amino-6-n~ethoxy-pyridine at 2.0"; constancy of A, equation ( l) in the presence of sotliuni perchlorate 3-Meth~larni1iopyridine 3-Methylaminopyridine 1 -oxide A_--_ ~-~ -~ -7r --A 7 0.075~-HC10, 0.250~-HC10, 0.0 1 OM-HC~O, 0.050~~HC10,+-0.425~-NaC10, +0.250~-NaC10, +0.490~-NaC10, 4-0.450~-N~ClO,j ~ ~T-.-A-p r-------___h--.__ r~--h~_-____-~-.-~h ~---7 1 O4IAmineIi/~ 0.7 0.7 1.4 (3.1 0.1 0.2 1.6 1.6 3.2'7 1.6 3.2 3.2 104Nitrous acidi/M 0.7 1.4 0.7 0.1 0.2 0.2 1.6 3.2 3.2 3.2 1.G 3.2 hz/l mol-1 s-1 15.7 17.1 15.4 52.8 56.2 53.2 2.55 2.54 2.7G 11.0 11.4 11.7 Mean hz/l molP s-l 16.1 f0.9 54.1 amp; 1.9 2.62 f0.12 11.4 3: 0.4 3-Amino-6-rnethoxypyridine3-Aminopyridine 3-Amino-2-chloropyridine ~ -7 0.01M-HC10, 0.100~-HC10, 0.025~-HC10, 0.075M-HC10+0.490~-Pbsol;TaC10, +0.400~-NaClO4 +0.475w-NaC10, -t0.425m-NaC*1O4 ~7 r--r-____-.h-----r-A----7I--1O4AmineIi/~ 1.4 1.4 2.8 1.0 2.0 23 0.5 0.5 1.0 0.5 0.5 1.o 104Nitrous acidi/~ 1.4 2.8 1.4 2.0 1.0 2.0 1.0 2.0 1.o 1.o 2.0 1*o hz/l mol-1 s-1 2.39 2.31 2.32 21.1 22.8 20.5 2.5G 2.64 2.64 6.29 6.24 6.74 Mean h,/1 mol-l s-l 2.34 amp; 0.04 21.5 f 1.1 2.61 f0.05 6.42 amp; 0.28 From the plot of log k, against -pH for the diazotis- the diazotisation of 3-amino-6-methoxypyridine obeys ation of 3-amino-6-methoxypyridine(Figure) it can be rate expression (2) at constant ionic strength. Thus seen that the rectilinear relationship predicted from values of k,' and k, (Table 7) for this reaction were cal- equation (5) holds for acidities up to O.l~-perchloric culated from equation (5) in which k, was substituted acid and that above this acidity the plot is a curve with by k,.decreasing slope. This deviation from a rectilinear Kate expressions (2) and (3) are similar to those TABLE7 Values of k,' and K, equations (5)and (6)in perchloric acid solutions kept at constant ionic strength of 0.60 and at 2.0" Amine 3-Methylaminopyridine 6.41 a -2.17' 5 13 13 190 171 3-Aminop yridine 6.03 'Ib -1.25' 9.98 10 690 194 3-Amino-Ci-rnethox y p yridine 4.02 +0.25 4.44 185 78 3-Amino-2-chloropyridine 1.96 -3.64 2.07 3.33 144 3-Meth ylaminopyridine 1 -oxide 1.67 -2.42 1.43 2.27 160 a At 20". Ref. 6. At 2". At 25". relationship is presumably due to the formation of the obtained in the nitrosation and diazotisation 8,9 of a-dication (11)of the amine (ph',, 4.62 at 2" and pK,, 0.25 and y-aminopyridines and therefore they are taken to at 2') in considerable amounts under the present experi- indicate that the nitrosation of 3-methylaminopyridine and 3-methylaminopyridine l-oxide and the diazotis- ation of 3-amino-, 3-amino-2-chloro-, and 3-amino-6- methoxy-pyridine involve the interaction of the nitrous acidium ion with the protonated rate expression (2) and the free form rate expression (3) of these amines.The (I) alternative possibility for rate expression (2) is (11) and this would indicate that in this case the reactions mental conditions. Since it is unlikely that the dication involve the free form of the amines and the nitrosonium would participate in the reaction it is convenient to re- ion.However, this alternative Possibility is excluded (as in the case of the nitrosation and diazotisation of the a-and y-arninopyridines 19899) because the concen- tration of the free amines and of the nitrosonium ion is Rate = k, Free amine HNO, 1z02 (11) too low to account for the observed rates of the above reactions even if these reactions were assumed to take place on enc~unter.~~ This argument is supported by the observation that in 0.50~-perchloric acid 3-amino- pyridine and 3-methylaminopyridine are 1.3 and 1.1 times more reactive than 3-amino-2-chloro-pyridine and 3-methylaminopyridine 1-oxide, respectively, in spite of the fact that the concentration of the free form of the former aniines is respectively 17 400 and ca.60 000 times smaller than that of the latter amines (Table 5). The values of k,rsquo; and k, (Table 7), which were deter- mined by the method of least squares, show that the free form (k,rsquo;) of the p-aminopyridines is more reactive than tlie protonated form (K,) towards the nitrous acidiuni ion. Moreover, in contrast to the nitrosation and the diazotisation of the aromatic amines more basic than p-nitroaniline for which the values of k,rsquo; appear to approach a limiting the nitrous acidium ion shows a distinct discrimination in its reaction with the free 8-aminopyridines examined in this work and does not seem to approach a limiting value. Indeed a plot of log (k3rsquo;10k3rsquo;) against log (KJOKal)is a straight line with a slope of -0.81 (ok3rsquo; and refer to 3-aminopyridine). These results are similar to those of the nitrosation and the diazotisation of the a-and y-aminopyridines 1*80and they suggest that the nitrosating agent associates with the heteroaromatic nucleus first (most probably the basic centre) and then, as a result of electronic re-arrangement, it migrates to tlie amino-group which is thus nit rosa ted.Although there is some uncertainty in the values of k,rsquo; due to the fact that the intercepts of the plots of E2 against 12, are small, especially in the case of the more basic amines, it is interesting to note that tlie free p-aminopyridines are more reactive than the free a-and y-aminopyridines 1,879 of comparable basicity. Thus the values of k,rsquo; of the nitrosation of 3-methylamino- pyridine and of the diazotisation of 3-aminopyridine at a constant ionic strength of 0.50 are 1.6 and 22.6 times greater than those of the nitrosation of 2-niet hyl- aminopyridirie and of the diazotisation of 3-aminoyyri- dine,g6 respectively, at a constant ionic strength of 3.0 in spite of the fact that the latter amines are, respect- ively, 5.3 and6.2 times more basic than the former amines and that the ionic strength of tlieir reaction solutions is 6 times greater.This is most probably due to the greater electron-donor capacity of the amino-group in the 3- position of the pyridine ring compared with that in the 2-or the 4-po;ition. This is because the amino-group in the 3-position is subject mainly to an inductive effect structure (III) whilst the amino-group in the 2-or the 4-position is subject mainly to a resonance effect struc- tures (IVb) and (Vb)which is more effective in depleting the amino-group of its electron pair.J.C.sect;. Perkin I1 It is evident from the values of k, (Table 7) that proton- ated p-aminopyridines are more reactive than protonated a-or y-amin0pyridines.l.89~ Thus protonated 3-methyl- aminopyridine is 855 or 452 times more reactive than the protonated 2-or 4-methylaminopyridine,l respect- ively. Also protonated 3-methylaminopyridine 1-oxide is 880 or 137 times more reactive than protonated 2-or 4-methylaminopyridine l-oxide,l respectively. These differences are difficult to explain by assuming that nitrosation or diazotisation of the protonated p-amino- pyridines involves attack of the nitrous acidium ion on the heteroaromatic nucleus as for nitrosation or diazo- tisation of the protonated a-and y-aminopyridines.1*8*9 This is because the differences in the reactivities indicated above are too large to be attributed to a greater electron- donor capacity of the heteroaromatic nucleus of the p-aminopyridines compared with that of the CC-and y-aminopyridines.Indeed these differences should have been in the opposite direction if tlie reactions involved an attack of the nitrous acidium ion on the heteroaromatic nucleus, because the electron donor capacity of the lsquo;rietero- aromatic nucleus of the protonated P-aminopyridines must be much smaller than that of the a-and y-amino- pyridines.This is so because, in the case of the proton- ated p-aminopyridines , the positive charge of the ring nitrogen is delocalised only into the x-system of the heteroaromatic nucleus structures (VIb and c) ,whilst in the case of the protonated a-and y-aminopyridines the delocalisation of the positive charge into the x-system of the ring is greatly diminished by resonance between the positively charged ring nitrogen and the exocyclic amino-group structures (VIIb) and (VIIIb). It is therefore more likely that nitrosation and diazo- tisation of the protonated y-aminopyridines proceed by a reaction path which involves direct attack of the nitrous acidium ion on the exocyclic amino-nitrogen and then migration of an amino-proton to the medium as shown in the Scheme. This reaction path resembles that of nitrosation and diazotisation of the free form of the aromatic aniines by the nitrous acidium i0n,36p4 in that the nitrosating agent directly attacks the amino- group and does not interact with the aromatic ring and that the values of k, (Table 7) show only a very small increase with an increase in the basic strength of the arnines.Thus in the case of the yrotonated p-amino- pyridines a plot of log (k3/amp;3) against log (KaJoKi2) gives a straight line with a slope of only -0.06 (OK3 and refer to 3-aminopyridine) . However, 2-amino- 6-methoxypyridine is much less reactive than expected from the ahovc plot nltliough it has a high phrsquo;,,,value 1981 I I I H H H Q-I N" 2 H (Table 7).'This is rnvst probably clue to a decrease in the acidity of the amino-protons because structurc (TXb) would be expected to contribute significantly to the resonance hybrid of the molecule thus greatly decreasing the attraction exerted by the protonated heteroaromatic nucleus on the amino-group. Thus the retarding effect on the migration of an amino-proton to the medium seems in this case to be more important than the increase in the availability of the electron pair of the amino-group. It is noteworthy that the values of k, (Table 7) do not vary greatly from one another and that they tend to approach a limiting value of ca.200 l2 mol--2 s--lat con- stant ionic strength of 0.50. These results 'are similar to those of nitrosation and diazotisation of the free aromatic amines more basic than +-nitr~aniline,~b** for which the values of k, do not differ greatly from one L J +HQ+ + + X= H2N02 R=CH3 or H SCHEME 253 another but they approach a limiting valuc of ca. 180 l2 mol-2 s-l at low ionic strengths. It is difficult to explain these results by assuming that the nitrous acidium ion acting, as a strong nitrosating agent, cannot discriminate between the protonated amine molecules because such limitation was not evident in the case of the free 3-aminopyridines and in the free 2-and 4-aminopyridines.8h It is, however, more likely that the above results are due to the opposite directions in which the polarisability and the polarisation of the amino- group act in the transition state.Thus during the approach of the nitrosating agent the polarisability of CH,O g-p---CH,O +uNH2 A A the amino-group becomes more important than its polarisation, which exerts only a small decreasing effect on the k, values. This explanation may also be applic- able for the case of nitrosation and diazotisation of free aromatic amines. It seems therefore reasonable that the values of k, should tend towards an upper limit corresponding to the complete availability of the lone pair of electrons of the amino-nitrogen, which for the free aromatic arnines and the monoprotonated p-aminopyridines seems to be about the same.Since the differences in the values of k, are relatively small it appears that only great changes in the polarisation of the amino-group would have a substantial effect on the values of k,. Thus the value of k, of the diazotisation of $-nitroaniline 4a is 161 l2 mol-2 s-l but that of 2,4-dinitroaniline 4a is only 3.7 l2 mol-2 s-l. EXPERIMENTAL MateriaZs.-3 Methylarninopyridine was prepared lo by treating 3-aminopyridine (Fluka ; purum) with toluene-p- sulphonate (Fluka ; pract.), methylating the toluene-p-sulphonamide formed with dimethyl sulphate (Merck; 98). and then hydrolysing the methyl derivative with SOo/, sulphuric acid. The product obtained after extraction with ether was distilletl twice at 110 "C and 7 mniHg (Iit.,lo 110 "C and 7 mmHg), yield 65.3-IL'lethylan~inopyri~ine 1-oxide was prepared l1 by treating 3-methylaminopvritline with acetic anhydride (Fluka; purum) and then oxidising the A'-acetyl derivative dissolved in acetic acid (Fluka; purum) with 35 hydrogen peroxide (Merck; pro analysi). The product obtained after hydrolysis with hydrochloric acid, neutralisation with solid sodium hydroxide, and then extraction with chloroform (solution saturated with sodium chloride) was recrystallized from ethyl acetate and then sublimed twice at 95 "C and 0.1 mmHg, yield 5076, m.p. 110-1 12 "C. 3-Aminopyridine (Fluka; purum) was sublimed twice at 35 "C and 0.2 mmHg. 3-Amino-2-chloropyridine (Flula; purum) was sublimed twice at 60 "C and 0.05 mmHg.3-Amino-6-methoxypyridine J.C.S. Perkin IT in a pre-cooled Unicam cell (1.0 cm) and maintaining the 3-methylaminopyridine and 3-absorbances in both cases of 3-methylaminopyridine, 3-nitrosomethylaminopyridine, and 3-nitrosomethylamino- lo2and 3.92 x lo2, 3-methylaminopyridine 1-oxide 3 sniino-2-chloropyridine at various pH values 3-Amino-2-chloro-pyridine 10 at 330 5.39 5.29 5.17 4.85 4.78 4.40 4.30 4.00 3.97 3.66 3.40 3.22 2.89 alkaline and then evaporated to dryness under vacuum (Biichi apparatus). The residue was extracted with chloro- form (Sohxlet apparatus) and then the solid obtained after evaporation of the chloroform extract was sublimed twice (Aldrich; 050/,) was twice distilled over potassium hydr- temoxide at 120 "C and 15 mmHg.3-Hydroxypyridine (Fluka; perature at 2.0 "C. Forpurum) was sublimed twice at 65 "C and 0.2 mmHg. the nitrosa tion of metSodium perchlorate (Mcrck; pro analysi), which gave a hylaminopyridine l-oxide wernegative chloride test, was dried at 140 "C for 4 h. Sodium e read at 340 nm at which E nitrite (AnalaK) was used without further purification pyriafter being dried under vacuum over phosphorus penta- dine l-oxide a re 3.03 x lo3, 2.74 x oxide. Perchloric acid (Mcrck; pro analysi) was diluted and niolarities of stock solutions were determined by TABLE8 Extititration against standard alkali solutions. All purified nction coefficients of products had satisfactory elemental analysis.Micro- and analyses were carried out by Dr. Ch. Mantzos. and at 2.0 "C 3-Nitrosomethylaminopyridine was prepared by treating 3-Methylaminopyridine sodium nitrite (4 g) in water (15 ml) with 3-methylamino- 1-oxide pyridine (1.5 g) in a solution of concentrated hydrochloric pH 10 at 340 nm acid (15 ml) and water (30 ml) at 0 "C. After 20 min standing the reaction solution was treated with solid sodium carbonate until alkaline and then extracted with ether. The liquid obtained was distilled twice at 114 "C and 4 0.20 0.50 0.60 0.76 0.82 3.13 3.09 3.05 mmHg to give 3-nitroso~et~cyZavninop~~r~d~ne(1.2 g, SO?/,) (Found: C, 52.8; H, 5.35; N, 30.3. C,H,N,O requires C, 52.55; 13, 5.1; N, 30.60/,). 3-Nitrosoniethylsminopyridine 0.91 1.02 1.17 1.21 2.98 2.92 2.81 l-oxide was prepared by reacting sodium nitrite (0.5 g) 1.33 in water (10 nil) with 3-methylaminopyridine l-oxide (0.3 g) 1.50 2.71 in 2.5~-hydrochloric acid (20 nil) at 2 "C.After 15 niin the 1.60 solution treated with solid sodium carbonate until 1.70 was 1.90 2.57 respectively, for all acidities exanijned. Values of E of 3-methylaminopyridine l-oxide at various acidities are in Table 8. at 105 "C and 0.2 mmHg to give 3-~aitrosometl~ylnr~~~~~~~~-For the diazotisation of 3-amino-, 3-smino-Ci-niethoxy-, dine 1-oxide (0.24 g, 80y0),m.p. 147-149 "C (Found: C, and 3-atnino-2-ctiloro-pyricline, sbsorbances were iead at 47.35; H, 4.65; N, 27.2. C,H,N,O, requires C, 47.05; 315, 303, and 330 nm, respectively.At all acidities values H, 4.6; N, 27.45). Kinetics.-Runs were 3-Aminopyridine 3-Methylaminopyridine 3-Nitrosomethylamino-pyridine 3-Dimethylamino-pyridine 3-Methy1a.minopyridinel-oxide 3-Amino-2-chloro-pyridine 3-Amino-6-methoxy-pyridine 4-Nitroaniline of E at 315 nm are 3.36 x lo3 for 3-aminopyridine, 0 for 3- carried out at 2.0 "C. Temper-hydroxypyridine, 4.24 x lo2 for pyridine-3-diazonium ion ; TABLE9 Concentr-Concentr-Ten1p. spread ation A.W.I.~ Temp. Spread ation A.w.1 ("C) PKlt," (f) ( 105~) (nm) ("C) PKa, (4x1 ( 1O"M) (nm) 2 -1.25 0.05 16.8 315 20 -1.38 0.02 11.3 315 20 6.41 0.03 5.22 267 20 -2.17 0.02 4.35 267 20 3.20 a 0.04 7.37 300 20 6.67 a 0.03 21.6 300 20 -1.91 0.01 21.6 340 2 1.67 0.03 20.0 360 25 -2.42 0.03 12.0 340 2 1.96 0.05 10.0 326 25 1.79 0.01 10.0 326 25 -3.64 0.07 10.0 324 2 4.62 a 0.04 20.6 305 2 0.25 0.06 10.3 285 25 4.24 0.02 20.0 305 25 0.21 0.06 10.0 285 2 1.16 0.04 5.0 380 a Values refer to the gain of one proton.A.w.1. = analytical wavelength. Values refer to the gain of a second proton. Buffers used had ionic strength 0.01. ature-adjusted aqueous solutions of calculated concen-trations of amine, perchloric acid (concentration adjusted to allow for the conversion of the amine into the perchlorate salt and sodium nitrite into nitrous acid), and, when re-quired, sodium perchlorate were mixed to such a volume (45.0 or 95.0 ml) that after the addition of temperature- adjusted aqueous sodium nitrite (5.0 ml) the total volume was 50.0 or 100.0 ml.The mixtures were then vigorously shaken and their U.V. spectra were recorded at regular intervals, after having placed a portion of these mixtures at 303 nm 6.55 x lo2 for 3-amino-6-methoxypyridine, 16.4 x lo3 for 6-methoxypyridine-3-diazonium ion; at 330 nm 1.11 x lo3 for 2-chloropyridine-3-diazonium ion. Values of E of 3-amino-2-chloropyridineat various acidities are in Table 8. Under the present experimental conditions the diazonium ions of 3-aniino-6-methoxy- and 3-amino-2-chloro-pyridine are stable for at least 24 and 3 h, respectively, whilst that of 3-aminopyridine is the least stable and its decomposition to 3-hydroxypyridine is ca. 7 after 1 h. Good isosbestic points were therefore obtained for cu.100 reaction during the kinetic runs for the diazotisation of 3-amino-6-methoxy- and 3-amino-2-chloro-pyridineand for 70 reaction during the kinetic runs for the diazotisation of 3-aminopyridine. Determination of pH.-Because the reactants were present as the perchlorate salts of the amines and as free nitrous acid in high concentrations in some cases, especially in the very dilute perchloric acid solutions ( 6 0. OM), it was necessary to determine, by pH meter, the pH of the final solutions at 2". The values obtained are in Tables 3, 5, and 8. Determination of pli, Values.-These were measured spectrophotometrically l2 in water at 2, 20, and 25 "C (Table 9). Cakculation of Rate Coe$icients.-The concentration of the amine in the reaction mixtures was calculated from the -expression Amine = (D-AE~)/(E~E~)where D is the observed optical density measured at a particular wave-length, A is the initial concentration of the amine, and and E~ are the extinction coefficients of the amine and the cor- responding nitrosamine or diazonium ion, respectively. The absorption of nitrous acid under the conditions used is negligible. The rate coefficients were calculated from the usual second-order expression 5C by using the individual values of absorbances.Typical data are in Table 3. Values of I, determined at 2" (Table 9) were used when calculating values of k,' and k,. 0/203 Received, 4th Februavy, 19801 REFERENCES Part 6, E. Kalatzis and P. Papadopoulos, preceding papcr. Cf. -4. Albert, ' Heterocyclic Chemistry,' Athlonc Press, London, 1968, 2nd edn., pp. 80-82. 3 (a)E. Kalatzis and J. H. Ridd, J. Chem. Soc. (B),1966, 52!); (b)E. C. R. de Fabrizio, E. Kalatzis, and J. H. Iiidd, ibid.,p. 533.* (a)J. H. Ridd, Quart. Rev., 1961, 4, 429; (b) E, I. Hughes,C. K. Ingold, and J. H. Ridd, J. Chem. Soc., 1958, 58, and sub-sequent papers. Cf.S. W. Benson, ' The Foundations of Chemical Kinetics, McGraw-Hill, New York, 1960, (a)p. 425; (b)p. 497; (c) p. 17. 6 B. C. Challis and J. H. Ridd J. Chem. Soc., 1963, 5197. A. Albert, J. Chem. Soc., 1960, 1020. 8 E. Kalatzis and Ch. Mastrokalos, J.C.S. Perkin 11, 1977,(a) 1830; (b) 1835. (a)E. ICalatzis, J. Chem. Soc. (B),1967, 277; (b)E. Kalatzis and Ch. Mastrokalos, J.C.S. Pcrkin 11, 1974, 498. lo J. W. Clark-Lewis and M. J. Thomson, J. Chenz. Soc., 1951, 442. 11 K. Undheim, M. A. F. El-Gendy, and T. Huruni, Acla Chent. Scand., 1974, B28,743. l2 A. Albert and E. P. Serjeant, ' The Determination of Ionization Constants, ' Chapman and Hall, London, 1971, 2nd edn.