Solvent azines

Careful study of mild conditions and of the effect of aprotic solvents will undoubtedly suggest methods for obtaining isolable intermediate complexes or lead to spectral evidence for their presence in many other reactions of azine derivatives with nucleophiles. 

If there is hydrogen bonding to the azine by the solvent, three effeets can result a) with an uneharged nueleophile sueh as an amine, steric hindranee to the reaetion at the oipAa-position, but not at the gumma-position, in a 4-substituted eompound (6) with an anionic... 

Hydrogen bonding to azine-nitrogen has been postulated to be responsible for 2-carboxamidopyridine being more rapidly hydrolyzed than the 4-isomer while the reverse is true in the esters, is Solvent-... 

It is postulated that hydrogen-bonded cyclic transition states such as 62 or the analogous one involving H0CH2CH20 will be found to increase relative reactivity adjacent to the azine-nitrogen in aprotic solvents cf. also Sections II,E,2,e and II,F. 

Hydrogen bonding with protic solvents or reagents occurs widely in azines even when they are not appreciably basic and the protic compounds are very poor acids. The latter do not have to be present... 

Even without a cage effect, the entropy effect will be somewhat more favorable for ortho reaction when hydrogen bonding to an azine-nitrogen atom generates the necessary nucleophile. The possibility of proton transfers between the solvent molecules (MeOH) near the reaction site and the more distant MeO is expected to produce a favorable increase (relative to other solvents) in the entropy of activation, which can reinforce the effect of a favorable point of... 

A hydrogen-bonded cyclic transition state can be postulated for a nucleophile like ethanolamine or ethylene glycol anion whose hydrogen bonding to an azine-nitrogen in aprotic solvents can facilitate reaction via a cyclic transition state such as 78, cf. Section II, F. Ethanolamine is uniquely reactive with 2-chloronitrobenzene by virtue of a cyclic solvate (17) of the leaving group, a postulate in line with kinetic evidence. 

The effect of hydrogen bonding to nuclear substituents in transition states is reviewed in Sections I,D, 2,b, and II, E. Relative reactivity at different ring-positions is postulated to be alterable by hydrogen bonding of an azine-nitrogen to the solvent or to the reagent (Section II, B, 3 and III,B). However, there appears to be no kinetic data relevant to this postulate. 

The.effect of the entropy of activation was noted above for the quaternary pyridine salts (280 and 281). In future work, it may also be found to reflect the electrostatic or hydrogen-bonding interactions in transition states of amination reactions and the effect of reversible cationization of an azine-nitrogen. Brower et observed a substantial rate difference between piperidino-dechlorinations of 2-chloropyrimidine in petroleum ether and in alcohol due partly to the higher entropy of activation in the latter solvent (Table III, lines 3 and 4). 

The reaction of 2,4,6-tribromopyridine with phenoxide ion illustrates, in our opinion, the effect of hydrogen bonding as discussed in Section II, B, 3. Reaction (150°, 24 hr) in water gave approximately equal amounts (18% yields) of 2- and 4-monosubstitution, but in phenol under the same conditions only the 2-phenoxy derivative (in high yield plus a small amount of the 2,6-diphenoxy compound) was formed. In water, reaction at the adjacent 2- and 6-position is hindered by the hydrogen bonding (cf. 61) of the solvent to the azine-nitrogen, compared to reaction at the 4-position. On the other hand, in... 

Covalent addition of solvent or of nucleophile prior to substitution will alter the reactivity characteristics of the substrate. Covalent addition of nucleophile after substitution will affect the kinetics in a way similar to the formation of 389. Covalent hydration and additions are especially likely to occur in bicyclic azines. (cf. Section IV,B,3,b).ii>i o>i i i4... 

The rate differences result primarily from the lowering of the activation energies, but in a few cases small entropy increases also contribute. The relatively high rate of reaction of 8-bromoquinoline (346) is postulated to be due to hydrogen bonding of the solvent, piperidine, to the nearby azine-nitrogen in the ground state and... 

The relations 4- > 2-position in rate and 4- < 2-position in will apparently apply to reactions with anions, but the reverse relation is observed in piperidination, presumably due to 2-substitution being favored by hydrogen bonding in the zwitterionic transition state (cf. 47, 59, and 277) or by solvent-assisted proton removal from the intermediate complex (235). Substitutions of polychloroquino-lines (in which there is a combined effect of azine-nitrogen and unequal mutual activation of the chlorine substituents) also show 4- > 2-position in reactivity contrary statements are documented by these same references. Examples are cited below of the relation 2- > 4-position when a protonated substrate or a cyclic transition state is involved. 

Practical experience enables us to emphasize the simplicity and the efficiency of the activation of aldehydes by their conversion into N- -haloalkyl)heteroarylium halides upon treatment with an azine and a thionyl halide. Preparation of these salts requires a minimum of precautions, and a wide variety of solvents can be used. Special glassware and/or the use of an inert gas is not necessary. Tire salts can be reacted under numerous experimental conditions and, in most cases, it is unnecessary to isolate them. Tire flexibility of the method represents an interesting feature for the study of the reactivity of A-(l-haloalkyl)heteroarylium halides and deserves further investigations in this held. Many elegant compromises can be found in a judicious choice of the precursors and of the experimental conditions, and it is possible to design readily a salt suitable for each individual purpose. 

A solution of 70 g of ethyl o-(psodium methoxide is heated on a steam bath for about 5 days. The solvent is removed by distillation and the residue Is triturated with water. The resulting solid is dissolved in ether and dried over sodium sulfate. Filtration and concentration then yields ethyl 4-[ [o-(p[Pg.77]

The use of extraction cartridges in the separation of azines, discussed in the last Section, is an example of on-column concentration using off-line column switching. A chromatogram can be cut off-line by collecting the zones of interest at the detector outlet followed by reinjection of the collected fraction onto a secondary column. The mobile phases used with the two columns should be compatible, eg they should be miscible and the mobile phase used with the first column should not have too high an eluting power in the second column. If the mobile phases are incompatible it may be possible to evaporate the primary mobile phase and redissolve the sample in a suitable solvent. 

Ifcobs is directly proportional to pyridine concentration. Therefore a plot of kobs vs. [pyridine] is linear, with a slope (k ) equal to the second order rate constant for ylide formation, and an intercept (k0) equal to the sum of all processes that destroy the carbene in the absence of pyridine (e.g.) intramolecular reactions, carbene dimerization, reactions with solvent, and, in the case of diazirine or diazo carbene precursors, azine formation. 

In order to safely identify k0 with intramolecular carbenic reactions (e.g., k and the formation of alkene 4 in Scheme 1), product analysis should demonstrate that the yield of intramolecular products exceeds 90%, while dimer, azine, and solvent-derived (intermolecular) carbene products should be absent or minimal. If these conditions are not met, mechanistic interpretation is often ambiguous, a result that is well illustrated by the saga of benzylchlorocarbene (see below, Section IV.C). Less desirably, k0 can be corrected for competitive intermolecular carbenic reactions. Bimolecular reactions like dimerization and azine formation can be minimized by working at low carbene precursor concentrations, and careful experimental practice should include quantitative product studies at several precursor concentrations to highlight potential product contamination by intermolecular processes. 

The Arrhenius curvature could be attributed to the occurrence of two competing reactions with different activation energies. However, photolysis of 9a at —80°C afforded only p-chlorostyrenes 11a and 12a no carbene-solvent insertion product was detected, and reaction of the carbene with diazirine to give azine was considered unimportant at the diazirine concentrations employed. 

Of course carbene C-H insertion reactions are well known absolute kinetics have been reported for the insertions of ArCCl into isooctane, cyclohexane, and n-hexane,67 and of PhCCl into Si-H, Sn-H, and C-H bonds.68 More recently, detailed studies have appeared of PhCCl insertions into a variety of substrates bearing tertiary C-H bonds, especially adamantane derivatives.69 Nevertheless, because QMT is considered important in the low temperature solution reactions of MeCCl,60,63 and is almost certainly involved in the cryogenic matrix reactions of benzylchlorocarbene,59 its possible intervention in the low temperature solution reactions of the latter is a real possibility. We are therefore faced with two alternative explanations for the Arrhenius curvature exhibited by benzylchlorocarbene in solution at temperatures < 0°C either other classical reactions (besides 1,2-H shift) become competitive (e.g., solvent insertion, azine formation), or QMT becomes significant.7,59,66... 

The possible intervention of classical, competitive reactions in the low temperature solution chemistry of benzylchlorocarbene (10a) requires careful investigation. There are reasons to suspect azine (48) formation Goodman reported minor yields of azine in analogous MeCCl experiments,60 and Liu et al. found 40% of 48 in the photolysis of neat diazirine 9a.65 Perhaps azine formation is also significant at low temperature in hydrocarbon solvents. If so, the intervention of bimolecular azine formation, in competition with the unimolecular carbene 1,2-H shift, could lead to a nonlinear temperature dependence for the disappearance of 10a. Arrhenius curvature could then be explained without invoking QMT. 

Photolytic decomposition of diazirine 9a in methylcyclohexane led to substantial C-H insertion of PI1CH2CCI into the solvent, although azine was a minor product. At 25°C, there were 74% of 1,2-H shift products and 14% of C-H insertion. Insertion increased to 44% at —75°C. Here too, a curved Arrhenius correlation reflected the competition of two classical reactions, not the incursion of QMT.71... 

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