H/D-exchange

Fig. 1-24. Absolute rate of H/D exchange (mole liter min ) in 1.8 N NaOD at 60°C of thiazole (Concentration, 3.2 mole liter" ) (430).

More recently, the use of phase-transfer catalysis to promote the deproto-deuteration of thiazole and various alkylthiazoles enabled Spil-lane and Dou (435) to increase considerably the rate of H/D exchange and afforded the possibility of labeling alkylthiazoles in preparative quantities and at positions otherwise difficult to label. 

This typical behavior of the very unsymmetrical thiazole ring led to a series of studies from the group of H. Erlenmeyer in Basle be studied the H/D exchange of 2,4-dimethyl-5-carboxythia2ole as well as that of similar methylated nitrogen heterocycles (507). The results are shown in Fig. 1-27. 

The destmction of the total TT-system causes the color to vanish the protonated molecule absorbs light in the uv region. Protonation has been proved by H/D exchange to be reversible (62,63). 

Solvent for Base-Catalyzed Reactions. The abihty of hydroxide or alkoxide ions to remove protons is enhanced by DMSO instead of water or alcohols (91). The equiUbrium change is also accompanied by a rate increase of 10 or more (92). Thus, reactions in which proton removal is rate-determining are favorably accompHshed in DMSO. These include olefin isomerizations, elimination reactions to produce olefins, racemizations, and H—D exchange reactions. 

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

The synthesis of the 11 deuterated derivatives of pyrazole (676) is described in (7QBSF1974). Seven can be obtained by H/D exchanges making use of the fact that the exchange rates... 

Weak acids (15 < pK < 30) undergo H/D exchange when placed in Na0D/D20. A reasonable mechanism is ... 

Methylcyclohexanone, pK 20, is typical of a weak acid that undergo H/D exchange. Identify the acidic protons of 2-methylcyclohexanone, i.e., those most susceptible to attack by base, as positions for which the value of the lowest-unoccupied molecular orbital (LUMO) is large. Use a LUMO map (the value of the LUMO mapped onto the electron density surface). Does this analysis correctly anticipate which of the anions obtained by deprotonation of 2-methylcyclohexanone is actually most stable Are any of the other ions of comparable stability, or are they aU much less stable ... 

LUMO map for 2-methylcyclohexanone reveals (in blue) acidic protons, susceptible to H/D exchange. 

Interesting results were also obtained on treatment of 2-amino-4,6,6-trimethyl-dihydropyrimidine 50 and 2,4,6,6-tetramethyldihydropyrimidine 51 with CD3OD in the absence of a base (91TL2057). It was shown that, under these conditions, the 4-methyl protons of 50, the 2,4-dimethyl protons of 51, and H(5) in 50 and 51 undergo H-D exchange. The suggested mechanism involves annular (1,4-dihydro 4,5-dihydro) as well as substituent tautomeric equilibria, as shown in Scheme 20 for H-D exchange in 50. 

These pentahydrides have attracted attention as catalysts for hydrogenation of the double bond in alkenes. IrH5(PPr3)2 catalyses vinylic H-D exchange between terminal alkenes and benzene, the isomerization of a,f3-ynones, isomerization of unsaturated alcohols and dehydrogenation of molecules such as secondary alcohols [176],... 

Gel chromatography Sedimentation studies H-D exchange Melting properties... 

If the diazonium acetate ion pair can lose a proton, it should also be possible to add a proton to the diazo-methylene compound 6.75. This hypothesis was checked experimentally by carrying out the indazole syntheses in the presence of D2S04. The result was not conclusive, as H/D exchange was observed to a small extent in two cases, but not in others. 

The experiment was carried out with (i )-(-)-2[l-(methoxycarbonyl)ethyl]benzene-diazonium chloride (6.80). The product, methyl 3-methyl-3-//-indazole-3-carboxylate (6.81), was racemic. With regard to the inconclusive H/D exchange experiments one therefore has to conclude that the cyclization of the diazo-methylene intermediate 6.75 is faster than the rate of deuterium incorporation. 

Stereochemical constraints in cyclic sulfones and sulfoxides impart increased weight to strain and conformational factors in the generation of carbanions and their stability, causing distinct differences between the behavior of cyclic and open-chain systems233, due primarily to the prevention of extensive rotation about the C —S bond, which is the major way that achiral carbanions racemize. Study of the a-H/D exchange rate fce and the racemization rate ka may provide information concerning the acidity-stereochemical relationships in optically active cyclic sulfone and sulfoxide systems. 

Of the studies which bear more particularly on electronic effects we mention first a study of the base-catalyzed H-D exchange in the 3-arylsulfonylbicyclo[2.2.1]hept-5-ene-2-carboxylic acids, cis (33), (35) and trans (34), and of the base-catalyzed inversion of the arylsulfonyl group in cis compounds (33) and (35)191. R comprised several meta- or para-... 

McDowell and Stirling194 studied electronic effects upon the reactivity of aryl vinyl sulfones towards amines. Rate constants for t-butylamine addition in ethanol at 25 °C were well correlated by the Hammett equation, with p = 1.59. Comparison of this with p values for H-D exchange mentioned above191 suggested considerable carbanionic character in the transition state, perhaps in a concerted mechanism. Rates of addition of amines to alkenyl, allenyl and alkynyl p-tolyl sulfones have also been measured195. 

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