C-H acidity

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... 

As a result of the 7r-deficiency of the pteridine nucleus, alkyl pteridines are activated in the a-positions. The common reactions based on C—H acidity are found with a wide variety of compounds. Bromination of 6- and 7-methyl groups leads to mono- and di-substitution selective formation of the monobromomethyl derivatives has not yet been achieved satisfactorily. 6-Methylisoxanthopterin is claimed to give the 6-bromomethyl derivative with bromine in acetic and sulfuric acids at 100 °C for 2 min (50ZN(B)132) and with 1,7-dimethyl-lumazine a 90% yield of the 7-bromomethyl derivative (60CB2668) is obtained after 4h... 

Properties of Fluorinated Compounds Table 13. Equilibrium C-H Acidities [6S, 66]... 

The effects of fluonnation on carbanion stability are largely deduced from C-H acidity data (p. 988) [64], a-Halogens stabilize carbanions in the order Br > Cl > F, which IS opposite the inductive electron-withdrawing order and reflects the... 

Several long-lived perfluorocarbanions have been observed in solution [137 138], and many stable salts such as 9, 10 [137, 139], 11 [137], 12 [137], and 13 [140] have been isolated Notably no long-hved a-fluorocarbanion has been detected, which is consistent with the order of amon stability, (Rf)3CF (Rf)2CF RfCp2, deduced from C-H acidities... 

Elimination of hydrogen halides from polyfluoroalkanes by bases also usually involves earbanion intermediates (ElcB mechanism) [<8/l, and orientation is there tore governed by relative C H acidities and leaving group mobility Some examples are shown in equations 16-18 [145]... 

Rochester, C.H. Acidity Functions , Academic Press London, 1970. 

The diazo coupling with C—H acidic aliphatic substrates is a feature of the Japp-Klingemann reaction. 

Due to the high a-C,H acidity in the alkoxyethylidene complexes 6 (e.g.,piCa=8 (R=Me)) [ 16], transformations via an enolate analog are possible and have been used to introduce additional functionality into the carbene side chain to access various Fischer carbene complexes [3]. The a,/J-unsaturated complex 8 could be obtained from 6 (R=Et) by an aldol-type condensation with benzaldehyde 7 in the presence of triethylamine and trimethylsilyl chloride (Scheme 2) [17]. This reaction proceeds completely diastereoselectively to yield only the trans-isomer. Analogously, binuclear complexes have been prepared from 6 and 1,3-and 1,4-phthaldialdehyde in good yields [17]. This type of condensation has... 

Several cyditol derivatives of varying ring size, for example, (69)/(70), have been prepared based on an enzymatic aldolization as the initial step. Substrates carrying suitably installed C,H-acidic functional groups such as nitro, ester, phosphonate (or halogen) functionalities made use of facile intramolecular nucleophilic (or radical) cyclization reactions ensuing, or subsequent to, the enzyme-catalyzed aldol addition (Figure 10.27) [134—137]. 

Rochester, C.H. Acidity Functions Academic Press NY, 1970. For discussion of the basicity of such compounds, see Liler, M. Reaction Mechanisms in Sulfuric Acid Academic Press NY, 1971, p. 118. 

C-H acidic compounds do not possess any basic properties. But they can form anions in the presence of strong bases, and these possess sufficiently strong nucleophilic properties to be able to add to a polarized carbonyl group. Examples are listed in Table 6. 

Table 6 Reaction of carbonyl compounds (aldehydes, ketones) with C-H acidic compounds, a selection.

As was shown for the mechanism of quinocyclopropene formation in acetic anhydride75 (see p. 20), acylation of the cyclopropenone is reasonable for the primary reaction step, then the O-acyl-cyclopropenium ion 74 forms methylene cyclopropene 73 through addition of the anion of the C-H acidic component and elimination of acetic acid. 

A study of the reactions of butadiene, isoprene, or allene coordinated to nickel in a metallacycle, with carbonylic compounds, has been reported by Baker (example 11, Table IV). In the presence of phosphines, these metallacycles adopt a cr-allyl structure on one end and a ir-allyl structure on the other, as mentioned in Section II,A,1. The former is mainly attacked by aldehydes or electrophilic reagents in general, the latter by nucleophiles (C—H acids, see Table I, or amines, see Table IX). 

Deprotonation of very weakly acidic C—H acids is accomplished by metallation with organolithium and organosodium compounds. 

Finally, the synthesis of allenyl ketones is also possible by carbonylation if carbonates 103 are treated with C-H acidic compounds 104 such as /3-diketones or derivatives of malonic ester to yield products of type 105 [143],... 

The attack of carbon nucleophiles such as Grignard reagents [116, 235, 236], cuprates [183, 237-242] and C-H acidic compounds [212] on allenes 155 leads generally to the non-conjugated products 158. However, it was observed early that 158 is the product of a kinetically controlled reaction also in these cases, whereas the thermodynamically more stable product 159 is formed at longer reaction times or subse-... 

The heterocycles 205 are accessible by addition of the reagents NuH2, acting as double nucleophiles, to the diallenes 204 [104]. Compound 206 can also be prepared by this method and C,H-acidic compounds can serve as double nucleophiles as well. 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

For synthetic purposes, crown ethers have been used frequently as phase-transfer catalysts under conditions where the sodium or potassium hydroxide is present as a concentrated aqueous solution. Various anions of C—H acids have been generated this way (Makosza and Ludwikow, 1974). The use of such conditions for the generation of carbenes will be dicussed in a separate section. 

NO2 may also feature as a substituent influencing C—H acidity from a more remote site. Thus for ring substitution in the series PhCH(N02)2, the pKa values for the m- and p-nitro compounds are 2.82 and 2.63, respectively, compared with 3.89 for the unsubstituted compound (values in water, 20 °C). The p value for this reaction series is about 1.7, and these results for m- and p-N(>2 appear to indicate that ordinary Hammett 0 values are applicable, whereas o values might have been expected to be more relevant. Presumably this means that the delocalization of the negative charge in the carbanion is dominated by the (N02)2 groups, so that delocalization into the ring plays a minor role. 

Attempts at correlation analysis for X—C—H acidity have been made for a long time. Bowden and colleagues192 examined the problem in 1970 for the pKa values of 9-X-fluorenes and related series. For a limited selection of substituents X in 9-X-fluorenes, a correlation with Taft s a values for X was found89. A more general correlation, albeit with considerable scatter, was found with AM, a parameter based on LCAO-MO calculations. Several dinitro-substituted diphenylmethanes fitted the line quite well and 2-nitrofluorene fitted passably 9-cyanofluorene also fitted quite well, but malononitrile deviated strongly. 

In recent years Pagani and coworkers have made detailed studies of the problem. In the space available we can only outline their work and interested readers should consult the very detailed papers. The authors have developed special scales of substituent constants for dealing with contiguous functionalities 193. These new substituent constants are a (which seems to be related fairly closely to the ordinary a ), aIB (which bears some relationship to o/, but not that close), and (Tr-, a special delocalization parameter. It is claimed194 that these scales are appropriate for describing interactions between contiguous functionalities, as opposed to literature values which account for remote interactions . Various C—H acidities in gas phase and in solution were successfully correlated by means of multiple regressions on am and chemical shifts for the central carbon in the carbanions. 

It is particularly interesting, that some titanium and tantalum carbene complexes olefinate derivatives of carboxylic acids. These reagents are, moreover, much less basic than phosphorus ylides, and thus enable the olefination of strongly C-H acidic carbonyl compounds. 

---