Methanol, addition reactions

As would be anticipated, the unsubstituted vinylidene species [(i75-C5H5)(PPh3)2Ru=C=CH2]+ (84) is correspondingly more reactive than the monosubstituted complexes. In fact, the reaction of ethyne with 1 in methanol at room temperature affords only the methoxycarbene 85, the methanol addition reaction being so rapid that isolation of the unsubstituted vinylidene 84 is impossible [Eq. (81)] (78). As the alcohol must... 

For case study B.4, a bulk lot sample of drug substance contained an unknown Impurity A present at 0.82% and an unknown Impurity B present at 1.12%. Identification of both impurities was requested within a 1-month time frame. It was confirmed that the impurities did not match any known standards. LC/MS data indicated that Impurity A had a molecular weight of M+60, suggesting propanol addition, and Impurity B had a molecular weight of M+32, suggesting methanol addition. The next step was to look into the synthesis to find possible propanol and methanol addition reactions. In this investigative step, it was found that the reagent 2-propanol was utilized in step 11 of the process synthetic route. 

Quinone Methides. The reaction between aldehydes and alkylphenols can also be base-cataly2ed. Under mild conditions, 2,6-DTBP reacts with formaldehyde in the presence of a base to produce the methylol derivative (22) which reacts further with base to eliminate a molecule of water and form a reactive intermediate, the quinone methide (23). Quinone methides undergo a broad array of transformations by way of addition reactions. These molecules ate conjugated homologues of vinyl ketones, but are more reactive because of the driving force associated with rearomatization after addition. An example of this type of addition is between the quinone methide and methanol to produce the substituted ben2yl methyl ether (24). 

The reaction course taken by photoexcited cycloalkenes in hydroxylic solvents depends on ring size. 1-Methylcyclohexene, 1-methylcycloheptene, and 1-methylcyclooc-tene all add methanol, but neither 1-methylcyclopentene nor norbomene does so. The key intermediate in the addition reactions is believed to be the highly reactive -isomer of the cycloalkene. 

Diels and Meyer found that the exothermic reaction obtained on dropping pyridine into dimethyl acetylenedicarboxylate in methanol gave a mixture of the indolizine (108) and a methoxymethylindolizine formulated as (109), and some dimethyl fumarate and dimethyl methoxyfumarate. Later workers - obtained only the methoxymethylindolizine in rather poor yield. The indolizine (108) has also been isolated from the products obtained when the addition reaction was carried out in ether, but in this case the course of the reaction was very susceptible to the presence of impurities in the ether, and the results indicated that ethanol was necessary as a reactant. ... 

Depending on the electronic state of azafulvalene and the reaction conditions, simple nucleophiles such as amines or alcohols show a different behavior. Upon heating methanol reacted with azafulvalenes as electron-rich olefins by addition to the central double bond (64BSF2857 67LA155). Using the TAF 77 (Ar = Ph), the addition reaction in a neutral benzene-ethanol solution required several days to obtain a minor amount of 147, while the reaction proceeded rapidly in the presence of a catalytic amount of potassium hydroxide (79JOC1241). Tlie yellow-colored adduct 147 can be reconverted to the quinoid starting material by irradiation (Scheme 58). 

The reaction between isobutylene and methyl and ethyl alcohols is an addition reaction catalyzed by a heterogeneous sulfonated polystyrene resin. When methanol is used a 98% yield of methyl-ter-butyl ether MTBE is obtained ... 

The highly electrophilic character of the POf ion would suggest a very unselective phosphorylation behavior. For example, the ratio of alkyl phosphate to inorganic phosphate obtained in hydrolyses of phosphoric esters in water/alcohol mixtures should reflect the molar ratio of water and alcohol. This is indeed found in numerous cases, e.g. in the hydrolysis of phenyl and 4-nitrophenyl phosphate monoanions 97) or of 4-nitrophenyl phosphate dianions 65) at 100 °C in methanol/ water mixtures of various compositions, as also in the solvolysis of the acetyl phosphate dianion at 37 °C 97) or of phosphoenol pyruvate monoanions 82). Calculations of the free energy of the addition reactions of water and ethanol to the POf ion support the energetic similarity of the two reactions 98) (Table 4). 

The dependence of relative rates in radical addition reactions on the nucleophilicity of the attacking radical has also been demonstrated by Minisci and coworkers (Table 7)17. The evaluation of relative rate constants was in this case based on the product analysis in reactions, in which substituted alkyl radicals were first generated by oxidative decomposition of diacyl peroxides, then added to a mixture of two alkenes, one of them the diene. The final products were obtained by oxidation of the intermediate allyl radicals to cations which were trapped with methanol. The data for the acrylonitrile-butadiene... 

Using a protocol for tandem carbonylation and cycloisomerization, Mandai et al.83 were able to synthesize cyclopentene and cyclohexene derivatives in high yield, including fused and 5/>/>0-bicycles (Scheme 25). The cyclohexene Alder-ene products were not isolable methanol addition across the exocyclic double bond (in MeOH/ toluene solvent) and olefin migration (in BuOH/toluene solvent) were observed. The mechanism of methanol addition under the mild reaction conditions is unknown. In contrast to many of the other Pd conditions developed for the Alder-ene reaction, Mandai found phosphine ligands essential additionally, bidentate ligands were more effective than triphenylphosphine. 

The attack of the nucleophile on the acceptor-substituted allene usually happens at the central sp-hybridized carbon atom. This holds true also if no nucleophilic addition but a nucleophilic substitution in terms of an SN2 reaction such as 181 — 182 occurs (Scheme 7.30) [245]. The addition of ethanol to the allene 183 is an exception [157]. In this case, the allene not only bears an acceptor but shows also the substructure of a vinyl ether. A change in the regioselectivity of the addition of nucleophilic compounds NuH to allenic esters can be effected by temporary introduction of a triphenylphosphonium group [246]. For instance, the ester 185 yields the phos-phonium salt 186, which may be converted further to the ether 187. Evidently, the triphenylphosphonium group induces an electrophilic character at the terminal carbon atom of 186 and this is used to produce 187, which is formally an abnormal product of the addition of methanol to the allene 185. This method of umpolung is also applicable to nucleophilic addition reactions to allenyl ketones in a modified procedure [246, 247]. 

The addition of bromide ion (Table 44) greatly retards the addition reaction in both methanol and acetic acid by making the kx step more reversible... 

Disubstituted alkynes and terminal alkynes form E-dibromoalkenes [4] when the tribromide is formed in situ in an essentially basic medium, an addition reaction followed by elimination of hydrogen bromide results in the conversion of terminal alkynes into the 1-bromoalkynes [5]. When the addition reaction is conducted in methanol, l,l-dibromo-2,2-dimethoxyalkanes are produced, in addition to the 1,2-dibromoalkenes [6], The dimethoxy compounds probably result from the initial intermediate formation of bromomethoxyalkenes. Under similar conditions, alkenes yield methoxy bromo compounds [7]. 

The water-soluble palladium complex prepared from [Pd(MeCN)4](Bp4)2 and tetrasulfonated DPPP (34, n=3, m=0) catalyzed the copolymerization of CO and ethene in neutral aqueous solutions with much lower activity [21 g copolymer (g Pd) h ] [53] than the organosoluble analogue in methanol. Addition of strong Brpnsted acids with weakly coordinating anions substantially accelerated the reaction, and with a catalyst obtained from the same ligand and from [Pd(OTs)2(MeCN)2] but in the presence of p-toluenesulfonic acid (TsOH) 4 kg copolymer was produced per g Pd in one hour [54-56] (Scheme 7.16). Other tetrasulfonated diphosphines (34, n=2, 4 or 5, m=0) were also tried in place of the DPPP derivative, but only the sulfonated DPPB (n=4) gave a catalyst with considerably higher activity [56], Albeit with lower productivity, these Pd-complexes also catalyze the CO/ethene/propene terpolymerization. 

---