Acylation isomer distribution

Olivier and Berger335, who measured the first-order rate coefficients for the aluminium chloride-catalysed reaction of 4-nitroben2yl chloride with excess aromatic (solvent) at 30 °C and obtained the rate coefficients (lO5/ ) PhCI, 1.40 PhH, 7.50 PhMe, 17.5. These results demonstrated the electrophilic nature of the reaction and also the unselective nature of the electrophile which has been confirmed many times since. That the electrophile in these reactions is not the simple and intuitively expected free carbonium ion was indicated by the observation by Calloway that the reactivity of alkyl halides was in the order RF > RC1 > RBr > RI, which is the reverse of that for acylation by acyl halides336. The low selectivity (and high steric hindrance) of the reaction was further demonstrated by Condon337 who measured the relative rates at 40 °C, by the competition method, of isopropylation of toluene and isopropylbenzene with propene catalyzed by boron trifluoride etherate (or aluminium chloride) these were as follows PhMe, 2.09 (1.10) PhEt, 1.73 (1.81) Ph-iPr, (1.69) Ph-tBu, 1.23 (1.40). The isomer distribution in the reactions337,338 yielded partial rate factors of 2.37 /mMe, 1.80 /pMe, 4.72 /, 0.35 / , 2.2 / Pr, 2.55337 339. 

Acyl chlorides were also tested in acylations promoted by B(OTf)3.231 Acylation of benzene and toluene in competitive reactions (molar ratio = 5 1) with acetyl chloride shows high para selectivity (92-95% with 2.5-7% of meta, kT/kB — 31-73), whereas the para isomer is formed only with 72-75% selectivity (8-10% of meta, k lkK = 78) in benzoylation with benzoyl chloride. Acetylation appears not to be affected by significant isomerization as indicated by isomer distributions and relative reactivity data. 

If the alkyl substituent is in position 3, the 2-position is the most favored from the electronic point of view, being ortho to the alkyl group and alpha to the heteroatom. The other a position (5) is, however, free from steric effects. Consequently, reactions of 3-alkyl thiophenes, -furans, and -pyrroles yield a mixture of 2- and 5-substituted isomers, the composition of which depends on the nature of the heteroatom, the electrophile, and the size of the alkyl group. Table XXI reports the isomer distribution in the acylation of 3-methyl-, 3-isopropyl-, and 3-i-butylthiophenes and shows the importance of the steric factor in determining the orientation. 

Acylating agent Overall yield (%) Isomer distribution (%) ortho meta para... 

In a detailed comparative kinetic study carried out with toluene and BAN, it is shown that the activity of pure Nation is about half of thaf of SZ. However, the isomer distribution is different the ortho/para acylation ratio is 0.25 for Nation, whereas it is 0.34 for SZP°... 

This acylation method is advantageous in terms of the mild conditions employed and the easy availability of acyl chlorides. While in the benzoylation of benzene with benzoyl chloride in the presence of hafnium triflate (5% mol) or triflic acid (5% mol) only 5-10% yields in benzophenone are obtained, with a combination of Lewis and protic acids (5% mol hafnium triflate and 5% mol triflic acid) benzophenone is isolated in 77% yield [18]. The yield is improved to 82% when hafnium triflate and triflic acid are used in higher quantities (10% mol each) a further increase of the catalyst amount does not improve the yield. Aromatic substrates such as benzene, toluene, chlorobenzene, and fluorobenzene react smoothly under these conditions with both aliphatic and aromatic acid chlorides, affording the corresponding / ara-arylketones 10 in 60-83% yield and 15 85-1 99 isomer distribution (Scheme 3.5). 

Alkylthio-5-alkylthiophens are chloromethylated at position 3 by chloromethyl methyl ether. 3-Methylthiothiophen has been nitrated at position 2. The influence of the reaction conditions on the isomer distribution in the acylation of 2-methoxy-, 2-methylthio-, and 2-dimethyl-amino-thiophen has been studied. Azo-coupling and aminomethylation occur at position 3 of some 4,5-disubstituted 2-acylaminothiophens. 3-Acetylamino-2-benzoylthiophen yields the 4,5-dichloro-derivative with sulphuryl chloride, while 3-acetylamino- or 3-benzoylamino-4-carbonyl-thiophen derivatives are chlorinated at position 2. ... 

The catalytic activity of hierarchical and conventional Beta zeolites for acylation of 2-MN is displayed in Figure 2(a) The Beta (PHAPTMS) sample shows a superior catalytic activity than the conventional one, due to its enhanced textural properties. In this case, the bulky nature of both substrate and products may cause the existence of diffusional problems inside the zeolitic channels, which are attenuated in the modified Beta sample due to the presence of the hierarchical porosity. Regarding the product distribution (Figure 2(b)), two main products are observed and a third isomer, 8-A,2-MN isomer is produced just in minor amounts. Interestingly, the selectivity towards the desired isomer increases in the material obtained from silanized seeds, reaching values around 75%. Probably, the active sites located on the surface of the secondary porosity are able to catalyze also the formation of 6-A,2-MN by transacylation. However, this reaction is expected to be strongly hindered in the conventional Beta zeolite since it requires the participation of two bulky molecules as reactants. 

Free radical acylation of pyridines generally results in predominant or exclusive formation of the 2- and 4-substituted isomers, and carbamoylation, carboxylation and halogenation show similar product distributions. In certain of these reactions, most notably carbamoylation, synthetically significant yields of substitution products can be realized, but in many cases while quoted yields can look impressive, actual conversions can be very low <74AHC(16)123>. 

Hay and Morrison (1971) later presented additional data on the fatty acid composition and structure of milk phosphatidylethanolamine and -choline. Additionally, phytanic acid was found only in the 1-position of the two phospholipids. The steric hindrance presented by the four methyl branches apparently prevents acylation at the 2-position. The fairly even distribution of monoenoic acids between the two positions is altered when the trans isomers are considered, as a marked asymmetry appears with 18 1 between the 1- and 2-positions of phosphatidylethanolamine, but not of phosphatidylcholine. Biologically, the trans isomers are apparently handled the same as the equivalent saturates because the latter have almost the same distribution. There are no appreciable differences in distribution of cis or trans positional isomers between positions 1 and 2 in either phospholipid. Another structural asymmetry observed is where cis, cis nonconjugated 18 2s are located mostly in the 2-position in both phospholipids. It appears that one or more trans double bonds in the 18 2s hinders the acylation of these acids to the 2-position. 

Q The Friedel-Crafts acylation of alkylated benzenes by [PhCO + ][SbF6-] (reaction 3.13) shows the following percentage distributions of isomers. As the number of methyl substituents on the ct-carbon atom is increased, the proportion of ortho isomer decreases. Is this likely to be an electronic or a steric effect ... 

The acylation of 2-MN with different anhydrides at low temperature (100°C) in the presence of the moderately protic acid MCM-41 mesoporous zeolite was studied. The selectivity toward 1-isomer 28 is practically 100% with the less bulky AAN (Scheme 4.20), whereas with the more bulky isobutyric anhydride, a small amount of 6-isomer is produced. At a higher temperature (-130°C), the reversibility of the acylation at the 1-position plays a fundamental role in the distribution of products, and a decrease in the selectivity for 1-position is observed. The catalyst can be recycled three times after each cycle, the catalyst is filtered, washed, dried, and reactivated by calcination for 2 d at 450°C, showing quite similar conversion (-40%) and selectivity (-97%) with respect to compound 28. 

Amides of the polyamine spermidine bearing aliphatic or hydroxycinnamic acyl residues are widely distributed in the plant kingdom (Bienz et al. 2002). In most cases the acyl moieties represent the latter residnes. For snch conjugates see Sect 6.6.4.3. A novel metabolite with an aUphatic acyl residue, A/ A/ -ditigloylspermi-dine, has been isolated from the seeds of Ipomoea nil (L.) Choisy collected on Zanzibar/Tanzania (Schimming et al. 2005). It turned out to dominate to an unusual extent in the alkaloid fraction beside seven minor congeners. Most of them were isomers of the main metabolite. All these metabolites were also present in unripe fruits and stems. However, they were not detectable in snch parts from another provenance (Ecnador) of this species (seeds not checked). 

The tin analog of (2) (M = Me3Sn) undergoes smooth coupling with various aryl bromides and acyl chlorides to produce 2-substituted allylsilanes (eq 8). Interestingly, the organozinc reagent (2) (M = ZnCl) has been shown to equilibrate to the allyl isomer (6) and react as such with electrophiles to produce vinylsilanes. However, it is possible in some cases to control the product distribution with the choice of catalyst (eq 9). ... 

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