Steric effects carbonyls

This approach to carbonyl protection uses the relative differences in the basicity and the differences in steric effects to protect selectively either the more basic... 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

Protecting groups are generally formed by nucleophilic attack on the carbonyl group and the rate of this process is determined by steric and electronic factors associated with the ketone. In steroid ketones steric effects are usually more important due to the rigid tetracychc skeleton. 

The most common method of epoxidation is the reaction of olefins with per-acids. For over twenty years, perbenzoic acid and monoperphthalic acid have been the most frequently used reagents. Recently, m-chloroperbenzoic acid has proved to be an equally efficient reagent which is commercially available (Aldrich Chemicals). The general electrophilic addition mechanism of the peracid-olefin reaction is currently believed to involve either an intra-molecularly bonded spiro species (1) or a 1,3-dipolar adduct of a carbonyl oxide, cf. (2). The electrophilic addition reaction is sensitive to steric effects. 

Hydrolysis of an enamine yields a carbonyl compound and a secondary amine. Only a few rate constants are mentioned in the literature. The rate of hydrolysis of l-(jS-styryl)piperidine and l-(l-hexenyl)piperidine have been determined in 95% ethanol at 20°C 13). The values for the first-order rate constants are 4 x 10 sec and approximately 10 sec , respectively. Apart from steric effects the difference in rate may be interpreted in terms of resonance stabilization by the phenyl group on the vinyl amine structure, thus lowering the nucleophilic reactivity of the /3-carbon atom of that enamine. 

Because of the frequent mutual interference of electronic, inductive, and steric effects, and because of the influence of ring strain, the carbonyl stretching frequency is naturally not an absolute criterion for the methylation course. The heterocyclic systems in question are too diverse for this to hold. Careful inspection of Table I discloses certain deviations from the relationships mentioned. These deviations will now be discussed. 

Thus, various kmds of bases are effective in inducing the Henry reaction The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes v/ith aldehydes, as summarized in Table 3 1 In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired ni tro-aldol products in good yield In such cases, self-condensation of the carbonyl compound is a serious side-reaction Several mochfied procedures for the Henry reaction have been developed... 

It reveals that either the steric effect of the bulky N-substituent on the interaction of Ce(IV) ion and urea reductant, or the electron withdrawing effect of the vinyl group, will reduce the coordination of Ce(lV) ion with the carbonyl group, thus resulting in a decrease of the Rp. 

Polk et al. reported27 that PET fibers could be hydrolyzed with 5% aqueous sodium hydroxide at 80°C in the presence of trioctylmethylammonium bromide in 60 min to obtain terephthalic acid in 93% yield. The results of catalytic depolymerization of PET without agitation are listed in Table 10.1. The results of catalytic depolymerization of PET with agitation are listed in Table 10.2. As expected, agitation shortened the time required for 100% conversion. Results (Table 10.1) for the quaternary salts with a halide counterion were promising. Phenyltrimethylammonium chloride (PTMAC) was chosen to ascertain whether steric effects would hinder catalytic activity. Bulky alkyl groups of the quaternary ammonium compounds were expected to hinder close approach of the catalyst to the somewhat hidden carbonyl groups of the fiber structure. The results indicate that steric hindrance is not a problem for PET hydrolysis under this set of conditions since the depolymerization results were substantially lower for PTMAC than for die more sterically hindered quaternary salts. 

The carbonyl stretching frequencies in the ir spectra of cis-3-substituted methyl acrylates (set 12-18) were also correlated with eq. (24) and eq. (2). Barely significant correlations were obtained with both equations. The value of i// obtained in the correlation with eq. (24) was not significant. We may therefore probably exclude cases (a) and (b). As the hcaic is not significantly different from hobs > we may exclude case (c). This set is therefore probably an example of case (d) that is, there is no meaningful steric effect. 

In this chapter, the definitions used by Perrin in his book on pA a prediction (which also includes a very convenient compilation of o values) will be used. One must be alert to the importance of the number of hydrogens directly attached to the carbonyl carbon several groups have pointed out that aldehydes and ketones give separate but parallel lines, with formaldehyde displaced by the same amount again. What this means is that given one equilibrium constant for an aldehyde (or ketone) one may estimate the equilibrium constant for other aldehydes (or ketones) from this value and p for the addition using a value from experiment, if available, or estimated if necessary. This assumes that there is no large difference in steric effects between the reference compound and the unknown of interest. 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

Entry 4 has siloxy substituents in both the (titanium) enolate and the aldehyde. The TBDPSO group in the aldehyde is in the large Felkin position, that is, perpendicular to the carbonyl group.121 The TBDMS group in the enolate is nonchelated but exerts a steric effect that governs facial selectivity.122 In this particular case, the two effects are matched and a single stereoisomer is observed. 

The stereoselectivity of the Wittig reaction is believed to be the result of steric effects that develop as the ylide and carbonyl compound approach one another. The three phenyl substituents on phosphorus impose large steric demands that govern the formation of the diastereomeric adducts.240 Reactions of unstabilized phosphoranes are believed to proceed through an early TS, and steric factors usually make these reactions selective for the d.v-alkcnc.241 Ultimately, however, the precise stereoselectivity is dependent on a number of variables, including reactant structure, the base used for ylide formation, the presence of other ions, solvent, and temperature.242... 

An alternative interpretation is that the carbonyl group rr-antibonding orbital, which acts as the LUMO in the reaction, has a greater density on the axial face.118 At the present time the importance of such orbital effects is not entirely clear. Most of the stereoselectivities that have been reported can be reconciled with torsional and steric effects being dominant.119... 

Grignard additions are sensitive to steric effects and with hindered ketones a competing process leading to reduction of the carbonyl group can occur. A cyclic TS is involved. 

Synclinal and antiperiplanar conformations of the TS are possible. The two TSs are believed to be close in energy and either may be involved in individual systems. An electronic tt interaction between the stannane HOMO and the carbonyl LUMO, as well as polar effects appear to favor the synclinal TS and can overcome the unfavorable steric effects.161bi 162 Generally the synclinal TS seems to be preferred for intramolecular reactions. The steric effects that favor the antiperiplanar TS are not present in intramolecular reactions, since the aldehyde and the stannane substituents are then part of the intramolecular linkage. 

The best carbonyl components for these reactions are highly electrophilic compounds such as glyocylate, pyruvate, and oxomalonate esters, as well as chlorinated and fluorinated aldehydes. Most synthetic applications of the carbonyl-ene reaction utilize Lewis acids. Although such reactions may be stepwise in character, the stereochemical outcome is often consistent with a cyclic TS. It was found, for example, that steric effects of trimethylsilyl groups provide a strong stereochemical influence.28... 

In 3, the amino functional group is two methylene units removed from the ferrocene nucleus. It appears from the instantaneous and quantitative formation of h from 3 that this feature minimizes steric effects and also enables 3 to undergo the Schotten-Baumann reaction readily without the classical a-metallocenylcarbenium ion effects providing any constraints. The IR spectrum of showed the characteristic N-H stretch at 3320 cm" (s), the amide 1 (carbonyl) stretch at 1625 an - -(s), the amide II (N—H) stretch at 1540 cm (s), and the amide III band at 1310 cm 1(m). In addition, characteristic absorptions of the ferrocenyl group were evident at 1100 and 1000 cm l (indicating an unsubstituted cyclopentadienyl ring) and at 800 cm"l. 

The catalyzed hydrogenation of an aldehyde- vs. a ketone-carbonyl is invariably faster because of steric effects (23), and the data for 6 vs. 10 are in line with this (eqs. 4 and 5). Thus, conversions of 6a-c after 0.5 h at standard conditions are 86, 47, and 97%, respectively, while corresponding values for lOa-c after 4 h are 78, 36 and 49%, respectively. Indeed, the aldehydes can be reduced at 25 °C under otherwise identical conditions (6b gives 38% conversion after 4 h, and 6c gives 99% after 15 h). The above reactivity trend for the ketones lOa-c shows that the hydrogenation rates depend on the substituent para to the carbonyl functionality and increase in the order H > OMe > OH. For the aldehyde susbtrates, the more limited data (substrate 6 with R = H and R = OMe was not available) suggest a similar para-substitucnt effect (at least OMe > OH). Note that this is the reverse trend to that observed for reduction of the activated C=C systems described above. 

The combined influences of polar and steric effects and of the strength of the newly formed bond93 was also recognized in the reaction of a,0-unsaturated carbonyl compounds and similar electron deficient alkenes95 with organomercurials and NaBH4. For the addition of alkyl radicals to substituted styrenes, p assumed a... 

So far as steric effects are concerned, the least energy-demanding direction of approach by the nucleophile to the carbonyl carbon atom will be from above, or below, the substantially planar carbonyl compound. It is also likely to be from slightly to the rear of the carbon atom (cf. 12), because of potential coulombic repulsion between the approaching nucleophile and the high electron density at the carbonyl oxygen atom ... 

The complex ds-[RhI(CO)(Ph2PCH2P(S)Ph2)] (9) is eight times more active than (1) for the carbonylation of methanol at 185 °C the X-ray crystal structure of the analogous complex with chloride in place of iodide was reported together with in situ spectroscopic evidence in the catalytic cycle.16 A more detailed study of (9) showed that indeed oxidative addition is faster, but that in this instance due to a steric effect the migratory insertion was also accelerated.17... 

Several modifications have been made to organoaluminum-based catalysts. Methylaluminum bis(2,6-di-tert-butyl-4-alkylphenoxide) (MAD) shows high diastereofacial selectivity in carbonyl alkylation (Scheme 72).31 11 Aluminum tris(2,6-diphenylphenoxide) (ATPH) has been developed as a catalyst for conjugate addition reactions. Since a carbonyl group is stabilized by steric effect of ATPH, the 1,4-adduct is obtained selectively.312... 

The induction of steric effects by the pore walls was first demonstrated with heterogeneous catalysts, prepared from metal carbonyl clusters such as Rh6(CO)16, Ru3(CO)12, or Ir4(CO)12, which were synthesized in situ after a cation exchange process under CO in the large pores of zeolites such as HY, NaY, or 13X.25,26 The zeolite-entrapped carbonyl clusters are stable towards oxidation-reduction cycles this is in sharp contrast to the behavior of the same clusters supported on non-porous inorganic oxides. At high temperatures these metal carbonyl clusters aggregate to small metal particles, whose size is restricted by the dimensions of the zeolitic framework. Moreover, for a number of reactions, the size of the pores controls the size of the products formed thus a higher selectivity to the lower hydrocarbons has been reported for the Fischer Tropsch reaction. 

Although some copper carbonyls were known before, the first crystallographic characterization of one of these compounds was carried out in 1973 with TpCu(CO). Similar complexes have been reported to date, particularly in the last decade, since the GO ligand can be used as a probe to estimate electronic and also, to some extent, steric effects of the Tpx ligand. The related trispyrazolylmethane group has also been employed to yield the... 

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