Carbonyl centers

The hydration reaction has been extensively studied because it is the mechanistic prototype for many reactions at carbonyl centers that involve more complex molecules. For acetaldehyde, the half-life of the exchange reaction is on the order of one minute under neutral conditions but is considerably faster in acidic or basic media. The second-order rate constant for acid-catalyzed hydration of acetaldehyde is on the order of 500 M s . Acid catalysis involves either protonation or hydrogen bonding at the carbonyl oxygen. 

Hammett treatments show good correlations with large negative p values for the hydrolysis of acetals of aromatic aldehydes. This is consistent with the development of a positive charge at the carbonyl center in the rate-determining step. 

The mechanistic pattern established by study of hydration and alcohol addition reactions of ketones and aldehydes is followed in a number of other reactions of carbonyl compounds. Reactions at carbonyl centers usually involve a series of addition and elimination steps proceeding through tetrahedral intermediates. These steps can be either acid-catalyzed or base-catalyzed. The rate and products of the reaction are determined by the reactivity of these tetrahedral intermediates. 

Pyridine is more nucleophilic than an alcohol toward the carbonyl center of an acyl chloride. The product that results, an acylpyridinium ion, is, in turn, more reactive toward an alcohol than the original acyl chloride. The conditions required for nucleophilic catalysis therefore exist, and acylation of the alcohol by acyl chloride is faster in the presence of pyridine than in its absence. Among the evidence that supports this mechanism is spectroscopic observation of the acetylpyridinium ion. An even more effective catalyst is 4-dimeftiyIaminopyridine (DMAP), which functions in the same wsy but is more reactive because of the electron-donating dimethylamino substituent. ... 

Certain molecules that can permit concerted proton transfers are efficient catalysts for reactions at carbonyl centers. An example is the catalytic effect that 2-pyridone has on the aminolysis of esters. Although neither a strong base (pA aH+ = 0.75) nor a strong acid (pJsfa = 11.6), 2-pyridone is an effective catalyst of the reaction of -butylamine with 4-nitrophenyl acetate. The overall rate is more than 500 times greater when 2-pyridone acts... 

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. 

The reactions that are discussed in this section involve addition of carbon nucleophiles to carbonyl centers having a potential leaving group. The tetrahedral intermediate formed in the addition step reacts by expulsion of the leaving group. The overall... 

The mechanistic aspects of nucleophilic substitutions at saturated carbon and carbonyl centers were considered in Part A, Chapters 4 and 7, respectively. In this chapter we discuss some of the important synthetic transformations that involve these types of... 

Other bonds that merit attention are those connecting C(7) through C(ll). These could be formed by one of the many methods for the synthesis of ketones. Bond disconnections at carbonyl centers can involve the 0=C-C(a) (acylation, organometallic addition), the C(a)-C((3) bond (enolate alkylation, aldol addition), or C((3)-C(7) bond (conjugate addition to enone). 

The use of an anionic reagent for addition at carbonyl carbon rather than a fully esterified form of a trivalent phosphorus acid obviates a troublesome aspect of the Abramov reaction. Specifically no dealkylation step is required. Mechanistic investigations257 258 indicate that the reaction proceeds much as a simple "aldol"-type reaction in which the anionic phosphorus site adds directly to the carbonyl center. While the initial efforts concerned with the "Pudovik reaction"259 were directed toward the use of sodium salts of the simple dialkyl phosphites, as shown in Equation 3.17,260 266 with a, 5-unsaturated carbonyl systems (vide infra) competition between sites for addition can occur. Addition at the carbonyl carbon site is the kinetically favored route.267-270... 

A sterically hindered structure so that nucleophilic attack of this base on the carbonyl centers can be prevented. 

Another mode of carbon-based activation of hemiacetals relies on carbonyl-centered electrophiles 89 (Scheme 3.14). These reagents have demonstrated the highest efficiency for disaccharide synthesis among electrophilic carbon activating agents. In the event, the hemiacetal 1 is activated with electrophile 89 for in situ... 

During transformation from the neutral molecules to the corresponding anion-radicals, the rate of the fragment rotation, relative to one another, decreases. This also results in the nonequivalence of the meta and ortho protons. Thus, 3-acetylpyridine gives two different anion-radicals as conformational isomers (Cottrell and Rieger 1967). In the case of 3-benzoylpyridine anion-radical, the phenyl group rotates freely about the carbonyl center, whereas the rotation of the pyridyl group is limited. The ESR spectrum shows that the spin density in the phenyl ortho positions is half of that... 

As a rule, if the unpaired electron density in the anion-radical is redistributed, the rotation barrier decreases. Thus, the barrier of the phenyl rotation in the benzaldehyde anion-radical is equal to 92 kJ mol", whereas in the 4-nitrobenzaldehyde anion-radical, the barrier decreases to 35 kJ mor (Branca and Gamba 1983). Ion-pair formation enforces the reflux of the unpaired electron from the carbonyl center to the nitro group. Being enriched with spin density, the nitro group coordinates the alkali metal cation and fixes the unpaired electron to a greater degree. The electron moves away from the rotation center. The rotation barrier decreases. The effect was revealed for the anion-radical of 4-nitrobenzophenone and its ionic pairs with lithium, sodium, potassium, and cesium (Branca and Gamba 1983 Scheme 6.19). 

The reaction of 8 with oxygen (Scheme 1) leads to the bis-carbonyl-0-oxide 10 and can be seen either as a reaction of two carbene centers or as a reaction of two radical centers, giving a bis-peroxide. The IR and UV data suggest that there is little interaction between the two carbonyl centers via the linker. 

In the context of photoinduced [2 -I- 2] cycloadditions, the reaction of an olefin with a carbonyl center, known as the Patemo-Biichi reaction, has to be mentioned. The resulting oxetanes are thereby produced with high regioselectivity and stereoselectivity. 

In view of crystallographic studies on interactions between nucleophilic and carbonyl centers 37a b, it has been suggested that there is a displacement of the perpendicular reactant trajectory due to repulsive interactions between the electrophile LUMO and the enolate oxygen38 ... 

Aldos-2-uk>ses, which have foe ketonic function at C-2, undergo mercaptaladon under the usual conditions, to afford only l,l-(dialkyl dithioacetal) derivatives. The ketone function in these compounds is distinctly unreactive toward thiols in acidic medium, probably as a consequence of electronic and steric effects [42] (Scheme 11). Examples of l,2-bis(dialkyl dithioacetal) derivatives have been prepared by indirect methods [43]. Dialdoses, on the other hand, in which the two carbonyl groups are separated by the sugar backbone, readily undergo mercaptalation at both carbonyl centers to afford bis(dialkyl dithioacetal) derivatives [44]. 

Steven K. Davidsen, Gerald W. Phi 11ips, and Stephen F. Martin 119 GEMINAL ACYLATION-ALKYLATION AT A CARBONYL CENTER USING DIETHYL N-BENZYLIDENEAMINOMETHYLPHOSPHONATE PREPARATION OF 2-METHYL-2-PHENYL-4-PENTENAL... 

Another concise strategy for the synthesis of alkaloids related to crinine features the application of a general and useful procedure for the elaboration at a carbonyl center of a quaternary carbon atom bearing differentially functionalized alkyl substituents. The application of this methodology to the total syntheses of ( )-crinine (359) and ( )-buphanisine (361) (Scheme 46) commenced with the... 

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