Acid catalysis carbonyl reactions

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

The point was made earlier (Section 5 9) that alcohols require acid catalysis in order to undergo dehydration to alkenes Thus it may seem strange that aldol addition products can be dehydrated in base This is another example of the way in which the enhanced acidity of protons at the a carbon atom affects the reactions of carbonyl com pounds Elimination may take place in a concerted E2 fashion or it may be stepwise and proceed through an enolate ion... 

Zn/EtOAc or THF, reflux, 3-12 h, 40-100% yield. It is more efficient to prepare this ketal by an exchange reaction with the dimethyl or diethyl ketal than directly from the carbonyl compound. Hydrolysis can eilso be effected by acid catalysis. 

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. 

Stereoselectivity in the condensation reaction of 2-arylethylamines with carbonyl compounds to give 1,2,3,4-tetrahydroisoquinoline derivatives was somewhat dependent on whether acid catalysis or superacid catalysis was invoked. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed with trifluorosulfonic acid (TFSA) as compared with the weaker acid, trifluoroacetic acid (TFA). Compound 43 was cyclized in the presence of TFA to give modest to good transicis product ratios. The analogous compound 44 was cyclized in the presence of TFSA to give slightly improved transicis product ratios. 

The reaction can be performed with base catalysis as well as acid catalysis. The former is more common here the enolizable carbonyl compound 1 is depro-tonated at the a-carbon by base (e.g. alkali hydroxide) to give the enolate anion 5, which is stabilized by resonance ... 

Keto-enol tautomerism of carbon) ] compounds is catalyzed by both acids and bases. Acid catalysis occurs by protonation of the carbonyl oxygen atom to give an intermediate cation that Joses H+ from its a carbon to yield a neutral enol (Figure 22.1). This proton loss from the cation intermediate is similar to what occurs during an El reaction when a carbocation loses H+ to form an alkene (Section 11.10). 

Kishimoto et al. (1974, 1981) found a general acid catalysis by protonated pyridines in coupling reactions of the 1-naphthoxide ion if weakly electrophilic diazonium ions were used. In this case it is likely that the general acid protonates the carbonyl oxygen of the o-complex, with a concerted or stepwise deprotonation at the 4-position (transition stage 12.150). 

The limitations of the reaction have not been systematically investigated, but the inherent lability of the aziridines can be expected to become troublesome in the case of epoxyketones which are slow to form hydrazones. The use of acid catalysis is curtailed by the instability of the aziridines, particularly the diphcnylaziridine, in acidic media. Because of their solvolytic lability, the hydrazones are best formed in inert solvents. A procedure proven helpful in some cases is to mix the aziridine and the epoxyketone in anhydrous benzene, and then to remove the benzene on a rotary evaporator at room temperature. Water formed in the reaction is thus removed as the azeotrope. This process is repeated, if necessary, until no carbonyl band remains in the infrared spectrum of the residue. 

Dihydrothiopyrans have also been prepared by cycloaddition between a,jS-unsaturated thioketones and carbonyl-activated dienophiles under Lewis-acid catalysis [78]. A marked dependence of the reaction yield on the catalyst was observed. The results of the cycloaddition reaction of thioketone 77 with methyl metacrylate, catalyzed by different catalysts, are illustrated in Equation 3.24. 

Regioselectivities [7] and endo selectivity [8, 9] increase upon Lewis acid catalysis of Diels-Alder reactions (Scheme 9). Houk and Strozier [10] found that protonation on the carbonyl oxygen of acrolein amplifies the LUMO at the terminal and... 

It turned out that the Friedel-Crafts reaction and the chlorination can be done in the same pot. The vhlorination needs to be chemoselective as reaction on -.he methyl group or next to the carbonyl group could ccur. Lewis acid catalysis Is the answer. 

Carbonyl reactions are extremely important in chemistry and biochemistry, yet they are often given short shrift in textbooks on physical organic chemistry, partly because the subject was historically developed by the study of nucleophilic substitution at saturated carbon, and partly because carbonyl reactions are often more difhcult to study. They are generally reversible under usual conditions and involve complicated multistep mechanisms and general acid/base catalysis. In thinking about carbonyl reactions, 1 find it helpful to consider the carbonyl group as a (very) stabilized carbenium ion, with an O substituent. Then one can immediately draw on everything one has learned about carbenium ion reactivity and see that the reactivity order for carbonyl compounds ... 

Both these methods require equilibrium constants for the microscopic rate determining step, and a detailed mechanism for the reaction. The approaches can be illustrated by base and acid-catalyzed carbonyl hydration. For the base-catalyzed process, the most general mechanism is written as general base catalysis by hydroxide in the case of a relatively unreactive carbonyl compound, the proton transfer is probably complete at the transition state so that the reaction is in effect a simple addition of hydroxide. By MMT this is treated as a two-dimensional reaction proton transfer and C-0 bond formation, and requires two intrinsic barriers, for proton transfer and for C-0 bond formation. By NBT this is a three-dimensional reaction proton transfer, C-0 bond formation, and geometry change at carbon, and all three are taken as having no barrier. 

In 1991, Li and Chan reported the use of indium to mediate Barbier-Grignard-type reactions in water (Eq. 8.49).108 When the allylation was mediated by indium in water, the reaction went smoothly at room temperature without any promoter, whereas the use of zinc and tin usually requires acid catalysis, heat, or sonication. The mildness of the reaction conditions makes it possible to use the indium method to allylate a methyl ketone in the presence of an acid-sensitive acetal functional group (Eq. 8.50). Furthermore, the coupling of ethyl 2-(bromomethyl)acrylate with carbonyl compounds proceeds equally well under the same reaction conditions, giving ready access to various hydroxyl acids including, for example, sialic acids. 

The reaction can, however, be made preparative for (91) by a continuous distillation/siphoning process in a Soxhlet apparatus equilibrium is effected in hot propanone over solid Ba(OH)2 (as base catalyst), the equilibrium mixture [containing 2% (91)] is then siphoned off. This mixture is then distilled back on to the Ba(OH)2, but only propanone (b.p. 56°) will distil out, the 2% of 2-methyl-2-hydroxypentan-4-one ( diacetone alcohol , 91, b.p. 164°) being left behind. A second siphoning will add a further 2% equilibrium s worth of (91) to the first 2%, and more or less total conversion of (90) — (91) can thus ultimately be effected. These poor aldol reactions can, however, be accomplished very much more readily under acid catalysis. The acid promotes the formation of an ambient concentration of the enol form (93) of, for example, propanone (90), and this undergoes attack by the protonated form of a second molecule of carbonyl compound, a carbocation (94) ... 

It is difficult to effect attack on the carbonyl carbon atom of RC02H, (171), with nucleophiles of the general type Y , as they commonly remove proton instead, and the resultant RCO20 is then insusceptible to nucleophilic attack. Weaker nucleophiles of the form YH, e.g. ROH, do not suffer this inability, but their reactions with the relatively unreactive carbonyl carbon atom of RC02H are slow. The carbonyl character may be enhanced by protonation, however, i.e. by acid catalysis in, for example, esterification [(171) — (172)] ... 

In almost the same manner, tandem hydroformylation/aldol condensation aldol condensation of ketoolefins, such as p,y-unsaturated ketones, gives a single cyclization product under acid catalysis. Similar to the stepwise reaction, the in situ generated aldehyde preferentially acts as the electrophilic carbonyl component, while the ketone acts as the nucleophilic enol to form the five-membered ring product. Subsequent dehydration and hydrogenation of the resulting enone readily occurs under the reductive reaction conditions used (Scheme 30) [84],... 

Nitrosobenzenes react with the carbonyl group of aldehydes to yield hydroxamic acids 73, according to reaction 20. Recently, the reactions between some X-substituted nitrosobenzenes (X = H, p-Me, p-C 1, m-Cl, p-Br) and formaldehyde were reported194 in order to investigate the mechanism of the hydroxamic acid formation. The mechanism reported in Scheme 9 involves a first equilibrium yielding the zwitterionic intermediate 74 which rearranges (by acid catalysis) into hydroxamic acid 75. The presence of a general acid catalysis, the substituent effect (p values of the Hammett equation equal —1.74),... 

Lewis acid catalysis enormously enriches the scope of Diels-Alder reactions, but it is limited to reagents containing Lewis basic sites, i.e. functional groups with lone pairs such as carbonyl, amino, ether or nitro close to the reaction centre. As we have seen in the discussion about the FMO aspects of Lewis acids, the major reason for catalysis is the reduction of the HOMO-LUMO gap. In case of Diels-Alder reactions with normal electron demand, it follows that the coordination of the Lewis acid lowers the LUMO energy of the dienophile. Such interactions are only possible if there is a spatial proximity or an electronic conjugation between the coordinated Lewis basic site and the reaction centre. Fortunately, in nearly every Diels-Alder reaction one of the reagents, mostly the dienophile, meets this requirement. 

Another example of the use of Lewis acids in organic reactions in water is the lan-thanide(III) triflate catalysed aza-Diels-Alder reaction, exemplified in Scheme 14. In this reaction the hetero-dienophile is formed in situ from a primary ammonium hydrochloride and a carbonyl compound followed by the actual Diels-Alder reaction288,289. This type of reaction proceeds readily in aqueous media290-296, and a dramatic increase in the yield upon addition of lanthanide triflates was observed288,289. The exact role of the catalyst, however, is not entirely clear. Although it was suggested that the catalyst binds to the dienophile, other mechanisms, such as simple proton catalysis, are also plausible. Moreover, these reactions are further complicated since they are often heterogeneous. 

The term acid catalysis is often taken to mean proton catalysis ( specific acid catalysis ) in contrast to general acid catalysis. In this sense, acid-catalyzed hydrolysis begins with protonation of the carbonyl O-atom, which renders the carbonyl C-atom more susceptible to nucleophilic attack. The reaction continues as depicted in Fig. 7. l.a (Pathway a) with hydration of the car-bonium ion to form a tetrahedral intermediate. This is followed by acyl cleavage (heterolytic cleavage of the acyl-0 bond). Pathway b presents an mechanism that can be observed in the presence of concentrated inorganic acids, but which appears irrelevant to hydrolysis under physiological conditions. The same is true for another mechanism of alkyl cleavage not shown in Fig. 7.Fa. All mechanisms of proton-catalyzed ester hydrolysis are reversible. 

General acid catalysis is schematized in Fig. 7J,b. Here, an acid A-H increases the polarity of the carbonyl group and, hence, the electrophilicity of the carbonyl C-atom. For entropy reasons, the reaction is greatly facilitated when it is an intramolecular one (Fig. 7J,b2), in other words, when the general acid catalyst is favorably positioned within the molecule itself. Such a mechanism is the one exploited and refined by nature during the evolution of the hydrolases, with the general acid catalyst and the H20 molecule replaced by adequate amino acid side chains, and the enzymatic transition state being de facto a supermolecule (see Chapt. 3). 

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