Proton transfer ketone/aldehyde

The aldehyde or ketone is called the keto form and the keto enol equilibration referred to as keto-enol isomerism or keto-enol tautomerism Tautomers are constitu tional isomers that equilibrate by migration of an atom or group and their equilibration IS called tautomerism The mechanism of keto-enol isomerism involves the sequence of proton transfers shown m Figure 9 6... 

Enols are related to an aldehyde or a ketone by a proton transfer equilibrium known as keto-enol tautomerism (Tautomensm refers to an mterconversion between two struc tures that differ by the placement of an atom or a group)... 

O Nucleophilic addition of a secondary amine to the ketone or aldehyde, followed by proton transfer from nitrogen to oxygen, yields an intermediate carbinolamine in the normal way. 

Step 1 of Figure 29.14 Transimination The first step in transamination is trans-imination—the reaction of the PLP—enzyme imine with an a-amino acid to give a PLP—amino acid imine plus expelled enzyme as the leaving group. The reaction occurs by nucleophilic addition of the amino acid -NH2 group to the C=N bond of the PLP imine, much as an amine adds to the C=0 bond of a ketone or aldehyde in a nucleophilic addition reaction (Section 19.8). The pro-tonated diamine intermediate undergoes a proton transfer and expels the lysine amino group in the enzyme to complete the step. 

Attack by eCN is slow (rate-limiting), while proton transfer from HCN or a protic solvent, e.g. HzO, is rapid. The effect of the structure of the carbonyl compound on the position of equilibrium in cyanohydrin formation has already been referred to (p. 206) it is a preparative proposition with aldehydes, and with simple aliphatic and cyclic ketones, but is poor for ArCOR, and does not take place at all with ArCOAr. With ArCHO the benzoin reaction (p. 231) may compete with cyanohydrin formation with C=C—C=0, 1,4-addition may compete (cf. p. 200). 

Proton transfer reactions are often the first step in many reactions that alcohols, ethers, aldehydes, ketones, esters, amides, and carboxylic acids undergo. 

Despite a very unfavorable proton transfer using (35) as an EGB, condensation of acetophenone with an aromatic aldehyde took place within a matter of hours. The reaction led to Q , 8-unsaturated ketones, which underwent the Michael addition with a second equivalent of deprotonated ketone. Scheme 30, [80, 81]. The EGB was generated ex situ. 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

Singlet excited state acid dissociation constants pK can be smaller or greater than the ground state constant pK by as much as 8 units. Phenols, thiols and aromatic amines are stronger acids upon excitation, whereas carboxylic acids, aldehydes and ketones with lowest >(71, ) states become much more basic. Triplet state constants pKr are closer to those for the ground state. Forster s cycle may be used to determine A pK =pK —pK) from fluorescence measurements if proton transfer occurs within the lifetime of the excited molecule. 

Tradition reserves the use of the name acid for substances that transfer protons measurably to water. Thus the carboxylic acids stand out from alkynes, halides, alcohols, and simple aldehydes and ketones in giving water solutions that are acidic to indicator papers or pH meters as the result of proton transfers from the carboxyl groups ... 

There are certain difficulties in achieving this type of aldol reaction. First, alkali-induced ester hydrolysis would compete with addition. Second, a Claisen condensation of the ester might intervene, and third, the ester anion is a stronger base than the enolate anions of either aldehydes or ketones, which means reaction could be defeated by proton transfer of the type... 

A crossed Claisen is die reaction of an ester enolate with an aldehyde or ketone to produce a /3-hydroxy ester. This works well because aldehydes and ketones are more reactive electrophiles than esters thus the ester enolate reacts faster with die aldehyde or ketone than it condenses with itself, avoiding product mixtures. Moreover, die aldehyde or ketone should not have a hydrogens so that proton transfer to die more basic ester enolate is avoided. This would lead to the formation of an aldehyde or ketone enolate in the mixture, and an aldol reaction would be a major competing reaction. 

As for the peroxidases, Compound I and water are formed in the first step from one equivalent of hydrogen peroxide and the resting state of the catalase. The back-reaction, however, does not proceed via Compound II but rather via a two-electron-two-proton transfer cascade, in which both hydrogen atoms of a second molecule of hydrogen peroxide are transferred to the ferryl subunit of the porphyrin cofactor. Due to the similarity of catalases and peroxidases, it is not too surprising that this reaction is also catalyzed by most peroxidases. Alternatively, catalases and some peroxidases react with alkyl hydroperoxides via the respective alkanol to an aldehyde or ketone (Scheme 2.17). A requirement for this reaction is an easily accessible active site for the hydroperoxide, so that only those peroxidases with open access such as CPO or CiP are able to promote this reaction. 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

Under conditions of kinetic control, the mixed Aldol Addition can be used to prepare adducts that are otherwise difficult to obtain selectively. This process begins with the irreversible generation of the kinetic enolate, e.g. by employing a sterically hindered lithium amide base such as LDA (lithium diisopropylamide). With an unsymmetrically substituted ketone, such a non-nucleophilic, sterically-demanding, strong base will abstract a proton from the least hindered side. Proton transfer is avoided with lithium enolates at low temperatures in ethereal solvents, so that addition of a second carbonyl partner (ketone or aldehyde) will produce the desired aldol... 

Data for the primary kinetic isotope effect, corresponding to the replacement of the simple aldehyde or ketone by the fully tr-deuterated compound, are roughly in agreement with transition state models in which the proton is not far from being half-transferred. For example, the value observed [6.5 (Hine et al., 1972) 6.7 (Toullec and Dubois, 1974)] for fully dissociated acid-catalysed enolisation of acetone are close to the theoretical maximum value which can be calculated for half proton transfer. 

The last nucleophile of this chapter, sodium bisulfite, NaHSC, adds to aldehydes and some ketones to give what is usually known as a bisulfite addition compound. The reaction occurs by nucleophilic attack of a lone pair on the carbonyl group, just like the attack of cyanide. This leaves a positively charged sulfur atom but a simple proton transfer leads to the product. 

Scheme 18). The formation can be explained by the initial conjugate umpolung of the aldehyde and subsequent 1,4-addition to the unsaturated ketone. After proton transfer, an intramolecular aldol-type addition results in the formation of the aforementioned zwitterions. Nucleophilic displacement of the imidazolium moiety by the alkoxide provides the p-laclonc, which exhibits increased strain, since it is annulated to a cyclopentane ring. Consequently, the P-lactone breaks apart and liberates CO2 and the observed cyclopentene products (Scheme 19). 

In order to protect the proton, and thereby suppress the kinetically favoured proton transfer route, it has been found out that gas-phase addition followed by elimination can be enhanced by reacting the proton bound dimer of the carbonyl compound rather than the protonated monomer [ 134]. In cases where the carbonyl compound has a higher proton affinity than the nucleophile, proton transfer is of course no problem. Alternatively, if the nucleophile already is protonated, as in the reactions between NH] and various carbonyl compounds, proton catalysed addition/elimination is possible as demonstrated experimentally by observation of immonium ion formation [135-137]. Likewise, the hydrazo-nium ion has been found to react with formaldehyde and a wide range of other aldehydes and ketones [138]. 

Methyl ketones can be distinguished from other ketones by the iodoform test. The methyl ketone is treated with iodine in a basic solution. Introduction of the first iodine atom increases the acidity of the remaining methyl protons, so halogenation stops only when the triiodo compound has been produced. The base then allows the relatively stable triiodomethyl carban-ion to leave and a subsequent proton transfer gives iodoform, a yellow crystalline solid of mp 119-123°C. The test is also positive for fragments easily oxidized to methyl ketones, such as CH3CHOH— and ethanol. Acetaldehyde also gives a positive test because it is both a methyl ketone and an aldehyde. 

Hindered phenolates have low nucleophilicity and in aprotic solvent may act usefully as EGBs. 2,6-Di-t-butyl-/ -cresol = 16.8) was reduced directly with concomitant hydrogen evolution to give, ex situ, the corresponding tetraethylammonium phenolate [59,60], which was clearly capable of deprotonating aromatic ketones and in the presence of aromatic aldehydes promoted aldol reaction to a, /3-unsaturated ketones which underwent Michael addition. The initial proton transfer from the aromatic ketone ] K = 24.7) is thermodynamically very unfavorable. Even so, aldol reaction took place within a matter of hours upon addition of an aromatic ketone together with an aromatic aldehyde leading to or, /3-unsaturated ketones which subsequently underwent Michael addition with a sec-... 

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