When two different carbonyl compounds (with `alpha`-`H` atoms) are used in an aldol condensation, four products are formed because each carbonyl compound can react with itself (self aldol) as well as with the other carbonyl compound (crossed aldol). For example, when two carbonyl compounds, A and B are treated with dil. `OH^(-)`, both can lose a proton from the `alpha`-carbon to form carbanion (acting as nucleophiles) `A^(-)` and `B^(-)` respectively. `A^(-)` can either react with A or B and `B^-` can react with either B or A. The reaction of `A^(-)` with B or `B^(-)` with A is called crossed aldol addition. All the four products have similar physical properties, making them difficult to separate. Consequently, crossed aldol addition is not a useful synthetic preparation. See fig.1.

All the four products are `beta`-hydroxy carbonyl compounds. Under certain conditions, a mixed aldol reaction can lead primarily to one product. When one of the carbonyl compound does not have any `alpha`-hydrogen, it cannot form carbanion and number of possible products reduces to two. A greater amount of one of the two products will be formed if the compound without `alpha`-hydrogen is present in excess. The carbanion will be more likely to attack the carbonyl compound without `alpha`-hydrogen because there is more of it in the solution. See fig.2.

Another way to obtain a single aldol product is to convert one carbonyl compound completely into carbanion. This cannot be done by using a weaker base (dil. `OH^-`). To achieve this, we make use of a much stronger base like LDA (lithium diisopropyl amide). Thus, this carbanion attacks over other carbonyl compound to give only one product. For example, See fig.3.

`LDA = [(CH_3)_2CH]_2NLi`

Note that when mixture of an aldehyde and a ketone with `alpha`-hydrogen atom are used, the carbanion is exclusively formed by ketone and the carbanion generated attacks the carbonyl carbon of aldehyde (as it is more electrophilic).

When a compound has two carbonyl groups, it can undergo intramolecular aldol condensation in the presence of dilute base (if `alpha` -`H` atoms are present in the compound). An intramolecular reaction is readily favoured if the reaction leads to the formation of a 5 or 6 - membered ring. When one of carbonyl group is an aldehyde and other is a ketone, it's the ketone, which forms carbanion and this carbanion attack the carbonyl group of an aldehyde in such a manner that 5 or 6 -membered ring is formed.

For example, 2, 5- hexanedione in presence of dilute `OH^(-)` undergoes intramolecular aldol condensation to give 2 set of products as there are 2 different types of `alpha`-hydrogens. One of the product has a 5 - membered ring and the other has a 3 - membered ring. The major product of the react ion is a 5 - membered ring compound as 5 - membered ring has greater stability than 3 - membered ring. See fig.1.

When 6 - oxoheptanal is treated with dilute base, a mixture of three products is formed, of which one of the product is major while other two are minor products. See fig.2.

Those aldehydes (aliphatic or aromatic), which do not have `alpha`-hydrogen atom on treatment with strong base undergoes a reaction involving its 2 moles, one getting oxidised to yield acid salt and the other getting reduced to primary alcohol. The important condition is that there should not be a good leaving group attached to the carbonyl group. See fig.1.

This reaction is an example of organic disproportionation.

`text(Mechanism :)`

The first step of the mechanism involve reversible attack of `OH^(-)` on an aldehyde molecule to give hydroxy alkoxide. This hydroxy alkoxide in the subsequent step transfer hydride ion to second molecule of either same aldehyde (simple Cannizaro) or different aldehyde (crossed Cannizaro). The hydroxy alkoxide on transferring hydride becomes carboxylic acid molecule while second aldehyde molecule becomes alkoxide. The carboxylic acid and alkoxide then undergoes proton exchange to form carboxylate and alcohol respectively.

The reaction requires presence of strong bases and the rate law with `PhCHO` is of the type

Rate `= k[PhCHO]^2[OH^(-)]`

The slowest (rate-determining) step of the reaction is transfer of hydride ion.

See fig.2.

It is evident from the mechanism that the species acting as hydride donor finally forms acid salt while the one, which accepts hydride will form primary alcohol.

When crossed Cannizaro reaction is carried out between formaldehyde and benzaldehyde. formaldehyde always forms formate salt while benzaldehyde yields benzyl alcohol.

`HCHO + PhCHO overset(50 % NaOH)-> HCO_3^(-)Na^(+) + PhCH_2OH`

This is because carbonyl carbon of formaldehyde is more electrophilic than that of benzaldehyde. So, `OH^-` initially attacks at formaldehyde (due to electronic, statistical and steric factors) to form hydroxy alkoxide, which acts as hydride donor to finally form carboxylate while benzaldehyde accepts hydride to form alcohol finally. The presence of electron withdrawing substituent increases the rate of Cannizaro reaction while electron releasing substituent decreases the rate.

For example,

`2HCHO underset(Delta)overset(50 % NaOH)-> CH_3OH +HCO_3^(-)Na^(+)`

`2PhCHO underset(Delta)overset(50 % NaOH)->PhCH_2OH +PhCO_2^(-)Na^(+)`

See fig.3.

`PhCHO +HCHO underset(Delta)overset(50 % KOH)-> PhCH_2OH +HCO_2^(-)K^(+)`

`(CH_3)_2CHCHO underset(Delta)overset(60 % KOH)-> (CH_3)_2CHCOO^(-) Na^(+) + (CH_3)_2CHCH_2OH` [Exception]

The above exception may be due to the fact that stability of `alpha`-carbanion is less & attack of this carbanion to the carbonyl carbon is difficult because of the steric crowding hence, aldol condensation is not feasible.

`(CH_3)_3CCHO +HCHO underset(Delta)overset(50 % NaOH)-> (CH_3)_3CCH_2OH +HCO_2^(-)Na^(+)`


`text(Intramolecular Cannizaro :)`

Glyoxal on reaction with concentrated `NaOH` gives 2 - hydroxy ethanoate by intramolecular Cannizaro reaction. The product is a `alpha`-hydroxy acid. See fig.4.

Phenyl glyoxal on similar reaction gives 2-hydroxy-2-phenyl ethanoate. See fig.5.

When ethyl acetate is treated with sodium ethoxide and the resulting mixture is acidified, then ethyl `beta`-ketobutyrate (ethyl 3 - oxobutanoate), generally known as ethyl acetoacetate or acetoacetic ester is obtained. See fig.1.

The reaction is similar to aldol condensation i.e involving nucleophilic attack by a carbanion on an electron-deficient carbonyl carbon, but with two differences. First difference is that the `alpha`-hydrogen of an ester is less acidic than that of aldehydes or ketones, became of conjugation occur in group, so dilute `OH^-` is not the base employed here. We need a much stronger base than `OH^ -` , that's why sodium ethoxide is used as a base. The second difference is that in aldol condensation, nucleophilic attack leads to addition but in Claisen condensation, nucleophilic attack leads to substitution (typical reaction of acyl compounds).

`text(Mechanism :)`

The generally accepted mechanism for the Claisen condensation is : See fig.2.

Ethoxide ion in the first step abstracts a hydrogen ion from the `alpha`-carbon of the ester to form carbanion, which in the next step undergoes nucleophilic attack on the carbonyl carbon of second molecule of ester to displace ethoxide ion and finally give `beta`-keto ester. But the product isolated is not a `beta`-keto ester, it is sodium salt of `beta`-keto ester. This is because acetoacetic ester (having `alpha`-hydrogens between two carbonyl groups) is much stronger acid than ethyl alcohol. So, acetoacetic ester reacts with ethoxide ion to form ethyl alcohol and the anion of sodio acetoacetic ester. The salt is readily stabilized by resonance. See fig.3.

Claisen condensation can be driven to completion by removing a proton from the `beta`-keto ester. This is easy to achieve as `alpha`- carbon of the `beta`- keto ester is flanked by two electron withdrawing groups, making its hydrogen more acidic than the `alpha`- hydrogen of the reacting ester.

Successful Claisen condensation requires an ester with two `alpha`-hydrogens and an equivalent amount of base rather than a catalytic amount of base.

While drawing the product of Claisen condensation directly (without writing the mechanism), we should remember to form carbanion (mentally) from `alpha`-carbon of the ester and attach it to the carbonyl carbon of other molecule of ester by ejecting ethoxide ion. The final product should be sodium salt of `beta`-keto ester. For example, See fig.4.

Mixed Claisen condensation is a condensation reaction between two different esters. Like mixed aldol condensation, a mixed Claisen condensation will be useful only when it is carried under conditions that allows the formation of primarily one product, other wise, the result is a mixture of products that are difficult to separate. Only one product will be formed when one of the ester has no `alpha`-hydrogen and is taken in excess while the other ester is added slowly to the reaction mixture. See fig.1.

Intramolecular Claisen condensation of esters with `alpha`-hydrogen atoms in the presence of sodium ethoxide leading to cyclization is called Dieckmann condensation.

When ethyl adipate is treated with sodium ethoxide, followed by acidification gives 2-carbethoxy cyclopentanone (a cyclic `beta`-keto ester). See fig.2.

Ethyl pimelate on treatment with sodium ethoxide gives 2-carbethoxy cyclohexanone. See fig.3.

The reaction between aromatic aldehydes and alkanoic anhydrides in presence of alkanoate is called Perkin reaction. The reaction is similar to aldol condensation.

In this reaction, the carbanion is obtained by the removal of an `alpha`-hydrogen atom from acid anhydride by carboxylate (anion of the corresponding acid of the acid anhydride). The carbanion then attacks the aromatic aldehyde to yield alkoxide anion. The transfer of acetyl group then takes place from the carboxyl oxygen to alkoxy oxygen via a cyclic intermediate to give a more stable anion. Removal of an `alpha`-hydrogen from this anion by carboxylate results in the loss of good leaving group from the `beta`-position to give anion of the `alpha`, `beta`-unsaturated acid. This on acidification gives `alpha`, `beta`-unsaturated acid. For example, `PhCHO` on reaction with excess acetic anhydride in presence of sodium acetate followed by acidification gives cinnamic acid (3-phenyl propenoic acid). See fig.

`2PhCHO underset(KCN)oversettext(Alcoholic)-> undersettext(Benzoin)(PhCH(OH)COPh)`

When aromatic aldehyde is treated with alcoholic `KCN`, the product is not a cyanohydrin but `alpha`-hydroxy aromatic ketone called benzoin. The product of aromatic aldehydes with `KCN` is different than aliphatic aldehydes because after the attack of `CN(-)`, the intermediate (I) in aromatic aldehyde has sufficient acidity (due to `-I` effect of `Ph`) so that intramolecular proton exchange takes place to form a carbanion, which is resonance stabilized. This carbanion then attacks another molecule of aromatic aldehyde, which undergoes intramolecular proton exchange and then ejection of `CN^(-)` to give final product i.e. benzoin. The rate - limiting step of the
reaction is attack of carbanion on second molecule of aromatic aldehyde.

`text(Mechanism :)` See fig.

The reaction of oxidation of ketones to esters by peroxy acids `(CF_3COOOH)` or `BF_3//H_2O_2` or `H_2O_2`/Base is called Baeyer- Villiger oxidation. See fig.1.

Product (I) is formed when migratory aptitude of `R'` is greater than that of `R` and if it is greater for `R`, then product (II) is produced.

For example, acetophenone on treatment with peroxy trifluoro acetic acid gives phenyl acetate and not methyl benzoate. This reflects phenyl group has a greater migrating tendency than methyl group. See fig.2.

When oximes (especially ketoximes) are treated with acidic catalyst like `H^(+)`, `PCl_5`, `SOCl_2`, `SO_3`, `P_2O_5` etc., they are transformed into substituted amides. The structure of the substituted amide depends on the structure of ketoxime as the migration of the groups does not depend on their migratory aptitude but on the group that is at trans position to the hydroxyl group. See fig.1.

`text(Mechanism :)` The given reaction adopts following mechanism, in which group that migrates is anti to the `-OH` group. See fig.2.

For example, See fig.3.

The acid catalysed rearrangement of 1, 2 dials (Vicinal dials) to aldehydes or ketones with the elimination of water is known as pinacol pinacolone rearrangement. See fig.1.

`text(Mechanism :)` See fig.2.

Migration of `CH_3 -` occurs in order to produce a more stable `C^(+)`. Positive charge on `C` bearing `:overset(. .)OH` can be easily stabilized.

In pinacol - pinacolone rearrangement , since there is migration of alkyl groups, we have to see something about migratory aptitute , i.e., when two different groups compete for migration which one will be migrate Answer to this can be obtained if closely look at how the group are migrating , migration is not a sudden jump. It passes through a transition state like. See fig.3.

If `R` is `CH_3`, then the transition state will be

See fig.4.

If `R` is `C_6H_5` : See fig.5.

So, the migratory aptitude depends on the stability of transition state. So the order of migration will be

(i) Hydrogen >aryl > alkyl

(ii) p - anisyl > p - tolyl > m - tolyl > m- an isyl >phenyl > p - chlorophenyl > o - an isyl > o - tolyl

(iii) `Me_3C` (`3^o` alkyl) > `Me_2CH` (`2^o` alkyl) > `MeCH_2` (`1^o` alkyl) > `Me`

But keep it in mind, this migratory aptitude comes only after the carbocation formation. So, first preference you should give to carbocation formation and then only migratory aptitude should be employed.

`text(Example)` : See fig.6.

Suppose if the compound is : See fig.7.

This is an acid treatment will give you a product by phenyl migration, since the `C^(+)` formed in the first step will be same on both carbons bearing `-OH` (i.e., This is a symmetrical diol). So reaction will be, Se fig.8.

Bicyclic 1, 2-diols also undergo pinacol -pinacolone type mechanism with the ring expansion/ring contraction depending on the ring sizes. See fig.9.

When carbonyl compounds are heated with aluminium isopropoxide in isopropanol solution, they are reduced to alcohols and isopropoxide is oxidised to acetone, which can be easily removed by distillation. Aldehydes are reduced to primary alcohols and ketones to secondary alcohols. This method is generally used for the reduction of ketones to secondary alcohols. The reducing agent employed in the reaction is a specific reagent, used for reducing ketones or aldehydes in presence of reducible functional groups like double bond, nitro group etc.

This reagent reduces only the carbonyl group, keeping other groups untouched. See fig.

The reverse of this reaction is called Oppenauer oxidation, in which alcohols are oxidised to carbonyl compounds. Primary alcohols are oxidised to aldehydes and ketones are obtained from secondary alcohols.

This is the reaction of a -haloester, usually an a - bromoester with an aldehyde or ketone in the presence of Zinc metal to produce b hydroxyester. See fig.1.

`text(Mechanism :)`

`BrCH_2COOC_2H_5 overset(Zn)-> Br - Zn - CH_3COOC_2H_5 `

See fig.2.