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Reactions Involving Aldehydes and Ketones

Basically there are two kinds of reactions involving nucleophiles and acyl compounds:

Nucleophilic Additions
Nucleophilic Substitutions

The factor that decides whether the acyl compound will undergo addition or substitution largely depends upon the ability for an atom attached to the acyl carbon to undergo heterolysis taking the bonding electrons with it as it leaves the acyl carbon having been displaced by the incoming nucleophile. Different atoms or groups of atoms will have different abilities to leave the acyl compound. The greater the "leaving group ability"(LGA) the more likely the acyl compound will undergo substitution instead of addition.

It might be instructive for us to review the ability for groups to leave an acyl carbon. Leaving group ability is largely dependent upon how well the group is stabilized after leaving the molecule. The more stable the group is the better able it is to depart and the morely it will be involved in a substitution reaction with an incoming nucleophile. This stability can be associated with its bascicity. Weaker bases will be so stable that they won't want to donate electrons. So we can say that the weaker the basic strength of the leaving group the less likely for it to reverse the substitution step. We have also learned in previous lessons that weak bases come from strong acids forming them as a conjugate base.

For example, we all know that HCl is a relatively strong acid, so when it donates a proton it produces the conjugate base, Chloride ion. The very fact that HCl is such a strong acid will mean that Chloride ion has to be a weak conjugate base of that acid and therefore has little inclination to reverse the acid base reaction. For all practical purposes, the reaction of HCl with say water as the base will be one sided directed vertually exclusively to the right because Chloride ion is not basic enough to pull a proton away from the Hydronium ion that has formed:

H-Cl + H₂O -----> H₃O⁺ + Cl^-

Generally speaking, stronger acids and bases always give rise to weaker acids and bases. Therefore the stronger the acid the weaker its conjugate base. Weak conjugate bases (coming from strong acids) always make better leaving groups. These groups attached to an acyl carbon will always stimulate nucleophilic substitution over addition.

Relative strength of acids are as follows:

H-X greater than carboxylic acids which are greater than H²O which are greater than R-OH which are greater than R-NR₂(amines) which are much greater than H₂ which are greater than hydrocarbons.

Therefore, the relative strengths of their conjugate bases would be as follows:

R^- are greater than H^- which are greater than NR₂^- which are greater than R-O^- which are greater than OH^- which are greater than RCOO^- which are greater than X^-.

This means that the relative leaving group ability is as follows:

X^- is greater than RCOO^- which is greater thanOH^- which are greater than R-O^- which are greater than NR₂^- which are much greater than H^- which are greater than R^-

In fact, Hydride ions and carbanions are so lousy as leaving groups substitutions rarely ,if ever, occur when they are attached to an acyl carbon. We are talking aldehydes and ketones here. Since substitutions are unlikely because of the relatively poor LGA(basicity) then nucleophilic additions are usually take place between such acyl compounds and an incoming nucleophile.

Let's look at some of these reactions along with other reactions that aldehydes and ketones undergo.

Hydration of Aldehydes and Ketones

Hydration is a nucleophilic addition of water accross the carbonyl and results in the production of geminal diols.(See Fig 1-a below). Because water is considered a relatively weak nucleophile, this reaction works best with a protic acid catalyst.

The reaction mechanism generally involves the protonation of the acyl Oxygen first which accentuates the positive charge on the acyl carbon making it more attractive to a water molecule. In the second step a water molecule will attach itself to the acyl carbon using a lone pair on the Oxygen atom of water and making the Oxygen atom positively charged. In a third step, a water molecule will pull a proton off of the Oxygen thus restoring its electrical neutrality and producing the geminal diol.(See Fig 1-b above)

The reaction works better if there is a highly electronegative atom like a halogen attached to the carbon bonded to the acyl carbon. For future reference this carbon is called the "alpha" carbon.

Reactions With Aldehydes and Ketones With Hydrazine and Its Derivatives

Hydrazine has the formula :NH₂-NH₂. There are derivatives of Hydrazine where one of the Hydrogen atoms has been replaced with another group of atoms. It makes no difference since it is the first nitrogen with its lone pair of electrons that will react with the acyl carbon and form a double bond between the acyl carbon and the nitrogen.(See Fig 4 below)

Phenyl hydrazine is simply hydrazine with one of the hydrogens on the right hand nitrogen being replaced with a phenyl (benzine ring) group. Reacting an aldehyde or ketone with Phenylhydrazine will produce the corresponding Phenyl Hydrazone. The chemistry is the same as outlined in Fig 4. One particularly favorite hydrazine derivative that is used by Organic Chemists in identifying aldehydyes and ketones is 2,4-D which stands for 2,4-Dinitrophenylhydrazine. This is similar to phenyl hydrazine except there are two nitro groups found on the 2 and 4 positions of the Benzene Ring. This makes the 2,4-PhenylHyrazone products very colorful. Generally, Organic Chemists can react a suspected aldehyde or ketone with 2,4-D reagent and produce a 2,4-D Hydroazone product that is insoluble in water and will precipitate. This can be filtered, washed, and dried, and a melting point can be determined for the 2,4-D hydrazone. There are tables of such derivatives which associate a particular aldehyde or ketone with the melpting point of the 2,4-D Hydrazone derivative. By matching the melting point of the 2,4-D Hydrazone with one in the reference table and then looking in another column for the associated aldehyde or ketone, one can identify the aldehyde or ketone present. There are reference tables found in Reference books that show the aldehyde or ketone in the first column and then the Hydrazone, PhenylHydrazone, and 2,4-Dinitrophenylhydrazone derivatives in other separate columns to the right in the table. By preparaing any one or more than one derivative and matching the melting points with the ones in the table will lead to the possible identification of the aldehyde or ketone.

The Wolf Kishner Reduction of Hydrazones

Hydrazones can be reduced where the C=N is converted to a -CH₂- group. This is very useful synthetic tool for converting the carbonyl C=O in an aldehyde or ketone to a -CH₂- group. This is done by first forming the hydrazone using Hydrazine and then reacting the Hydrazone with Potassium Hydroxide (KOH) at elevated temperature to complete the conversion. (See Fig 5 below)

Addition of HCN To Aldehydes and Ketones

The reaction of either an Aldehyde or Ketone with HCN must be done in a buffered solution since the HCN is a weak acid and the Cyanide ion CN^- will hydrolyze (react with water) to form Hydroxide ion tending to make the solution basic were it not for a buffer inserted into the reaction. The reaction is acid catalyzed and results in the production of a cyano Hydrin. (See Fig 6-a below)

The reaction mechanism involves the initial protonization of the acyl Oxygen with a lone pair on the Oxygen serving as bonding electrons for attaching the proton. This accentuates the positive charge on the acyl carbon. In the second step, the Cyanide ion from the HCN will act as the nucleophile and attach itself to the acyl carbon displacing the Pi electrons out onto the Oxygen atom thereby neutralizing the positive charge previously there. (See Fig 6-b above). The cyano Hydrins are not of themselves important as an end product. They can be further reacted to give some rather important end products, however.

For example, If you react a cyano Hydrin with aquous HCl then the cyano group will be hydrolyzed to a carboxyl group to produce an alpha Hydroxy carboxylic acid. (See 7-a below). The use of 95% Sulfuric Acid will affect both the Hydroxyl group as well as the cyano group. Since Sulfuric Acid is good at not only hydrolyzing the cyano group to a carboxyl group as all aquous acids do but it is also a good dehydrator and will cause the loss of water from the molecule in an elimination dehydration reaction producing a Pi bond between the alpha and beta carbons of a carboxylic acid. This dual reaction is enhanced by the fact that the product which is an alpha,Beta unsaturated acid is resonance stabilized due to the conjugation of the Pi bonds between the alpha and beta carbons and the carbonyl.(See Fig 7-b below) A third reaction that cyano Hydrins can undergo is the use of Lithium Aluminum Hydride followed by hydrolysis to produce an Beta Hydroxy amine.(See Fig 7-c below)

Addition of Bisulfite to Aldehydes and Ketones

The Nucleophilic addition of Bisulfite accross the Pi bond of the carbonyl will produce a water soluble Sodium Salt of an Organic Sulfite.(See Fig 8-a below) Sodium Bisulfite will react with both aldehydes and ketones in this manner. This is another example of a reaction is noted more for its ability to separate aldehydes and ketones from other water insoluble organic compounds in a mixture. The extraction of the organic mixture containing the aldehyde or ketone using 15% NaHSO₃ will result in the formation of the water soluble Organosulfite salt. The aldehyde or ketone will then be extracted or drawn out of the organic layer into the aqueous layer. Once the layers have been separated using a separatory funnel, the the aqueous layer can be acidified which will convert the sulfite salt back to the aldehyde aor ketone and consequently the aldehyde or ketone will separate out of the aqueous layer and can then be separated from the water layer by extraction with a suitable organic extractant such as ether.(See Fig 8-b below)

Addition of Organo-Metallic Reagents to Aldehydes and Ketones

Organo-metallic reagents like the Grignard(OrganoMagnesium) or the Organo Lithium reagents will react with aldehydes to produce secondary alcohols upon acidification. Formaldehyde will produce a primary alcohol (see Fig 9-a below), but all other aldehydes will react with these organo-metallic reagents to produce secondary alcohols.(See Fig 9-b below) Ketones react with such reagents to produce tertiary alcohols. (See Fig 9-c below)

Oxidation of Aldehydes and Ketones

Oxidation of aldehydes will result in the formation of carboxylic acids or if done in a basic media the formation of the salt of a carboxylic acid. The use of alkaline hot Potassium Permanganate followed by acidification will produce the corresponding carboxylic acid. (See Fig 10-a below) The product can also be produced with the use of Silver Oxide in basic solution. (See Fig 10-b below).

Aldehydes will react with an ammoniacal solution of Silver Nitrate which produces a Silver Diammine Hydroxide solution called Tollen's Reagent. This reagent will oxidize only aldehydes to a salt of an acid with the result that the Silver ion will be reduced to free silver. Depending on the concentration of the Tollen's Reagent and the surface of the reaction vessel, the free silver deposition will form a layer of silver atoms on the inside of the reaction vessel which is highly reflective. This is called the silver mirror effect and is a positive indication of the presence of an aldehyde. Other oxidizing agents like Fehlings Solutions and Benedict's solution will also oxidize aldehydes to a salt of the acid. Both solutions have Copper II ion which is reduced to Copper(I) ion. This ion reacts with the Hydroxide present to produce a orange red colored solid precipitate signaling the presence of an aldehyde. However Benedict's solution will also react with reducing sugars which have aldehyde groups or Hydroxyl groups within the molecule to give the same positive indication.

Ketones are resistent to oxidation. Only Methyl ketones will undergo oxidation in the presence of Potassium Hydroxide and Iodine solution. This is referred to as the Iodoform reagent and results in the production of the salt of an acid and a compound known as Iodoform, CHI₃ which is insoluble in water and precipitates as a yellow crystalline solid. This is indicative of the presence of a methyl ketone or an alcohol with a methyl group on the carbanol carbon like ethanol. Aldehydes will not react with Iodoform Reagent.