The distinction between reversible and irreversible carbonyl addition reactions may be clarified by considering the stability of alcohols having the structure shown below in the shaded box. If substituent Y is not a hydrogen, an alkyl group or an aryl group, there is a good chance the compound will be unstable (not isolable), and will decompose in the manner shown. Most hydrates and hemiacetals ( Y = OH & OR), for example, are known to decompose spontaneously to the corresponding carbonyl compounds. Aminols ( Y = NHR) are intermediates in imine formation, and also revert to their carbonyl precursors if dehydration conditions are not employed. Likewise, α-haloalcohols ( Y = Cl, Br & I) cannot be isolated, since they immediately decompose with the loss of HY. In all these cases addition of H– Y to carbonyl groups is clearly reversible. If substituent Y is a hydrogen, an alkyl group or an aryl group, the resulting alcohol is a stable compound and does not decompose with loss of hydrogen or hydrocarbons, even on heating. It follows then, that if nucleophilic reagents corresponding to H: (–) , R: (–) or Ar: (–) add to aldehydes and ketones, the alcohol products of such additions will form irreversibly. Free anions of this kind would be extremely strong bases and nucleophiles, but their extraordinary reactivity would make them difficult to prepare and use. Fortunately, metal derivatives of these alkyl, aryl and hydride moieties are available, and permit their addition to carbonyl compounds. Reduction by Complex Metal Hydrides Addition of a hydride anion to an aldehyde or ketone would produce an alkoxide anion, which on protonation should yield the corresponding alcohol. Aldehydes would give 1º-alcohols (as shown) and ketones would give 2º-alcohols. RCH=O + H: (–) RCH 2 O (–) + H 3 O (–) RCH 2 OH Two practical sources of hydride-like reactivity are the complex metal hydrides lithium aluminum hydride (LiAlH 4 ) and sodium borohydride (NaBH 4 ). These are both white (or near white) solids, which are prepared from lithium or sodium hydrides by reaction with aluminum or boron halides and esters. Lithium aluminum hydride is by far the most reactive of the two compounds, reacting violently with water, alcohols and other acidic groups with the evolution of hydrogen gas. The following table summarizes some important characteristics of these useful reagents. Reagent Preferred Solvents Functions Reduced Reaction Work-up Sodium Borohydride NaBH4 ethanol; aqueous ethanol 15% NaOH; diglyme avoid strong acids aldehydes to 1º-alcohols ketones to 2º-alcohols inert to most other functions 1) simple neutralization 2) extraction of product Lithium Aluminum Hydride LiAlH4 ether; THF avoid alcohols and amines avoid halogenated compounds avoid strong acids aldehydes to 1º-alcohols ketones to 2º-alcohols carboxylic acids to 1º-alcohols esters to alcohols epoxides to alcohols nitriles & amides to amines halides & tosylates to alkanes most functions react 1) careful addition of water 2) remove aluminum salts 3) extraction of product Some examples of aldehyde and ketone reductions, using the reagents described above, are presented in the following diagram. The first three reactions illustrate that all four hydrogens of the complex metal hydrides may function as hydride anion equivalents which bond to the carbonyl carbon atom. In the LiAlH 4 reduction, the resulting alkoxide salts are insoluble and need to be hydrolyzed (with care) before the alcohol product can be isolated. In the borohydride reduction the hydroxylic solvent system achieves this hydrolysis automatically. The lithium, sodium, boron and aluminum end up as soluble inorganic salts. The last reaction shows how an acetal derivative may be used to prevent reduction of a carbonyl function (in this case a ketone). Remember, with the exception of epoxides, ethers are generally unreactive with strong bases or nucleophiles. The acid catalyzed hydrolysis of the aluminum salts also effects the removal of the acetal. This equation is typical in not being balanced ( i.e. it does not specify the stoichiometry of the reagent). Figure 1: Aldehyde and ketone reductions Reduction of α,β-unsaturated ketones by metal hydride reagents sometimes leads to a saturated alcohol, especially with sodium borohydride. This product is formed by an initial conjugate addition of hydride to the β-carbon atom, followed by ketonization of the enol product and reduction of the resulting saturated ketone (equation 1 below). If the saturated alcohol is the desired product, catalytic hydrogenation prior to (or following) the hydride reduction may be necessary. To avoid reduction of the double bond, cerium(III) chloride is added to the reaction and it is normally carried out below 0 ºC, as shown in equation 2. 0 1 2 3 4 5 6 1) RCH=CHCOR' + NaBH4 (aq. alcohol) ——> RCH=CHCH(OH)R' + RCH2-CH2CH(OH)R' NaN NaN NaN NaN 1,2-addition product NaN 1,4-addition product 2) RCH=CHCOR' + NaBH4 & CeCl3 -15º ——> RCH=CHCH(OH)R' RCH=CHCH(OH)R' RCH=CHCH(OH)R' NaN NaN NaN NaN 1,2-addition product 1,2-addition product 1,2-addition product Before leaving this topic it should be noted that diborane, B 2 H 6 , a gas that was used in ether solution to prepare alkyl boranes from alkenes , also reduces many carbonyl groups. Consequently, selective reactions with substrates having both functional groups may not be possible. In contrast to the metal hydride reagents, diborane is a relatively electrophilic reagent, as witnessed by its ability to reduce alkenes. This difference also influences the rate of reduction observed for the two aldehydes shown below. The first, 2,2-dimethylpropanal, is less electrophilic than the second, which is activated by the electron withdrawing chlorine substituents. Figure 2: Comparative reduction rates of diborane vs metal hydride reagents Addition of Organometallic Reagents The two most commonly used compounds of this kind are alkyl lithium reagents and Grignard reagents . They are prepared from alkyl and aryl halides, as discussed earlier . These reagents are powerful nucleophiles and very strong bases (pK a 's of saturated hydrocarbons range from 42 to 50), so they bond readily to carbonyl carbon atoms, giving alkoxide salts of lithium or magnesium. Because of their ring strain, epoxides undergo many carbonyl-like reactions, as noted previously . Reactions of this kind are among the most important synthetic methods available to chemists, because they permit simple starting compounds to be joined to form more complex structures. Examples are shown in the following diagram. Figure 3: Organometallic addition reactions A common pattern, shown in the shaded box at the top, is observed in all these reactions. The organometallic reagent is a source of a nucleophilic alkyl or aryl group (colored blue), which bonds to the electrophilic carbon of the carbonyl group (colored magenta). The product of this addition is a metal alkoxide salt, and the alcohol product is generated by weak acid hydrolysis of the salt. The first two examples show that water soluble magnesium or lithium salts are also formed in the hydrolysis, but these are seldom listed among the products, as in the last four reactions. Ketones react with organometallic reagents to give 3º-alcohols; most aldehydes react to produce 2º-alcohols; and formaldehyde and ethylene oxide react to form 1º-alcohols (examples #5 & 6). When a chiral center is formed from achiral reactants (examples #1, 3 & 4) the product is always a racemic mixture of enantiomers. Two additional examples of the addition of organometallic reagents to carbonyl compounds are informative. The first demonstrates that active metal derivatives of terminal alkynes function in the same fashion as alkyl lithium and Grignard reagents. The second example again illustrates the use of acetal protective groups in reactions with powerful nucleophiles. Following acid-catalyzed hydrolysis of the acetal, the resulting 4-hydroxyaldehyde is in equilibrium with its cyclic hemiacetal. Figure 4: Carbonyl compunds formed from organometallic addition reactions Contributors William Reusch, Professor Emeritus ( Michigan State U. ), Virtual Textbook of Organic Chemistry