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Aldehydes and Ketones   Background for Aldehydes and Ketones An aldehyde contains at least one hydrogen attached to the C of a C=O (carbonyl group).  A ketone contains two alkyl groups attached to the C of the carbonyl group. The carbon in the carbonyl is sp2 hybridized, has a bond angle of 120o, and is trigonal planar. Aldehydes and ketones have dipole-dipole attractions between molecules, and no hydrogen bonding between molecules.  These compounds can hydrogen bond with compounds have O-H or N-H bonds.  The melting points and boiling points of aldehydes and ketones are between alkanes and alcohols.  Small aldehydes and ketones are soluble in water.  Some compounds are very flammable. Uses of Aldehydes and Ketones Formaldehyde can be used to preserve dead animals.  Acetone is a common fingernail polish remover and is a solvent.  Acetone is very flammable. 2-Butanone (MEK, methyl ethyl ketone) is used as a solvent and paint stripper.  2-Butanone is very flammable.  Benzaldehyde is an almond extract. (-)-Carvone is used as spearmint flavoring.  (+)-Carvone is used as caraway seed flavoring.  Vanillin is the vanilla flavoring.   1. Nomenclature of Aldehydes and Ketones Aldehydes and ketones are organic compounds which incorporate a carbonyl functional group, C=O. The carbon atom of this group has two remaining bonds that may be occupied by hydrogen or alkyl or aryl substituents. If at least one of these substituents is hydrogen, the compound is an aldehyde. If neither is hydrogen, the compound is a ketone. The IUPAC system of nomenclature assigns a characteristic suffix to these classes, al to aldehydes and one to ketones. For example, H2C=O is methanal, more commonly called formaldehyde. Since an aldehyde carbonyl group must always lie at the end of a carbon chain, it is by default position #1, and therefore defines the numbering direction. A ketone carbonyl function may be located anywhere within a chain or ring, and its position is given by a locator number. Chain numbering normally starts from the end nearest the carbonyl group. In cyclic ketones the carbonyl group is assigned position #1, and this number is not cited in the name, unless more than one carbonyl group is present. If you are uncertain about the IUPAC rules for nomenclature you should review them now. Examples of IUPAC names are provided (in blue) in the following diagram. Common names are in red, and derived names in black. In common names carbon atoms near the carbonyl group are often designated by Greek letters. The atom adjacent to the function is alpha, the next removed is beta and so on. Since ketones have two sets of neighboring atoms, one set is labled α, β etc., and the other α', β' etc. Very simple ketones, such as propanone and phenylethanone (first two examples in the left column), do not require a locator number, since there is only one possible site for a ketone carbonyl function. Likewise, locator numbers are omitted for the simple dialdehyde at the bottom left, since aldehyde functions must occupy the ends of carbon chains. The hydroxy butanal and propenal examples (2nd & 3rd from the top, left column) and the oxopropanal example (bottom right) illustrate the nomenclature priority of IUPAC suffixes. In all cases the aldehyde function has a higher status than either an alcohol, alkene or ketone and provides the nomenclature suffix. The other functional groups are treated as substituents. Because ketones are just below aldehydes in nomenclature suffix priority, the "oxo" substituent terminology is seldom needed.Simple substituents incorporating a carbonyl group are often encountered. The generic name for such groups is acyl. Three examples of acyl groups having specific names are shown below.   Back to the Top 2. Occurrence of Aldehydes and Ketones Natural Products Aldehydes and ketones are widespread in nature, often combined with other functional groups. Example are shown in the following diagram. The compounds in the top row are found chiefly in plants or microorganisms; those in the bottom row have animal origins. With the exception of the first three compounds (top row) these molecular structures are all chiral. When chiral compounds are found in nature they are usually enantiomerically pure, although different sources may yield different enantiomers. For example, carvone is found as its levorotatory (R)-enantiomer in spearmint oil, whereas, caraway seeds contain the dextrorotatory (S)-enantiomer. Note that the aldehyde function is often written as –CHO in condensed or complex formulas. 3. Synthetic Preparation of Aldehydes and Ketones Aldehydes and ketones are obtained as products from many reactions . The following diagram summarizes the most important of these. With the exception of Friedel-Crafts acylation, these methods do not increase the size or complexity of molecules. In the following sections  we shall find that one of the most useful characteristics of aldehydes and ketones is their reactivity toward carbon nucleophiles, and the resulting elaboration of molecular structure that results. In short, aldehydes and ketones are important intermediates for the assembly or synthesis of complex organic molecules. Back to the Top 4. Properties of Aldehydes and Ketones  A comparison of the properties and reactivity of aldehydes and ketones with those of the alkenes is warranted, since both have a double bond functional group. Because of the greater electronegativity of oxygen, the carbonyl group is polar, and aldehydes and ketones have larger molecular dipole moments (D) than do alkenes. The resonance structures on below illustrate this polarity, and the relative dipole moments of formaldehyde, other aldehydes and ketones confirm the stabilizing influence that alkyl substituents have on carbocations (the larger the dipole moment the greater the polar character of the carbonyl group). We expect, therefore, that aldehydes and ketones will have higher boiling points than similar sized alkenes. Furthermore, the presence of oxygen with its non-bonding electron pairs makes aldehydes and ketones hydrogen-bond acceptors, and should increase their water solubility relative to hydrocarbons. Specific examples of these relationships are provided in the following table. Compound Mol. Wt. Boiling Point Water Solubility (CH3)2C=CH2 56 -7.0 ºC 0.04 g/100 (CH3)2C=O 58 56.5 ºC infinite CH3CH2CH2CH=CH2 70 30.0 ºC 0.03 g/100 CH3CH2CH2CH=O 72 76.0 ºC 7 g/100 96 103.0 ºC insoluble 98 155.6 ºC 5 g/100                     The polarity of the carbonyl group also has a profound effect on its chemical reactivity, compared with the non-polar double bonds of alkenes. Thus, reversible addition of water to the carbonyl function is fast, whereas water addition to alkenes is immeasurably slow in the absence of a strong acid catalyst. Curiously, relative bond energies influence the thermodynamics of such addition reactions in the opposite sense.The C=C of alkenes has an average bond energy of 146 kcal/mole. Since a C–C σ-bond has a bond energy of 83 kcal/mole, the π-bond energy may be estimated at 63 kcal/mole (i.e. less than the energy of the sigma bond). The C=O bond energy of a carbonyl group, on the other hand, varies with its location, as follows:     H2C=O     170 kcal/mole        RCH=O    175 kcal/mole        R2C=O     180 kcal/mole     The C–O σ-bond is found to have an average bond energy of 86 kcal/mole. Consequently, with the exception of formaldehyde, the carbonyl function of aldehydes and ketones has a π-bond energy greater than that of the sigma-bond, in contrast to the pi-sigma relationship in C=C. This suggests that addition reactions to carbonyl groups should be thermodynamically disfavored, as is the case for the addition of water. All of this is summarized in the following diagram (ΔHº values are for the addition reaction). Although the addition of water to an alkene is exothermic and gives a stable product (an alcohol), the uncatalyzed reaction is extremely slow due to a high activation energy . The reverse reaction (dehydration of an alcohol) is even slower, and because of the kinetic barrier, both reactions are practical only in the presence of a strong acid. The microscopically reversible mechanism for both reactions was described earlier. In contrast, both the endothermic addition of water to a carbonyl function, and the exothermic elimination of water from the resulting geminal-diol are fast. The inherent polarity of the carbonyl group, together with its increased basicity (compared with alkenes), lowers the transition state energy for both reactions, with a resulting increase in rate. Acids and bases catalyze both the addition and elimination of water. Proof that rapid and reversible addition of water to carbonyl compounds occurs is provided by experiments using isotopically labeled water. If a carbonyl reactant composed of 16O (colored blue above) is treated with water incorporating the 18O isotope (colored red above), a rapid exchange of the oxygen isotope occurs. This can only be explained by the addition-elimination mechanism shown here. Reactions of Aldehydes and Ketones 1. Reversible Addition Reactions A. Hydration and Hemiacetal Formation It has been demonstrated (above) that water adds rapidly to the carbonyl function of aldehydes and ketones. In most cases the resulting hydrate (a geminal-diol) is unstable relative to the reactants and cannot be isolated. Exceptions to this rule exist, one being formaldehyde (a gas in its pure monomeric state). Here the weaker pi-component of the carbonyl double bond, relative to other aldehydes or ketones, and the small size of the hydrogen substituents favor addition. Thus, a solution of formaldehyde in water (formalin) is almost exclusively the hydrate, or polymers of the hydrate. Similar reversible additions of alcohols to aldehydes and ketones take place. The equally unstable addition products are called hemiacetals. R2C=O   +   R'OH      R'O–(R2)C–O–H   (a hemiacetal) Back to the Top  B. Acetal Formation Acetals are geminal-diether derivatives of aldehydes or ketones, formed by reaction with two equivalents of an alcohol and elimination of water. Ketone derivatives of this kind were once called ketals, but modern usage has dropped that term. The following equation shows the overall stoichiometric change in acetal formation, but a dashed arrow is used because this conversion does not occur on simple mixing of the reactants. R2C=O   +   2 R'OH      R2C(OR')2   +   H2O   (an acetal) In order to achieve effective acetal formation two additional features must be implemented. First, an acid catalyst must be used; and second, the water produced with the acetal must be removed from the reaction. The latter is important, since acetal formation is reversible. Indeed, once pure acetals are obtained they may be hydrolyzed back to their starting components by treatment with aqueous acid. The mechanism shown here applies to both acetal formation and acetal hydrolysis by the principle of microscopic reversiblity . Some examples of acetal formation are presented in the following diagram. As noted, p-toluenesulfonic acid (pKa = -2) is often the catalyst for such reactions. Two equivalents of the alcohol reactant are needed, but these may be provided by one equivalent of a diol (example #2). Intramolecular involvement of a gamma or delta hydroxyl group (as in examples #3 and 4) may occur, and is often more facile than the intermolecular reaction. Thiols (sulfur analogs of alcohols) give thioacetals (example #5). In this case the carbonyl functions are relatively hindered, but by using excess ethanedithiol as the solvent and the Lewis acid BF3 as catalyst a good yield of the bis-thioacetal is obtained. Thioacetals are generally more difficult to hydrolyze than are acetals. The importance of acetals as carbonyl derivatives lies chiefly in their stability and lack of reactivity in neutral to strongly basic environments. As long as they are not treated by acids, especially aqueous acid, acetals exhibit all the lack of reactivity associated with ethers in general.Among the most useful and characteristic reactions of aldehydes and ketones is their reactivity toward strongly nucleophilic (and basic) metallo-hydride, alkyl and aryl reagents (to be discussed shortly). If the carbonyl functional group is converted to an acetal these powerful reagents have no effect; thus, acetals are excellent protective groups, when these irreversible addition reactions must be prevented. C. Formation of Imines and Related Compounds The reaction of aldehydes and ketones with ammonia or 1º-amines forms imine derivatives, also known as Schiff bases, (compounds having a C=N function). This reaction plays an important role in the synthesis of 2º-amines. Water is eliminated in the reaction, which is acid-catalyzed and reversible in the same sense as acetal formation. R2C=O   +   R'NH2      R'NH–(R2)C–O–H      R2C=NR'   +   H2O Imines are sometimes difficult to isolate and purify due to their sensitivity to hydrolysis. Consequently, other reagents of the type Y–NH2 have been studied, and found to give stable products (R2C=N–Y) useful in characterizing the aldehydes and ketones from which they are prepared. Some of these reagents are listed in the following table, together with the structures and names of their carbonyl reaction products. An interesting aspect of these carbonyl derivatives is that stereoisomers are possible when the R-groups of the carbonyl reactant are different. Thus, benzaldehyde forms two stereoisomeric oximes, a low-melting isomer, having the hydroxyl group cis to the aldehyde hydrogen (called syn), and a higher melting isomer in which the hydroxyl group and hydrogen are trans (the anti isomer). At room temperature or below the configuration of the double-bonded nitrogen atom is apparently fixed in one trigonal shape, unlike the rapidly interconverting pyramidal configurations of the sp3 hybridized amines. With the exception of unsubstituted hydrazones, these derivatives are easily prepared and are often crystalline solids - even when the parent aldehyde or ketone is a liquid. Since melting points can be determined more quickly and precisely than boiling points, derivatives such as these are useful for comparison and identification of carbonyl compounds. If the aromatic ring of phenylhydrazine is substituted with nitro groups at the 2- & 4-positions, the resulting reagent and the hydrazone derivatives it gives are strongly colored, making them easy to identify. It should be noted that although semicarbazide has two amino groups (–NH2) only one of them is a reactive amine. The other is amide-like and is deactivated by the adjacent carbonyl group.The rate at which these imine-like compounds are formed is generally greatest near a pH of 5, and drops at higher and lower pH's. This agrees with a general acid catalysis in which the conjugate acid of the carbonyl reactant combines with a free amino group, as shown in the above animation. At high pH there will be a vanishingly low concentration of the carbonyl conjugate acid, and at low pH most of the amine reactant will be tied up as its ammonium conjugate acid. With the exception of imine formation itself, most of these derivatization reactions do not require active removal of water (not shown as a product in the previous equations). The reactions are reversible, but equilibrium is not established instantaneously and the products often precipitate from solution as they are formed. Other Derivatives of Aldehydes and Ketones Examples of other carbonyl derivatives, and a striking case of kinetic control vs. thermodynamic (equilibrium) control of products in these reactions may be examined by Clicking Here. Back to the Top D. Enamine Formation The previous reactions have all involved reagents of the type: Y–NH2, i.e. reactions with a 1º-amino group. Most aldehydes and ketones also react with 2º-amines to give products known as enamines. Two examples of these reactions are presented in the following diagram. It should be noted that, like acetal formation, these are acid-catalyzed reversible reactions in which water is lost. Consequently, enamines are easily converted back to their carbonyl precursors by acid-catalyzed hydrolysis. E. Cyanohydrin Formation The last example of reversible addition is that of hydrogen cyanide (HC≡N), which adds to aldehydes and many ketone to give products called cyanohydrins. RCH=O   +   H–C≡N      RCH(OH)CN     (a cyanohydrin) Since hydrogen cyanide itself is an acid (pKa = 9.25), the addition is not acid-catalyzed. In fact, for best results cyanide anion, C≡N(-) must be present, which means that catalytic base must be added. Cyanhydrin formation is weakly exothermic, and is favored for aldehydes, and unhindered cyclic and methyl ketones. Two examples of such reactions are shown below. The cyanohydrin from benzaldehyde is named mandelonitrile. The reversibility of cyanohydrin formation is put to use by the millipede Apheloria corrugata in a remarkable defense mechanism. This arthropod releases mandelonitrile from an inner storage gland into an outer chamber, where it is enzymatically broken down into benzaldehyde and hydrogen cyanide before being sprayed at an enemy. 2. Irreversible Addition Reactions 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. Back to the Top A. 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:(–)      RCH2O(–)   +   H3O(–)      RCH2OH Two practical sources of hydride-like reactivity are the complex metal hydrides lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4). 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 ethanol15% NaOH; diglyme avoid strong acids aldehydes to 1º-alcoholsketones to 2º-alcohols inert to most other functions 1) simple neutralization 2) extraction of product Lithium Aluminum Hydride    LiAlH4 ether; THF avoid alcohols and aminesavoid halogenated compounds avoid strong acids aldehydes to 1º-alcoholsketones to 2º-alcohols carboxylic acids to 1º-alcoholsesters to alcoholsepoxides to alcoholsnitriles & amides to amineshalides & tosylates to alkanesmost functions react 1) careful addition of water 2) remove aluminum salts3) 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 LiAlH4 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). 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. 1)   RCH=CHCOR'   +   NaBH4 (aq. alcohol)   ——>  RCH=CHCH(OH)R'   +   RCH2-CH2CH(OH)R' 1,2-addition product 1,4-addition product 2)   RCH=CHCOR'   +   NaBH4 & CeCl3 -15º   ——>  RCH=CHCH(OH)R' 1,2-addition product Before leaving this topic it should be noted that diborane, B2H6, 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. Dissolving Metal ReductionCarbonyl groups and conjugated π-electron systems are reduced by metals such as Li, Na and K, usually in liquid ammonia solution. Back to the Top B. 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 (pKa'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. 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. 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. Reactions with Phosphorus and Sulfur Ylides The ylides are another class of nucleophilic organic reagents that add rapidly to the carbonyl function of aldehydes and ketones. 3. Other Carbonyl Group Reactions A. Reduction The metal hydride reductions and organometallic additions to aldehydes and ketones, described above, both decrease the carbonyl carbon's oxidation state, and may be classified as reductions. As noted, they proceed by attack of a strong nucleophilic species at the electrophilic carbon. Other useful reductions of carbonyl compounds, either to alcohols or to hydrocarbons, may take place by different mechanisms. For example, hydrogenation (Pt, Pd, Ni or Ru catalysts), reaction with diborane, and reduction by lithium, sodium or potassium in hydroxylic or amine solvents have all been reported to convert carbonyl compounds into alcohols. However, the complex metal hydrides are generally preferred for such transformations because they give cleaner products in high yield. Aldehydes and ketones may also be reduced by hydride transfer from alkoxide salts.   Back to the Top Meerwein-Pondorf-Verley Reduction Reduction of aldehydes and ketones to alcohols is most commonly carried out by metal hydride reagents, dissolving metal reagents, and sometimes by catalytic hydrogenation. Prior to the development of these new and powerful reduction methods, the conversion of carbonyl compounds to alcohols was often effected by hydrogen transfer from an alkoxide salt. This procedure, known as the Meerwein-Pondorf-Verley reaction, is illustrated by the following equation and mechanism ( the hydride-like hydrogen is colored red). Aluminum isopropoxide has been the most common hydrogen source in most cases, but lanthanide salts, such as ROSmI2 have been used with good results. This reduction is specific for aldehyde and ketone carbonyl functions, so other easily reduced functions such as nitro groups and halogen are unaffected.  Not only are two hydrogens delivered independently from the least hindered (convex) side of the cis-decalin substrate in example 1, but the easily reduced double bond of the enedione remains unchanged. The initially formed cis-diol undergoes lactonization with the neighboring methyl ester. It should be noted that a similar reductive hydride transfer takes place when large alkyl Grignard reagents react with hindered ketones, as shown in equation 2. The MVP reduction is also an oxidation, as evidenced by the conversion of isopropoxide to acetone. Consequently, the reaction can be converted into an oxidation of alcohols to ketones or aldehydes. This procedure is called the Oppenauer oxidation. The reaction displayed below is an example of the Oppenauer oxidation in which benzophenone is the oxidant. Two significant features may be noted. First, the oxidation is specific for alcohols, and does not oxidize other sensitive functions such as amines and sulphides. Second, although aluminum or other coordinating metals are often used as cationic partners, alkali metals alone will suffice. The Cannizzaro Reaction When a non-enolizable aldehyde is heated in strong aqueous base, a redox transformation known as the Cannizzaro reaction takes place. Two examples are shown in the following diagram. In the first, formaldehyde disproportionates into methanol and formic acid (sodium salt). In the second, a benzaldehyde derivative is similarly converted into an equimolar mixture of the corresponding benzyl alcohol and benzoic acid derivatives. A hydride transfer mechanism analogous to that of the MVP reaction is drawn in the shaded box. If the Cannizzaro reaction is run in D2O with NaOD as a base, no C-D incorporation is observed. Thus the new carbon-bonded hydrogen in the alcohol cannot have come from the solvent. It is important to remember that the the Cannizzaro reaction is restricted to non-enolizable aldehydes. The strong base used for this reaction would initiate aldol and other reactions that take place via enolate anions. A useful crossed Cannizzaro reaction employs an excess of formaldehyde to reduce aryl aldehyde substrates to 1 º-alcohols. The success of this procedure may be attributed to the high concentration of the hydrate, H2C(OH)2, in aqueous solutions of formaldehyde, making it the only significant hydride donor in the system. An intramolecular Cannizzaro reaction, sometimes termed a Cannizzaro rearrangement will be displayed above . A variant of the Cannizzaro reaction, known as the Tischenko reaction is also shown. In this reaction the alcohol and acid products combine to form an ester. The reductive conversion of a carbonyl group to a methylene group requires complete removal of the oxygen, and is called deoxygenation. In the shorthand equation shown here the [H] symbol refers to unspecified reduction conditions which effect the desired change. Three very different methods of accomplishing this transformation will be described here. R2C=O   +   [H]      R2CH2   +   H2O 1. Wolff-Kishner Reduction Reaction of an aldehyde or ketone with excess hydrazine generates a hydrazone derivative, which on heating with base gives the corresponding hydrocarbon. A high-boiling hydroxylic solvent, such as diethylene glycol, is commonly used to achieve the temperatures needed. The following diagram shows how this reduction may be used to convert cyclopentanone to cyclopentane. A second example, in which an aldehyde is similarly reduced to a methyl group, also illustrates again the use of an acetal protective group. The mechanism of this useful transformation involves tautomerization of the initially formed hydrazone to an azo isomer, and will be displayed on pressing the "Show Mechanism" button. The strongly basic conditions used in this reaction preclude its application to base sensitive compounds. Back to the Top 2. Clemmensen Reduction This alternative reduction involves heating a carbonyl compound with finely divided, amalgamated zinc. in a hydroxylic solvent (often an aqueous mixture) containing a mineral acid such as HCl. The mercury alloyed with the zinc does not participate in the reaction, it serves only to provide a clean active metal surface. The first example below shows a common application of this reduction, the conversion of a Friedel-Crafts acylation product to an alkyl side-chain. The second example illustrates the lability of functional substituents alpha to the carbonyl group. Substituents such as hydroxyl, alkoxyl & halogens are reduced first, the resulting unsubstituted aldehyde or ketone is then reduced to the parent hydrocarbon. 3. Hydrogenolysis of Thioacetals In contrast to the previous two procedures, this method of carbonyl deoxygenation requires two separate steps. It does, however, avoid treatment with strong base or acid. The first step is to convert the aldehyde or ketone into a thioacetal, as described earlier. These derivatives may be isolated and purified before continuing the reduction. The second step involves refluxing an acetone solution of the thioacetal over a reactive nickel catalyst, called Raney Nickel. All carbon-sulfur bonds undergo hydrogenolysis (the C–S bonds are broken by addition of hydrogen). In the following example, 1,2-ethanedithiol is used for preparing the thioacetal intermediate, because of the high yield this reactant usually affords. The bicyclic compound shown here has two carbonyl groups, one of which is sterically hindered (circled in orange). Consequently, a mono-thioacetal is easily prepared from the less-hindered ketone, and this is reduced without changing the remaining carbonyl function. B. Oxidation The carbon atom of a carbonyl group has a relatively high oxidation state. This is reflected in the fact that most of the reactions described thus far either cause no change in the oxidation state (e.g. acetal and imine formation) or effect a reduction (e.g. organometallic additions and deoxygenations). The most common and characteristic oxidation reaction is the conversion of aldehydes to carboxylic acids. In the shorthand equation shown here the [O] symbol refers to unspecified oxidation conditions which effect the desired change. Several different methods of accomplishing this transformation will be described here. RCH=O   +   [O]      RC(OH)=O In discussing the oxidations of 1º and 2º-alcohols, we noted that Jones' reagent (aqueous chromic acid) converts aldehydes to carboxylic acids, presumably via the hydrate. Other reagents, among them aqueous potassium permanganate and dilute bromine, effect the same transformation. Even the oxygen in air will slowly oxidize aldehydes to acids or peracids, most likely by a radical mechanism. Useful tests for aldehydes, Tollens' test, Benedict's test & Fehling's test, take advantage of this ease of oxidation by using Ag(+) and Cu(2+) as oxidizing agents (oxidants). RCH=O   +   2 [Ag(+) OH(–)]      RC(OH)=O   +   2 Ag (metallic mirror)   +   H2O When silver cation is the oxidant, as in the above equation, it is reduced to metallic silver in the course of the reaction, and this deposits as a beautiful mirror on the inner surface of the reaction vessel. The Fehling and Benedict tests use cupric cation as the oxidant. This deep blue reagent is reduced to cuprous oxide, which precipitates as a red to yellow solid. All these cation oxidations must be conducted under alkaline conditions. To avoid precipitation of the insoluble metal hydroxides, the cations must be stabilized as complexed ions. Silver is used as its ammonia complex, Ag(NH3)2(+), and cupric ions are used as citrate or tartrate complexes. Saturated ketones are generally inert to oxidation conditions that convert aldehydes to carboxylic acids. Nevertheless, under vigorous acid-catalyzed oxidations with nitric or chromic acids ketones may undergo carbon-carbon bond cleavage at the carbonyl group. The reason for the vulnerability of the alpha-carbon bond will become apparent in the following section. Stable Carbonyl Hydrates & Hemiacetals Although most aldehydes and ketones do not form stable hydrates or hemiacetals, a number of interesting exceptions are known. Some examples are shown here. The factors that act to favor hydrate or hemiacetal formation include inductive charge repusion (chloral) dipole repusion (ninhydrin) and angle strain (cyclopropanaone). It is important to note that cases in which 5 or 6-membered cyclic hemiacetals can form usually favor such constitutions. The simple sugars offer many examples of this kind. Because these additions are readily reversible, all compounds of this type exhibit carbonyl-like chemical reactivity.  Back to the Top Aldehyde and Ketone Derivatives 1. Kinetic vs. Equilibrium Control in Semicarbazone Formation A striking demonstration of kinetic control vs. thermodynamic (equilibrium) control of products is provided by an experiment in which equimolar amounts of cyclohexanone, furfuraldehyde and semicarbazide are mixed in a buffered solvent at pH=5. The semicarbazide reacts with cyclohexanone 60 times faster than it does with the aldehyde, and within 45 seconds a nearly quantitative amount of the semicarbazone derivative of cyclohexanone has precipitated and may be isolated by filtration. However, if the initial reaction mixture containing the cyclohexanone product is refluxed for a few hours an equally good yield of the more stable furfuraldehyde semicarbazone is obtained. Note that in both cases the semicarbazone derivative is favored over the initial reactants, but the equilibrium constant for the aldehyde is about 300 times greater than that of the ketone. The aldehyde semicarbazone is therefore the thermodynamically favored product, assuming there is equilibrium at all steps. 2. Dinitrophenylhydrazones Another commonly used carbonyl derivative is prepared from 2,4-dinitrophenylhydrazine, as shown below. The reagent and its hydrazone derivatives are distinctively colored solids, which can be isolated easily. Saturated ketones and aldehydes are usually yellow to light orange in color. Conjugation of the carbonyl group with a double bond or benzene ring shifts the color to shades of red. 3. Aldehyde Derivatives Among aldehydes, formaldehyde, H2C=O, has many unique properties. For example, with ammonia it reacts in a 3:2 ratio to give a tricyclic product, shown on the right, and known as hexamethylenetetramine. This interesting compound may function as an ammonia derivative for the synthesis of 1º-amines, or as a convenient high-melting source of formaldehyde by way of acid-catalyzed hydrolysis. An interesting reagent that distinguishes aldehydes from ketones is the hydrazine derivative, 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole, best known as Purpald (formula shown below). Although this reagent reacts with both aldehydes and ketones, only the aldehyde product is further oxidized to a purple, 10 π-electron aromatic heterocycle on exposure to air. Note that the pair of electrons on the nitrogen atom common to both rings is part of the π-electron system.   Reactions at the α-Carbon Many aldehydes and ketones undergo substitution reactions at an alpha carbon, as shown in the following diagram (alpha-carbon atoms are colored blue). These reactions are acid or base catalyzed, but in the case of halogenation the reaction generates an acid as one of the products, and is therefore autocatalytic. If the alpha-carbon is a chiral center, as in the second example, the products of halogenation and isotopic exchange are racemic. Indeed, treatment of this ketone reactant with acid or base alone serves to racemize it. Not all carbonyl compounds exhibit these characteristics, the third ketone being an example. Two important conclusions may be drawn from these examples. First, these substitutions are limited to carbon atoms alpha to the carbonyl group. Cyclohexanone (the first ketone) has two alpha-carbons and four potential substitutions (the alpha-hydrogens). Depending on the reaction conditions, one or all four of these hydrogens may be substituted, but none of the remaining six hydrogens on the ring react. The second ketone confirms this fact, only the alpha-carbon undergoing substitution, despite the presence of many other sites. Second,the substitutions are limited to hydrogen atoms. This is demonstrated convincingly by the third ketone, which is structurally similar to the second but has no alpha-hydrogen. Back to the Top   1. Mechanism of Electrophilic α-Substitution Kinetic studies of these reactions provide additional information. The rates of halogenation and isotope exchange are essentially the same (assuming similar catalsts  and concentrations), and are identical to the rate of racemization for those reactants having chiral alpha-carbon units. At low to moderate halogen concentrations, the rate of halogen substitution is proportional (i.e. first order) to aldehyde or ketone concentration, but independent of halogen concentration. This suggests the existence of a common reaction intermediate, formed in a slow (rate-determining step) prior to the final substitution. Acid and base catalysts act to increase the rate at which the common intermediate is formed, and their concentration also influences the overall rate of substitution.From previous knowledge and experience, we surmise that the common intermediate is an enol tautomer of the carbonyl reactant. Several facts support this proposal: (i)   Compounds that do not have any α-hydrogen atoms cannot enolize and do not undergo any of the reactions described above.(ii)   The carbon-carbon double bond of an enol is planar, so any chirality that existed at the α carbon is lost on enolization. If chiral products are           obtained from enol intermediates they will necessarily be racemic.(iii)   In simple aldehydes and ketones enol tautomers are present in very low concentration. Reactions that involve enol reactants will therefore be limited in rate by the enol concentration. Increasing the amounts of other reactants will have little effect on the reaction rate.(iv)   Enolization is catalyzed by acids and bases. These catalysts will therefore catalyze reactions proceeding via enol intermediates. The reactions shown above, and others to be described, may be characterized as an electrophilic attack on the electron rich double bond of an enol tautomer. This resembles closely the first step in the addition of acids and other electrophiles to alkenes. Therefore, if electrophilic substitution reactions of this kind are to take place it is necessary that nucleophilic character be established at the alpha-carbon. A full description of the acid and base-catalyzed keto-enol tautomerization process (shown below) discloses that only two intermediate species satisfy this requirement. These are the enol tautomer itself and its conjugate base (common with that of the keto tautomer), usually referred to as an enolate anion. Clearly, the proportion of enol tautomer present at equilibrium is a critical factor in alpha substitution reactions. In the case of simple aldehydes and ketones this is very small, as noted above. A complementary property, the acidity of carbonyl compounds is also important, since this influences the concentration of the more nucleophilic enolate anion in a reaction system. Ketones such as cyclohexanone are much more acidic than their parent hydrocarbons (by at least 25 powers of ten); nevertheless they are still very weak acids (pKa = 17 to 21) compared with water. Together with some related acidities, this is listed in the following table. Even though enol tautomers are about a million times more acidic than their keto isomers, their low concentration makes this feature relatively unimportant for many simple aldehydes and ketones. Acidity of α-Hydrogens in Some Activated Compounds Compound RCH2–NO2 RCH2–COR RCH2–C≡N RCH2–SO2R pKa 9 20 25 25 In cases where more than one activating function influences a given set of alpha-hydrogens, the enol concentration and acidity is increased.   In view of these facts it may seem surprising that alpha-substitution reactions occur at all. However, we often fail to appreciate the way in which a rapid equilibrium involving a minor reactive component may spread the consequences of its behavior throughout a much larger population. Consider, for example, a large group of hungry, active hampsters running about in a big cage. Opening onto the cage there is a small annex that can hold a maximum of three hampsters. Out of two hundred hampsters in the cage, there are an average of two hampsters in the annex at any given time. The hampsters are free to enter and exit the annex, but any hampster that does so is marked by a bright red dye. Although the hampster concentration in the annex is small relative to the whole population, it will not be long before all the hampsters are dyed red. If we substitute molecules for hampsters, their numbers will be extraordinarily large (recall the size of Avogadro's number), but the equilibrium between keto tautomers (hampsters in the cage) and enol tautomers (hampsters in the annex) is so rapid that complete turnover of all the molecules in a sample may occur in fractions of a second rather than minutes or hours. The principle is the same in both cases.Racemization and isotope exchange are due to the rapid equilibrium between chiral keto tautomers and achiral enol tautomers, as well as statistical competition between hydrogen and its deuterium isotope. For halogenation there is also a thermodynamic driving force, resulting from increased bond energy in the products. For example,the alpha-chlorination of cyclohexane, shown above, is exothermic by over 10 kcal/mole. The Haloform Reaction Methyl ketones undergo a unique oxidative cleavage on treatment with halogens in aqueous base. Back to the Top 2. The Aldol Reaction A useful carbon-carbon bond-forming reaction known as the Aldol Reaction or the Aldol Condensation is yet another example of electrophilic substitution at the alpha carbon in enols or enolate anions. Three examples of the base-catalyzed aldol reaction are shown in the following diagram, and equivalent acid-catalyzed reactions also occur. The fundamental transformation in this reaction is a dimerization of an aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the carbonyl group of a second reactant molecule. By clicking the "Structural Analysis" button below the diagram, a display showing the nucleophilic enolic donor molecule and the electrophilic acceptor molecule together with the newly formed carbon-carbon bond will be displayed. Stepwise mechanisms for the base-catalyzed and acid-catalyzed reactions may be seen by clicking the appropriate buttons. In the presence of acid or base catalysts the aldol reaction is reversible, and the beta-hydroxy carbonyl products may revert to the initial aldehyde or ketone reactants. In the absence of such catalysts these aldol products are perfectly stable and isolable compounds. Because of this reversibility, the yield of aldol products is related to their relative thermodynamic stability. In the case of aldehyde reactants (as in reactions #1 & 2 above), the aldol reaction is modestly exothermic and the yields are good. However, aldol reactions of ketones are less favorable (e.g. #3 above), and the equilibrium product concentration is small. A clever way of overcoming this disadvantage has been found. A comparatively insoluble base, Ba(OH)2, is used to catalyze the aldol reaction of acetone, and the product is removed from contact with this base by filtration and recirculation of the acetone.  A. Dehydration of Aldol Products The products of aldol reactions often undergo a subsequent elimination of water, made up of an alpha-hydrogen and the beta-hydroxyl group. The product of this beta-elimination reaction is an α,β-unsaturated aldehyde or ketone, as shown in the following diagram. Acid-catalyzed conditions are more commonly used to effect this elimination (examples #1, 2 & 5), but base-catalyzed elimination also occurs, especially on heating (examples #3, 4 & 5). The additional stability provided by the conjugated carbonyl system of the product makes some ketone aldol reactions thermodynamically favorable (#4 & 5), and mixtures of stereoisomers (E & Z) are obtained from reaction #4. Reaction #5 is an interesting example of an intramolecular aldol reaction; such reactions create a new ring. Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product such as water are termed Condensations. Hence the following examples are properly referred to as aldol condensations. The dehydration step of an aldol condensation is also reversible in the presence of acid and base catalysts. Consequently, on heating with aqueous solutions of strong acids or bases, many α, β-unsaturated carbonyl compounds fragment into smaller aldehyde or ketones, a process known as the retro-aldol reaction. The acid-catalyzed elimination of water is not exceptional, since this was noted as a common reaction of alcohols. Nevertheless, the conditions required for the beta-elimination are found to be milder than those used for simple alcohols. The most surprising aspect of beta-elimination, however, is that it can be base-catalyzed. In earlier discussions we have noted that hydroxyl anion is a very poor leaving group. Why then should the base-catalyzed elimination of water occur in aldol products? To understand this puzzle we need to examine plausible mechanisms for beta-elimination, and these will be displayed by clicking the "Beta-Elimination Mechanism" button under the diagram.As shown by the equations, these eliminations might proceed from either the keto or enol tautomers of the beta-hydroxy aldol product. Although the keto tautomer route is not unreasonable (recall the enhanced acidity of the alpha-hydrogens in carbonyl compounds), the enol tautomer provides a more favorable pathway for both acid and base-catalyzed elimination of the beta oxygen. Indeed, the base-catalyzed loss of hydroxide anion from the enol is a conjugated analog of the base-catalyzed decomposition of a hemiacetal. Back to the Top  B. Mixed Aldol Condensations The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, nd under certain conditions such crossed aldol condensations can be effective. Some examples are shown below, and in most cases beta-elimination of water occurs under the conditions used. The exception, reaction #3, is conducted under mild conditions with an excess of the reactive aldehyde formaldehyde serving in the role of electrophilic acceptor. The first reaction demonstrates that ketones having two sets of alpha-hydrogens may react at both sites if sufficient acceptor co-reactant is supplied. The interesting difference in regioselectivity shown in the second reaction (the reactants are in the central shaded region) illustrates some subtle differences between acid and base-catalyzed aldol reactions. The base-catalyzed reaction proceeds via an enolate anion donor species, and the kinetically favored proton removal is from the less substituted alpha-carbon. The acid-catalyzed aldol proceeds via the enol tautomer, and the more stable of the two enol tautomers is that with the more substituted double bond. Finally, reaction #4 has two reactive alpha-carbons and a reversible aldol reaction may occur at both. Only one of the two aldol products can undergo a beta-elimination of water, so the eventual isolated product comes from that reaction sequence. The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction. The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.ACH2CHO   +   BCH2CHO   +   NaOH     A–A   +   B–B  +  A–B   +   B–A Directed Stereoselective Aldol Reactions The effectiveness of the aldol reaction as a synthetic tool has been enhanced by controlling the enolization of donor compounds, and subsequent reactions with acceptor carbonyls. 3. Irreversible Substitution Reactions In its simplest form the aldol reaction is reversible, and normally forms the thermodynamically favored product. To fully appreciate the complex interplay of factors that underlie this important synthesis tool, we must evaluate the significance of several possible competing reaction paths. A. The Ambident Character of Enolate Anions Since the negative charge of an enolate anion is delocalized over the alpha-carbon and the oxygen, as shown earlier, electrophiles may bond to either atom. Reactants having two or more reactive sites are called ambident, so this term is properly applied to enolate anions. Modestly electrophilic reactants such as alkyl halides are not sufficiently reactive to combine with neutral enol tautomers, but the increased nucleophilicity of the enolate anion conjugate base permits such reactions to take place. Because alkylations are usually irreversible, their products should reflect the inherent (kinetic) reactivity of the different nucleophilic sites. If an alkyl halide undergoes an SN2 reaction at the carbon atom of an enolate anion the product is an alkylated aldehyde or ketone. On the other hand, if the SN2 reaction occurs at oxygen the product is an ether derivative of the enol tautomer; such compounds are stable in the absence of acid and may be isolated and characterized. These alkylations (shown above) are irreversible under the conditions normally used for SN2 reactions, so the product composition should provide a measure of the relative rates of substitution at carbon versus oxygen. It has been found that this competition is sensitive to a number of factors, including negative charge density, solvation, cation coordination and product stability.For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the absence of other strong nucleophiles and bases. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of simple carbonyl compounds are formed in very low concentration, and hydroxide or alkoxide bases induce competing SN2 and E2 reactions of alkyl halides. It is necessary, therefore, to achieve complete conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25) in a non-hydroxylic solvent before any alkyl halides are added to the reaction system. Some bases having pKa's greater than 30 were described earlier, and some others that have been used for enolate anion formation are: NaH (sodium hydride, pKa > 45), NaNH2 (sodium amide, pKa = 34), and (C6H5)3CNa (trityl sodium, pKa = 32). Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. Certain other strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to carbonyl groups. Nevertheless, these very strong bases are useful in making soluble amide bases. In the preparation of lithium diisopropylamide (LDA), for example, the only other product is the gaseous alkane butane.   C4H9–Li   +   butyl lithium [(CH3)2CH]2N–H   diisopropylamine [(CH3)2CH]2N(–) Li(+)  +  C4H10 LDA       O=C-C-H   +     LDA       (–)O–C=C  +  [(CH3)2CH]2N–H Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application one equivalent of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate reactions and is easily removed from the products by washing with aqueous acid. Although the reaction of carbonyl compounds with sodium hydride is heterogeneous and slow, sodium enolates are formed with the loss of hydrogen, and no other organic compounds are produced. The following equation provides examples of electrophilic substitution at both carbon and oxygen for the enolate anion derived from cyclohexanone. Back to the Top A full analysis of the factors that direct substitution of enolate anions to carbon or oxygen is beyond the scope of this text. However, an outline of some significant characteristics that influence the two reactions shown above is illustrative. Reactant Important Factors CH3–I The negative charge density is greatest at the oxygen atom (greater electronegativity), and coordination with the sodium cation is stronger there. Because methyl iodide is only a modest electrophile, the SN2 transition state resembles the products more than the reactants. Since the C-alkylation product is thermodynamically more stable than the O-alkylated enol ether, this is reflected in the transition state energies. (CH3)3Si–Cl Trimethylsilyl chloride is a stronger electrophile than methyl iodide (note the electronegativity difference between silicon and chlorine). Relative to the methylation reaction, the SN2 transition state will resemble the reactants more than the products. Consequently, reaction at the site of greatest negative charge (oxygen) will be favored. Also, the high Si–O bond energy (over 25 kcal/mole greater than Si–C) thermodynamically favors the silyl enol ether product.  B. Alkylation Reactions of Enolate Anions The reaction of alkyl halides with enolate anions presents the same problem of competing SN2 and E2 reaction paths that was encountered earlier in the alkyl halide. Since enolate anions are very strong bases, they will usually cause elimination when reacted with 2º and 3º-halides. Halides that are incapable of elimination and/or have enhanced SN2 reactivity are the best electrophilic reactants for this purpose. Four examples of the C-alkylation of enolate anions in synthesis are displayed in the following diagram. The first two employ the versatile strong base LDA, which is the reagent of choice for most intermolecular alkylations of simple carbonyl compounds. The dichloro alkylating agent used in reaction #1 nicely illustrates the high reactivity of allylic halides and the unreactive nature of vinylic halides in SN2 reactions. The additive effect of carbonyl groups on alpha-hydrogen acidity is demonstrated by reaction #3. Here the two hydrogen atoms activated by both carbonyl groups are over 1010 times more acidic than the methyl hydrogens on the ends of the carbon chain. Indeed, they are sufficiently acidic (pKa = 9) to allow complete conversion to the enolate anion in aqueous or alcoholic solutions. As shown (in blue), the negative charge of the enolate anion is delocalized over both oxygen atoms and the central carbon. The oxygens are hydrogen bonded to solvent molecules, so the kinetically favored SN2 reaction occurs at the carbon. The monoalkylated product shown in the equation still has an acidic hydrogen on the central carbon, and another alkyl group may be attached there by repeating this sequence.The last example (reaction #4) is an interesting case of intramolecular alkylation of an enolate anion. Since alkylation reactions are irreversible, it is possible to form small highly strained rings if the reactive sites are in close proximity. Reversible bond-forming reactions, such as the aldol reaction, cannot be used for this purpose. The use of aqueous base in this reaction is also remarkable, in view of the very low enolate anion concentration noted earlier for such systems. It is the rapid intramolecular nature of the alkylation that allows these unfavorable conditions to be used. The five-carbon chain of the dichloroketone can adopt many conformations, two of which are approximated in the preceding diagram. Although conformer II of the enolate anion could generate a stable five-membered ring by an intramolecular SN2 reaction, assuming proper orientation of the α and γ' carbon atoms, the concentration of this ideally coiled structure will be very low. On the other hand, conformations in which the α and γ-carbons are properly aligned for three-membered ring formation are much more numerous, the result being that as fast as the enolate base is formed it undergoes rapid and irreversible cyclization.Ring closures to four, five, six and seven-membered are also possible by intramolecular enolate alkylation, as illustrated by the following example. In general, five and six-membered rings are thermodynamically most stable, whereas three-membered ring formation is favored kinetically. Aldehyde Ketone Reaction Summary Preparation Commonly by oxidation of 1º & 2º-alcohols by chromium+6 reagents (e.g. PCC and Jones' reagent). Reactions Aldehydes are oxidized to carboxylic acids by Jones' reagent or Tollens' reagent. Ketones are not. Both classes undergo the following chemical transformations: Acetals and hemiacetals by reversible addition-elimination of alcohols. (acetals require removal of water) Imines and enamines by reversible addition-elimination of 1º & 2º-amines respectively. (removal of water is necessary) Cyanohydrins by reversible addition-elimination of HCN. Reduction to1º & 2º-alcohols by NaBH4 and LiAlH4 (irreversible hydride addition). Reduction to alkanes by Wolff-Kishner or Clemmensen conditions. Formation of 1º, 2º or 3º-alcohols by addition of organometallic reagents to formaldehyde, other aldehydes or ketones.    Back to the Top                                                                     to Alcohols                                                                                                               to Alkyl Halides                                                                                                                to Carboxylic Acids                                                                                                   Go to Main Menu