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.

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)

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 reversibility   .

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, as discussed earlier.

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

An addition-elimination mechanism for this reaction was proposed, and an animation showing this mechanism is activated by the button. 

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.

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. A mechanism for enamine formation may be seen by pressing the "Show Mechanism" button.

mec

hanism:

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. Cyanohydrin 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.

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; diglymeavoid strong acids

aldehydes to 1º-alcoholsketones to 2º-alcoholsinert to most other functions

1) simple neutralization 2) extraction of product

Lithium Aluminum Hydride    LiAlH4

ether; THFavoid alcohols and aminesavoid halogenated compoundsavoid strong acids

aldehydes to 1º-alcoholsketones to 2º-alcoholscarboxylic acids to 1º-alcoholsesters to alcoholsepoxides to alcoholsnitriles & amides to amineshalides & tosylates to alkanesmost functions react

1) careful addition of water2) 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 product2)   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. 

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, 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.

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.

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.

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.

mechanismm

mechanism:

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. A possible mechanism for the Clemmensen reduction will be displayed by clicking the "Show Mechanism" button.

MEchanism:

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.

Alpha Halogenation

A carbonyl containing compound with α hydrogens can undergo a substitution reaction with halogens. This reaction comes about because of the tendency of carbonyl compounds to form enolates in basic condition and enols in acidic condition. In these cases even weak bases, such as the hydroxide anion, is sufficient enough to cause the reaction to occur because it is not necessary for a complete conversion to the enolate. For this reaction Cl2, Br2 or I2 can be used as the halogens.

 

General reaction

Example

 

Acid Catalyzed Mechanism

Under acidic conditions the reaction occurs thought the formation of an enol which then reacts with the halogen. 

 

1) Protonation of the carbonyl

 

2) Enol formation

3) SN2 attack

 

4) Deprotonation

Base Catalyzed Mechanism

Under basic conditions the enolate forms and then reacts with the halogen.  Note! This is base promoted and not base catalyzed because an entire equivalent of base is required. 

 

1) Enolate formation

 

2)  SN2 attack

Overreaction during base promoted α halogenation

The fact that an electronegative halogen is placed on an α carbon means that the product of a base promoted α halogenation is actually more reactive than the starting material. The electron withdrawing effect of the halogen makes the α carbon even more acidic and therefor promotes further reaction. Because of this multiple halogenations can occur.  This effect is exploited in the haloform reaction discussed later. If a monohalo product is required then acidic conditions are usually used.

 

The Haloform ReactionMethyl ketones typically undergo halogenation three times to give a trihalo ketone due to the increased reactivity of the halogenated product as discussed above. This trihalomethyl group is an effective leaving group due to the three electron withdrawing halogens and can be cleaved by a hydroxide anion to effect the haloform reaction. The product of this reaction is a carboxylate and a haloform molecule (CHCl3, CHBr3, CHI3).  Overall the haloform reaction represents an effective method for the conversion of methyl ketones to carboxylic acids. Typically, this reaction is performed using iodine because the subsequent iodoform (CHI3) is a bright yellow precipitate which is easily filtered off.General reaction

Example: The Haloform Reaction

Mechanism

1) Formation of the trihalo species

2)  Nulceophilic attack on the carbonyl carbon

3) Removal of the leaving group

4)  Deprotonation

 

Aldol Condensation

In some cases, the adducts obtained from the Aldol Addition can easily be converted (in situ) to α,β-unsaturated carbonyl compounds, either thermally or under acidic or basic catalysis. The formation of the conjugated system is the driving force for this spontaneous dehydration. Under a variety of protocols, the condensation product can be obtained directly without isolation of the aldol.

The aldol condensation is the second step of the Robinson Annulation.

Mechanism of the Aldol Condensation

Tests for Aldehydes and Ketones

2,4-DNP Test for Aldehydes and Ketones

Tollen's Test for Aldehydes

Jones (Chromic Acid) Oxidation Test for Aldehydes

Iodoform Test for Methyl Ketones

2,4-DNP Test for Aldehydes and Ketones

Aldehyde or Ketone

StandardsCyclohexanone, Benzophenone, and Benzaldehyde

ProcedureAdd a solution of 1 or 2 drops or 30 mg of unknown in 2 mL of 95% ethanol to 3 mL of 2,4-dinitrophenylhydrazine reagent. Shake vigorously, and, if no precipitate forms immediately, allow the solution to stand for 15 minutes.The 2,4-dinitrophenylhydrazine reagent will already be prepared for you.

Positive testFormation of a precipitate is a positive test.

Complications

Some ketones give oils which will not solidify. Some allylic alcohols are oxidized by the reagent to aldehydes and give a

positive test. Some alcohols, if not purified, may contain aldehyde or ketone impurities.

 

Tollen’s Test for Aldehydes

Aldehyde

StandardsCyclohexanone and Benzaldehyde

ProcedureAdd one drop or a few crystals of unknown to 1 mL of the freshly prepared Tollens reagent. Gentle heating can be employed if no reaction is immediately observed.Tollens reagent: Into a test tube which has been cleaned with 3M sodium hydroxide, place 2 mL of 0.2 M silver nitrate solution, and add a drop of 3M sodium hydroxide. Add 2.8% ammonia solution, drop by drop, with constant shaking, until almost all of the precipitate of silver oxide dissolves. Don't use more than 3 mL of ammonia. Then dilute the entire solution to a final volume of 10 mL with water.

Positive TestFormation of silver mirror or a black precipitate is a positive test.

Complications

The test tube must be clean and oil-free if a silver mirror is to be observed. Easily oxidized compounds give a positive test. For example: aromatic amine

and some phenols.

Cleaning upPlace all solutions used in this experiment in an appropriate waste container.

 

Jones (Chromic Acid) Oxidation Test for Aldehydes

Aldehydes

StandardsCyclohexanone and Benzaldehyde

ProcedureDissolve 10 mg or 2 drops of the unknown in 1 mL of pure acetone in a test tube and add to the solution 1 small drop of Jones reagent (chronic acid in sulfuric acid). A positive test is marked by the formation of a green color within 5 seconds upon addition of the orange-yellow reagent to a primary or secondary alcohol. Aldehydes also give a positive test, but tertiary alcohols do not.The Jones reagent will already be prepared for you.

Positive TestA positive test for aldehydes and primary or secondary alcohols consists in the production of an opaque suspension with a green to blue color. Tertiary alcohols give no visible reaction within 2 seconds, the solution remaining orange in color. Disregard any changes after 15 seconds.

Complications

Aldehydes are better characterized in other ways. The color usually develops in 5-15 seconds.

Cleaning upPlace the test solution in the appropriate waste container.

 

Iodoform Test for Methyl Ketones

Ketone

StandardAcetone

ProcedureIf the substance to be tested is water soluble, dissolve 4 drops of a liquid or an estimated 50 mg of a solid in 2 mL of water in a large test tube. Add 2 mL of 3 M sodium hydroxide and then slowly add 3 mL of the iodine solution. Stopper the test tube and shake vigorously. A positive test will result in the brown color of the reagent disappearing and the yellow iodoform solid precipitating out of solution. If the substance to be tested is insoluble in water, dissolve it in 2 mL of 1,2-dimethoxyethane, proceed as above, and at the end dilute with 10 mL of water.

Positive TestFormation of solid iodoform (yellow) is a positive test. (Iodoform can be recognized by its odor and yellow color and, more securely, from the melting point 119o-123oC).

ComplicationsTest will not be positive if the R group is a di-ortho substituted aryl group

Cleaning UpPlace solutions in the appropriate waste container.

 Reductive amination:

Reductive amination (also known asreductive alkylation) is a form of aminationthat involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde.

Reaction process

In this organic reaction, the amine first reacts with the carbonyl group to form a hemiaminal species, which subsequently loses one molecule of water in a reversible manner byalkylimino-de-oxo-bisubstitution, to form the imine. The equilibrium between aldehyde/ketone and imine can be shifted toward imine formation by removal of the formed water through physical or chemical means. This intermediate imine can then be isolated and reduced with a suitable reducing agent (e.g., sodium borohydride). This method is sometimes called indirect reductive amination.

Imine formation and reduction occur sequentially in one pot. This approach, known as direct reductive amination, employs reducing agents that are more reactive toward protonated imines than towards the ketone/aldehyde precursors. These hydride reagents also must tolerate moderately acidic conditions. Typical reagents that meet these criteria includesodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OCOCH3)3).[2] This reaction can be performed in an aqueous environment, which casts doubt on the necessity of forming the imine.[3]

[4] Possibly the reaction proceeds via reduction of the hemiaminal species.[5]

Biochemistry[edit]

A step in the biosynthesis of many α-amino acids is the reductive amination of an α-ketoacid, usually by a transaminase enzyme. The process is catalyzed by pyridoxamine phosphate, which is converted into pyridoxal phosphate after the reaction. The initial step entails formation of an imine, but the hydride equivalents are supplied by a reduced pyridine to give an aldimine, which hydrolyzes to the amine.[9] The sequence from keto-acid to amino acid can be summarized as follows:

HO2CC(O)R → HO2CC(=NCH2–X)R → HO2CCH(N=CH–X)R → HO2CCH(NH2)R

Reductive Amination

Related

Reduction of imines

Name Reactions

Eschweiler-Clarke Reaction

Recent Literature

By optimizing the metal hydride/ammonia mediated reductive amination of aldehydes and hemiacetals, primary amines were selectively prepared with no or minimal formation of the usual secondary and tertiary amine byproduct. The methodology was performed on a range of functionalized aldehyde substrates, including in situ formed aldehydes from a Vasella reaction.

E. M. Dangerfield, C. H. Plunkett, A. L. Win-Mason, B. L. Stocker, M. S. M. Timmer, J. Org. Chem., 2010, 75, 5470-5477.

A simple and convenient procedure enables the reductive alkylation of primary and secondary amines and N,N-dimethylation of amino acids using sodium borohydride as reducing agent in 2,2,2- trifluoroethanol without use of a catalyst or any other additive. The solvent can be revovered and reused.M. Taibakhsh, R. Hosseinzadeh, H. Alinezhad, S. Ghahari, A. Heydari, S. Khaksar, Synthesis, 2011, 490-496.

Sodium triacetoxyborohydride is a general, mild, and selective reducing agent for the reductive amination of various aldehydes and ketones. 1,2-Dichloroethane (DCE) is the preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran and occasionally in acetonitrile. Acetic acid may be used as catalyst with ketone reactions. Acid sensitive functional groups such as acetals and ketals, and reducible functional groups such as C-C multiple bonds and cyano and nitro groups are tolerated.A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff, R. D. Shah, J. Org. Chem., 1996, 61, 3849-3862.

In the reductive amination of some aldehydes with primary amines where dialkylation is a problem, a stepwise procedure involving imine formation in MeOH followed by reduction with NaBH4 was developed.A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff, R. D. Shah, J. Org. Chem., 1996, 61, 3849-3862.

Aldehydes and ketones were easily converted to the corresponding amines by the reaction of amines in methanol using decaborane (B10H14) at room temperature under nitrogen. The reaction is simple and efficient.J. W. Bae, S. H. Lee, Y. J. Cho, C. M. Yoon, J. Chem. Soc., Perkin Trans. 1, 2000, 145-146.

Reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH system is highly chemoselective and can be applied to various cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are tolerated.O.-Y. Lee, K.-L. Law, C.-Y. Ho, D. Yang, J. Org. Chem., 2008, 73, 8829-8837.

A simple and convenient procedure allows the reductive amination of aldehydes and ketones using sodium borohydride as reducing agent and boric acid, p-toluenesulfonic acid monohydrate or benzoic acid as activator under solvent-free conditions.B. T. Cho, S. K. Kang, Tetrahedron, 2005, 61, 5725-5734.

Nickel nanoparticles catalyse the reductive amination of aldehydes by transfer hydrogenation with isopropanol at 76°C.F. Alonso, P. Riente, M. Yus, Synlett, 2008, 1289-1292.

N-heterocyclic carbene boranes (NHC-boranes) are among the most nucleophilic classes of neutral hydride donors. Reductions of highly electron-poor C=N and C=C bonds provide hydrogenation products along with new, stable borylated products. The results suggest that NHC-boranes have considerable untapped potential as neutral organic reductants.M. Horn, H. Mayr, E. Lacôte, E. Merling, J. Deaner, S. Well, T. McFadden, D. P. Curran, Org. Lett., 2012, 14, 82-85.

An effective reductive alkylation of electron-deficient o-chloroarylamines was developed. The derived N-alkylated o-chloroarylamines were elaborated to N-alkylazaindoles and N-alkylindoles via a novel one-pot process comprising copper-free Sonogashira

alkynylation and a base-mediated indolization reaction.M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett., 2006, 8, 3307-3310.

An efficient methodology for the reductive alkylation of secondary amines with aldehydes and Et3SiH using an iridium complex as a catalyst has been developed. In addition, a cheaper, easy-to-handle, and environmentally friendly reducing reagent such as polymethylhydrosiloxane (PMHS) in place of Et3SiH was also useful.T. Mizuta, S. Sakaguchi, Y. Ishii, J. Org. Chem., 2005, 70, 2195-2199.

An oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent enables a mild and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure of amines with alcohols.I. A. Khan, A. K. Saxena, J. Org. Chem., 2013, 78, 11656-11669.

Cooperative catalysis of an Ir(III)-diamine complex and a chiral phosphoric acid or its conjugate base enables a direct reductive amination of a wide range of ketones.C. Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc., 2009, 131, 6967-6969.

α-Imino esters derived from aryl and alkyl keto esters could be reduced to the corresponding α-amino esters in excellent yields and in high enantiomeric excesses using 5 mol-% of a chiral phosphoric acid as catalyst, Hantzsch ester as hydride donor,

and toluene as solvent.G. Li, Y. Liang, J. C. Antilla, J. Am. Chem. Soc., 2007, 129, 5830-5831.

A direct reductive amination of ketones using the Hantzsch ester in the presence of S-benzyl isothiouronium chloride as a recoverable organocatalyst converts a wide range of ketones as well as aryl amines to the expected products in good yields.Q. P. B. Nguyen, T. H. Kim, Synthesis, 2012, 44, 1977-1982.

A biomimetic direct reductive amination of ketones relies on selective imine activation by hydrogen bond formation with thiourea as hydrogen bond donor and utilizes the Hantzsch ester for transfer hydrogenation. The method allows the efficient synthesis of structurally diverse amines.D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter, S. Rudolph, Org. Lett., 2006, 8, 741-744.

A hydrogen-bond-catalyzed, acid- and metal-free direct reductive amination of aldehydes uses thiourea as organocatalyst and the Hantzsch ester for transfer-hydrogenation. This methods allows for the high-yielding synthesis of diverse amines.D. Menche, F. Arikan, Synlett, 2006, 841-844.

A selective and direct access to secondary amines by reductive mono-N-alkylation of primary amines with carbonyl compounds in the presence of Ti(i-PrO)4 and NaBH4 gave exclusively secondary amines.H. J. Kumpaty, S. Bhattacharyya, E. W. Rehr, A. M. Gonzalez, Synthesis, 2003, 2206-2210.

An experimentally simple Microwave-assisted reductive alkylation of methyl carbamate with a range of aldehydes provides, after basic work-up, structurally diverse primary amines. This method is particularly amenable to high-throughput synthesis.F. Lehmann, M. Scobie, Synthesis, 2008, 1679-1681.

Treatment of ketones with ammonia in ethanol and titanium(IV) isopropoxide, followed by in situ reduction with sodium borohydride allows a highly chemoselective reductive mono-alkylation of ammonia. A simple workup afforded primary amines in good to excellent yields. Reductive alkylation of ammonia with aldehydes afforded the corresponding symmetrical secondary amines selectively.B. Miriyala, S. Bhattacharyya, J. S. Williamson, Tetrahedron, 2004, 60, 1463-1471.

A mild and efficient one-pot reductive amination of aldehydes and ketones with amines using α-picoline-borane as a reducing agent in the presence of small amounts of AcOH is described. The reaction has been carried out in MeOH, in H2O, and in neat conditions. This is the first successful reductive amination in water and in neat conditions.S. Sato, T. Sakamoto, E. Miyazawa, Y. Kikugawa, Tetrahedron, 2004, 60, 7899-7906.

N-Alkylaminobenzenes were prepared in a simple and efficient one-pot synthesis by reduction of nitrobenzenes followed by reductive amination with decaborane (B10H14) in the presence of 10% Pd/C.J. W. Bae, Y. J. Cho, S. H. Lee, C.-O. M. Yoon, C. M. Yoon, Chem. Commun., 2000, 1857-1858.

J. W. Bae, Y. J. Cho, S. H. Lee, C.-O. M. Yoon, C. M. Yoon, Chem. Commun., 2000, 1857-1858.

An efficient, directed reductive amination of β-hydroxy-ketones allows the stereoselective preparation of 1,3-syn-amino alcohols using Ti(iOPr)4 for coordination of the intermediate imino alcohol and PMHS as the reducing agent.D. Menche, F. Arikan, J. Li, S. Rudolph, Org. Lett., 2007, 9, 267-270.

An efficient method for the direct reductive alkylation of hydrazine derivatives with α-picoline-borane provided various N-alkylhydrazine derivatives upon fine-tuning of the substrates and the reagent equivalency in a one-pot manner. The method was applied to the synthesis of active pharmaceutical ingredients of therapeutic drugs such as isocarboxazid.Y. Kawase, T. Yamagishi, J.-y. Kato, T. Kutsuma, T. Kataoka, T. Iwakuma, T. Yokomatsu, Synthesis, 2014, 46, 455-464.

An achiral amine in combination with a catalytic amount of a chiral Brønsted acid can accomplish an aldol addition-dehydration-conjugate reduction-reductive amination with 2,6-diketones to provide cyclohexylamines as potential intermediates of pharmaceutically active compounds in good yields and excellent enantioselectivities.J. Zhou, B. List, J. Am. Chem. Soc., 2007, 129, 7498-7499.

A one-pot, tandem reductive amination-transamidation-cyclization reaction produces substituted piperazin-2-ones in good yields.D. C. Beshore, C. J. Dinsmore, Org. Lett., 2002, 4, 1201-1204.

Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride.

Abstract

Sodium triacetoxyborohydride is presented as a general reducing agent for the

reductive amination of aldehydes and ketones. Procedures for using this mild and

selective reagent have been developed for a wide variety of substrates. The scope of

the reaction includes aliphatic acyclic and cyclic ketones, aliphatic and aromatic

aldehydes, and primary and secondary amines including a variety of weakly basic and

nonbasic amines. Limitations include reactions with aromatic and unsaturated ketones

and some sterically hindered ketones and amines. 1,2-Dichloroethane (DCE) is the

preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran

(THF) and occasionally in acetonitrile. Acetic acid may be used as catalyst with ketone

reactions, but it is generally not needed with aldehydes. The procedure is carried out

effectively in the presence of acid sensitive functional groups such as acetals and

ketals; it can also be carried out in the presence of reducible functional groups such as

C−C multiple bonds and cyano and nitro groups. Reactions are generally faster in DCE

than in THF, and in both solvents, reactions are faster in the presence of AcOH. In

comparison with other reductive amination procedures such as NaBH3CN/MeOH,

borane−pyridine, and catalytic hydrogenation, NaBH(OAc)3 gave consistently higher

yields and fewer side products. In the reductive amination of some aldehydes with

primary amines where dialkylation is a problem we adopted a stepwise procedure

involving imine formation in MeOH followed by reduction with NaBH4.

Reductive Amination via Imines

Reaction type : Nucleophilic Addition then Oxidation - Reduction

Summary

Aldehydes and ketones react (chapter 17) with  1o amines to give substituted imines and 2o amines to give enamines

These N species can then be reduced to amines. The method provides access to 1o, 2o, or 3o amines. Typical reagents : step 1 : acidic buffer  step 2 :  most commonly catalytic hydrogenation (e.g. H2/Pd) Sodium cyanoborohydride (NaBH3CN) (which is like NaBH4) can be used for smaller scale reductions. R, R' and R" may be either hydrogen, alkyl, or aryl.