ORGANIC CHEMISTRY
Organic synthesis via enolates
Dr. Vimal Rarh Lecturer Dept. of Chemistry S.G.T.B. Khalsa College Delhi
(14.06.2007)
CONTENTS Acidity of Alpha Hydrogens Acidity of β-dicarbonyl Compounds Hydrogen-Deuterium Exchange Alkylation of Enolate Anions Alkylation Reactions of Enolate Anions Regioselectivity in Enolate Anion Formation and Reaction Keto-enol tautomerism of Ethyl Acetoacetate Equilibrium of keto-enol Mixtures Enolisation Modern Theories of Tautomerism Position of Equilibrium in keto-enol Tautomerism Factors affecting the Enol Content Synthesis of Ethyl Acetoacetate: the Claisen Condensation Alkylation of Diethyl Malonate and Ethyl Ace toacetate Alkylation of 1,3-Dithianes Alkylation and Acylation of Enamines Enamines, Enols and Enolate Ions
1
Acidity of Alpha Hydrogens The α (alpha) - hydrogen is the hydrogen atom that is bound to the carbon (called as α -carbon atom) adjacent to the carbonyl carbon. The next carbon is the β-carbon and the hydrogen atoms attached to it are called as β -hydrogen atoms and so on.
Aldehydes and ketones are weak acids and have remarkably low pK a values (between 15 and 20). Hence, they may act as a Bronsted acid in an acid-base reaction with a strong base. But, aldehydes and ketones are much stronger acids than alkanes. Due to the only minor difference in electronegativity between hydrogen and carbon, C-H bonds in alkanes are hardly polarized. Thus, hydrogens of alkanes are in fact not acidic. The pK a values of alkanes are around 50.
The acidity of α of α-hydrogens of aldehydes and ketones is much less than carboxylic acids, which have pK a values around 3 to 4. Reason for acidity: The α - hydrogen of carbonyl compounds is acidic, as it is connected with the α -carbon that is directly bound to the electron withdrawing carbonyl group.
The carbonyl compounds' relatively high acidity (as compared to alkanes) may be explained by the resonance stabilization of the conjugate base by the carbonyl group, or, in other words, through the stabilization of the anion formed by deprotonation. This anion is called an enolate anion. The negative charge is mainly distributed among the α -carbon and the carbonyl oxygen, by resonance, which leads to the stabilization of the otherwise highly, energized carbanion. The distribution of the negative charge and the nucleophilic qualities are at the carbon (in carbanion) and at the oxygen (in enolate anion). As a result, the α- carbon and the carbonyl oxygen are the nucleophilic positions of enolate anions.
2
Further, as the negative charge is more stable at more electronegative oxygen, than at electropositive carbon, the negative charge is bound more strongly and closely to the oxygen atom than is the case with the α− carbon. Thus, the α− carbon (as anion) is a soft base, while the carbon carbonyl oxygen (as anion) is a hard base. As a result, soft Lewis acids (electrophiles), such as alkyl halides and the carbonyl carbon of carbonyl compounds, tend to be nucleophilically attacked by the enolate's α− carbon. In simple words, an enolate anion has two nucleophilic positions, namely the α- carbon and the carbonyl oxygen. Enolate anions are hence ambident, that is, they possess two reactive (nucleophilic) centres. Protonation of an enolate may yield two different products, the enol (enolic form of a carbonyl compound), or the carbonyl compound (keto form).
α−hydrogen atoms is enhanced if an electron Variation of acidity: The acidities of these α−hydrogen withdrawing group is attached to the α−carbon α−carbon atom.
On the other hand, the acidity of the α−hydrogen α−hydrogen atoms decreases if an electron donating group is attached to the α−carbon α−carbon atom. 3
Keto-enol tautomerism The keto form and enolic form are in equilibrium called as keto-enol tautomerism .
The establishment of equilibrium may be catalyzed by both acids and bases. Through suitable means, such as by fractional crystallization or careful distillation in the absence of any acid and any base, the keto and the enolic form may be separated from each other. The keto and enolic form of a carbonyl compound are constitutional isomers. The separation must be carried out in the absence of all acids and bases, as the equilibrium reaction would otherwise proceed too rapidly. As a result, the separated, pure keto and enolic form would immediately be "contaminated" at least to some degree by the other form again. The various structural formulas of an enolate, in which the negative charge is located at various positions, are actually merely resonance formulas of one and the same compound! Equilibrium position in keto-enol tautomerism : The position of the keto-enol equilibrium is influenced by the temperature and the solvent (if present). The keto form usually exceeds the enolic form to a considerable degree. -4
For example, Acetone contains only 1.5 x 10 % of the enolic form. Ketones are usually not enolized to such a degree as aldehydes are. However , β-dicarbonyl compounds are significantly much more enolized, as the double bond of a monoenolized βdicarbonyl compound is additionally stabilized through resonance with the second carbonyl group. As a result, the α- hydrogen between the two carbonyl groups of β-dicarbonyl compounds is much more acidic. On the other extreme, the classic example of a compound that is virtually completely enolized is phenol. The equilibrium constant of keto-enol tautomerism equilibrium of phenol amounts to 10 roughly 10 . It follows that the enolic form of phenol predominates to over 99.99 %. Due to the strikingly high resonance stabilization of the aromatic system, the enolic form of phenol is much
4
more stable than the non-aromatic keto form (cyclohexadienone). Also, phenol's enolate is much more stable than non-aromatic enolates are, as its negative charge is stabilized through resonance with the aromatic system. As a result, phenol is considerably more acidic than other enols or alcohols. The pK a value of is 9.95.
Fig: keto and enol form of phenol Acidity of β-dicarbonyl compounds The acidity of β-dicarbonyl compounds is considerably higher than that of monocarbonyl compounds and other dicarbonyl compounds. In keto-enol equilibrium of β-dicarbonyl compounds, the (mono)enolic form usually exceeds the keto form. For example, 2,4-Pentadione consists of about 76 % enolic form.
The reason for this is the noticeably higher stabilization of the enol in comparison to other carbonyl compounds. On the one hand, a β-dicarbonyl compound's enol is additionally stabilized through resonance of the enol's carbon-carbon double bond with the second carbonyl group. On the other hand, the enol's hydroxyl hydrogen is connected to the carbonyl oxygen by an intramolecular hydrogen bond. The formation of this hydrogen bond is further facilitated by the six membered planar structure of the enol-carbonyl resonance system.
Hydrogen-Deuterium Exchange Due to the acidity of the α-hydrogens of enolizable carbonyl compounds, the α hydrogen may easily be exchanged for deuterium (H/D exchange). H/D exchange may, for instance, occur when the carbonyl compound is treated with heavy water (D2O).
5
Whenever a carbonyl compound is treated with a large excess of D2O, for instance, if it is dissolved in D2O, virtually all α hydrogens of the carbonyl compound are exchanged. A large excess of D2O is essential, since H/D exchange is an equilibrium reaction. The H/D exchange happens faster in the presence of acids or bases.
Alkylation of enolate anions Enolate anions are nulceophiles. Thus, they can participate in S N2 reactions. If reacted with alkyl halides as electrophiles, alkylation of the enolate occurs. Due to the enolate's ambident character, O-alkylation or C-alkylation may take place. The practicality of the reaction therefore depends on the selectivity for one of the alkylation variations. The question is which position in the enolate displays the highest nucleophilicity? Nucelophilicity also depen ds on the electrophile. C-alkylation or O-alkylation? In alkylation with alkyl halides, the electrophile is a relatively soft Lewis acid. For that reason, C-alkylation of the enolate is favored, as, due to carbon's lower electronegativity, the enolate's carbon position is a much softer Lewis base than the oxygen position. According to the HSAB concept, a soft Lewis base tends to react with a soft Lewis acid, while a hard Lewis base tends to react with a hard Lewis acid.
On the other hand, if it is reacted with a harder base as an electrophile, O-alkylation is the preferential route.
The complexity between reaction at C or at O in enolates is illustrated by the following example:
6
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 S N2 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.
Trimethylsilyl chloride is a stronger electrophile than methyl iodide (note the electronegativity difference between silicon and chlorine). Relative to the methylation reaction, the S N2 transition state will resemble the reactants (CH3)3Si–Cl 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. O-alkylation: Because of the substantial negative charge on the oxygen of ambident anions, it might be expected that O-alkylation would be the rule rather than the exception. This, in fact, is true when fully or extensively ionized enolate salts are reacted with strong electrophiles. Ionization of enolates is facilitated by high dielectric solvents, such as DMSO and DMF (dimethylformamide), especially for potassium and cesium cation salts. As shown in the lower part of the second diagram, the negatively charged oxygens of DMSO cluster about a cation, providing substantial solvation stabilization. No such solvation exists for the enolate anion, leaving it open to reaction with an electrophile. Lithium enolates have significant covalent character in the metal-oxygen bond, and this retards electrophile attack at oxygen. Ether solvents such as THF and DME (dimethoxyethane or glyme) are commonly used for alkylations because they are inert to strong base and dissolve enolate salts more effectively than hydrocarbons. The difunctional ether DME (dimethoxyethane) is especially effective at solvating cations; and this fact has led to the preparation of cyclic polyethers, known as crown ethers, which are extraordinarily powerful solvating agents. Crown ethers may be added to enolate salt solutions to enhance their ionization. Indeed, the size of the crown ether can be tailored to fit the cation being used, providing additional control over the course of enolate reactions. The nomenclature of crown ethers consists of two numbers. The first (larger) number designates the overall ring size. The second number indicates the number of ether oxygens. A symmetrical arrangement of the oxygens in the ring is assumed.
7
Another problem: Multiple alkylation : The possibility of a low selectivity between C- and Oalkylation is not the only problem of the alkylation of enolates. In addition, multiple Calkylation may also occur. As a result, a mixture of products is obtained. For example,
In alkylation of carbonyl compounds, the enolate is actually the attacking nucleophile. Thus, if enolization cannot occur, alkylation cannot take place. Therefore, carbonyl compounds that contain only one α - hydrogen atom (i.e. CR 3COCHR 2) can only be monoalkylated. Multiple alkylation is not an option. If the carbonyl compound possesses more than one α- hydrogen atom, multiple alkylation can largely be prevented by applying a bulky, sterically demanding base, such as the widely used lithium diisopropylamide (LDA). In this case, further deprotonation and, thus, enolate formation of an existing monoalkylated carbonyl compound is hampered by additional steric interactions between the alkyl group and the bulky isopropyl substituents of LDA. Alkylation Reactions of Enolate Anions 1. Use of a strong base LDA, leads to intermolecular alkylations of simple carbonyl compounds. For example,
2.
3. This shows the additive effect of carbonyl groups on alpha-hydrogen acidity.
10
Here the two hydrogen atoms activated by both carbonyl groups are over 10 times more acidic than the methyl hydrogens on the ends of the carbon chain. 8
Ring closures to four, five, six and seven-membered rings are also possible by intramolecular enolate alkylation. For example,
Regioselectivity in Enolate Anion Formation and Reaction The importance of enolate anions as synthetic intermediates is well established. Nevertheless, problems remain concerning their selective formation and reaction. The ambident nature of enolate anions also enables electrophilic attack at both oxygen and carbon, but in most synthesis applications bonding to carbon is desired. Finally, enolate anions may often be formed as E/Z stereoisomers, and it has been shown that reaction stereoselectivity, when new chiral centers are created, depends on the enolate configuration.
The following diagram illustrates how the conditions under which enolate anion formation is accomplished can influence the regioselectivity of the reaction. For example, the two ketone substrates, 2-heptanone and 2-methylcyclohexanone, each have differently substituted alpha-carbons. In each case, enolate anion mixtures are generated by reaction with a strong 2º-amide base (LDA is the usual choice). - If the ketone is added to a cold THF solution of excess base, enolate anion formation is fast and irreversible (procedure a). - On the other hand, if a slight excess of ketone is allowed to remain in solution, an equilibrium involving the ketone and the various enolate species is established (procedure b). - At equilibrium the more stable enolate anion will predominate. The examples given in the diagram also report results from an equilibrating preparation in which the lithium metal in LDA is replaced by potassium (procedure c).
In both of the examples shown above (I and II), the conditions used in procedure (a) are typical of kinetically favored enolate formation , whereas those used in procedure (b) favor 9
thermodynamic enolate formation . The comparative acidities provided by pK a values are derived from measurements made under equilibrating conditions, and therefore reflect thermodynamic acidity.
The second reaction (II) is an intramolecular alkylation that can occur in two different ways. If the kinetically favored enolate (methyl proton removal) is formed at low temperature, it reacts rapidly on warming to form a seven-membered ring. Alternatively, the weaker base, potassium tert-butoxide (in the alcohol as solvent), generates an equilibrium mixture of enolates which eventually react by intramolecular alkylation. The thermodynamically favored α'-enolate predominates, and the resulting alkylation generates a five-membered ring. Keto-enol tautomerism of ethyl acetoacetate Acetic ester or ethyl acetoacetate is the ethyl ester of acetoacetic acid CH3 · CO · CH 2 · CO2 H , a
β-ketonic acid. Acetoacetic ester was first discovered by Geuther (1863), who prepared it by the action of sodium on ethyl acetate, and gave the formula as CH3 · C(OH) : CH · CO2C 2 H5 (β-hydroxycrotonic ester). In 1865, Frankland and Duppa , also prepared acetoacetic ester by the action of sodium on ethyl acetate,but they proposed a different formula CH3 · CO · CH 2 · CO2C 2 H5 (β-ketobutyric ester).
Which of these is correct? Evidence in favour of the Geuther formula (reactions of an unsaturated alcohol), (i) When acetoacetic ester is treated with sodium, hydrogen is evolved and the sodium derivative is formed. This showed the presence of a hydroxyl group.
(ii) When acetoacetic ester is treated with an ethanolic solution of bromine, it readily decolourises. This indicates the presence of an olefinic double bond. (iii) When acetoacetic ester is treated with ferric chloride , a reddish-violet colour is produced. This is characteristic of compounds containing the eno lic group ( -C(OH)=C<) like phenols. Evidence in favour of the Frandland-Duppa formula (reactions of a ketone). (i) With sodium hydrogen sulphite, acetoacetic ester forms a bisulphate derivative.
(ii) With hydrogen cyanide , acetoacetic ester forms a cyanohydrin. Thus, evidence for both the structure were there. The controversy continued until about 1910, when chemists came to the conclusion that both formula were correct, and that the two compounds existed together in equilibrium in solution (or in the liquid state): OH CH3 · CO · CH2 · CO2C2H5
CH3 · C
CH · CO2C2H5
10
When a reagent which reacts with ketones removed. This upsets the equilibrium, and hydroxyl form of acetoacetic ester changes reagent is added, acetoacetic ester
is added to acetoacetic ester, the ketone form is in order to restore the equilibrium mixture, the into the ketone form. Thus provided insufficient reacts completely as the ketone form.
Similarly, when a reagent which reacts with olefins or with hydroxy-compounds is added in sufficient quantity, acetoacetic ester reacts completely as the hydroxyl form. Knorr (1911) succeeded in isolating both forms. 1. Ketone form: On cooling a solution of acetoacetic ester in light petrol to –78°, he obtained crystals which melted at –39°. This substance gave no coloration with ferric chloride and did not combine with bromine, and was therefore, the pure ketone form corresponding to the FranklandDuppa formula. 2. Hydroxyl form: By suspending the sodium derivative of acetoacetic ester in light petrol cooled to –78°C, and treating this suspension with just enough HCl to decompose the sodium salt, he obtained a glassy solid when cooled. This substance gave an intense coloration with ferric chloride, and was therefore the pure hydroxyl form corresponding to the Geuther formula.
Thus acetoacetic ester is a substance that does the duty of two structural isomers, each isomer being capable of changing rapidly into the other when the equilibrium is distributed, e.g., by the addition of certain reagents. This is a case of dynamic isomerism, and the name tautomersim(Greek: same parts) was given to this phenomenon by Laar (1885). The two forms are known as tautomers or tautomerides, the phenomenon being called the ketoenol tautomerism . The word enol is a combination of -en for double bond and -ol for hydroxyl. Stability of tautomers: When one tautomer is more stable than the other under ordinary conditions, the former is known as the stable form, and the latter as the labile form.
It is generally difficult to say which is the labile form, since very often a slight change in the conditions, e.g., temperature, solvent, shifts the equilibrium from keto to enol or vice versa. Tautomerism in the solid state is rare, and hence, in the solid state, one or other tautomer is normally stable, but in the liquid or gaseous state, or in solution, the two forms usually exist as an equilibrium mixture. It has been found that the enol form is more volatile than the keto. The change fromenol to keto is extremely sensitive to catalysts like acid or bases. Experiments using deuterium exchange reactions have also shown the presence of keto-enol mixtures. 11
Equilibrium of keto-enol mixtures Physical methods: Physical methods do not disturb the equilibrium as they do not depend on the removal of one. Hence, they should be used wherever possible to determine the equilibrium position.
(i) The refractive index of the equilibrium mixture is determined experimentally. The refractive indices of both the keto and enol forms are calculated (from the literature references of atomic refractions). From these figures it is then possible to calculate the amount of each form present in the equilibrium mixture. (ii) If one form is an electrolyte, the electrical conductivity of the mixture is determined experimentally, and the amount of this form present may be calculated from the results. (iii) The composition of the equilibrium mixture may be determined by means of optical rotation measurements, spectroscopy (I.R, N.M.R, etc). Lately, physical methods, specially N.M.R are being extensively used to estimate the relative percentage of keto and enol forms and to determine the equilibrium position. Chemical methods : As these methods cause the removal of one form, it is necessary to use a reagent that reacts with this form faster than the rate of interconversion of the tautomers.
Meyer (1911, 1912) found that in the case of keto-enol tautomerism, bromine reacts instantaneously with the enol form. On the other hand, it reacts very slowly with the keto form. He gave two methods: a. Direct method: A weighed sample of the keto-enol mixture dissolved in ethanol is rapidly titrated with a dilute ethanolic solution of bromine at 0º (to slow down the interconversion of the tautomers). The first appearance of excess bromine indicates the end point. The titration must be carried out rapidly; otherwise the keto form changes into the enol during the time taken for the titration. This is practically impossible. So this method always results in too high a value for the enol form. b. Indirect method: An excess of dilute ethanolic solution of bromine is added rapidly to the weighed sample dissolved in ethanol, and then an excess of 2-naphthol dissolved in ethanol is added immediately.
By this means, the excess bromine is removed almost instantaneously, and so the keto-enol equilibrium is not given time to be disturbed. Potassium iodide solution and hydrochloric acid are now added, and the liberated iodine is titrated with standard thiosulphate. The overall equation is : CH 3 . CO . CHBr . CO 2 Et + 2I − + H + ⎯ ⎯→ CH 3 . CO . CH 2 . CO 2 Et + I 2 + Br −
Mechanism of bromination:
12
OH Br
Br CH
+OH
C · CH3
Br – + CHBr · C · CH3
H+
CH3 · CO · CHBr · CO2Et
CO2Et
CO2Et
More reliable results may be obtained by the indirect method.
Table showing % of enol content
Compound
% enol (in ethanol)
CH3 . CO . CH 2 . CO2CH3
4.8
CH3 . CO . CH 2 . CO2C 2 H5
7.5
CH . CO . CH . CO . CH
76
CH3 . CO . CH(CH3 ) . CO . CH3
31
C H . CO . CH . CO . C H
96
3
6
2
5
3
2
6
5
CH 2 (CO2C 2 H 5 ) 2
trace
Aldehydes of type R . CH 2 . CHO
trace
Ketones of type R . CH 2 . CO . CH 2 . R
trace
Enolisation The phenomenon of enolisation is exhibited by compounds containing either a methylene group, ·CH · , or a methine group, ,adjacent to a carbonyl group. The actual amount of enol form present 2
depends on a number of factors; these are discussed later. When the methylene or methine group is attached to two or three carbonyl groups, the hydrogen atom may migrate equally well to one or other carbonyl group. However, practically, this is not the case for unsymmetrical ketones and usually one enol form predominates. e.g., in acetoacetic ester the hydrogen atom migrates exclusively to the acetyl carbonyl group. When two or more enol forms are theoretically possible, ozonolysis may be used to ascertain the structure of the form present; e.g., in hexane-2, 4-dione, CH3 . CO . CH 2 . CO . CH 2 . CH3 , the two possible enols are :
Ozonolysis of (I) will give CH3 . CO2 H and CH3 . CH 2 . CO . CHO; (II) will give CH3 . CO . CHO and CH3 . CH 2 . CO2 H. Identification of these compounds will decide whether the enol is (I) or (II), or
both. In ethyl acetoacetate, it is predominately the (I) form. 13
Enols resemble phenols in a number of ways; e.g., both form soluble sodium salts; both give characteristic colorations with ferric chloride; and both couple with diazonium salts. Modern theories of tautomerism Ingold (1927) suggested the names a. Cationotropy for all those cases of tautomerism which involve the separation of a cation Lowry (1923) suggested the name prototropy for those cases in which a proton separates, and called such systems prototropic systems. It can be seen that prototropy is a special case of cationotropy.
b.Anionotropy for those cases which involve the separation of an anion. Braude and Jones (1944) proposed the term oxotropy for aniontropic rearrangements involving only the migration of hydroxyl group. According to Hughes and Ingold, base-catalysed enolisation of a ketone proceeds through the enolate anion, whose formation is controlled largely by the inductive effects of the alkyl groups.
Acid catalysed enolisation involves the removal of a proton from the conjugate acid of the ketone, and this process is dependent mainly on the hyperconjugation by the alkyl groups in the transition state for the formation of the carbon-carbon do uble bond.
Termolecular mechanism: In other cases, acid and base catalysis of enolisation take place by a concerted or push-pull mechanism, i.e., the molecule undergoing change is attacked simultaneously at two places. Thus the enolisation of e.g., acetone, proceeds by the simultaneous removal of a proton from an α-carbon and the addition of a proton to the oxygen of the carbonyl group. This may be represented as follows (B is a general base, and HA is a general acid): B
H
B ..... H..... CH2
CH2 C CH3
O
HA
C
CH2 O ..... HA
+
BH + C
CH3
OH + A –
CH3
transition state
Position of equilibrium in keto-enol tautomerism
As ∆G° = ∆H° – T∆S° = –RTlnK
14
If the values of the enthalpy and entropy changes are known, ∆G° and thus K, the equilibrium constant of the following reaction can be calculated
K = [enol]/[keto] Consider the following equilibria: H O
acetylacetone
Me
C
O CH2
C
O
O
C · Me
Me · C
Me
CH H O
ethyl acetoacetate Me
C
CH2
C
O
O
O
C · OEt
Me · C
OEt
CH H
O
ethyl malonate
EtO · C
O CH2
C
O
O EtO · C
OEt
C · OEt CH
Factors affecting the enol content
1. Ring strain: If the enol form is intra-molecularly hydrogen bonded, it is more stable and would lead to a higher enol content. Cyclic monoketones contain more enol than the corresponding acyclic 2-one. In the cyclic ketones, change from keto to enol involves a relatively small change in strain in the ring due to the introduction of a double bond. For acyclic ketones, the introduction of the double bond has a much greater effect on the freedom to take up different conformations. 2. Steric factor: The enol content of acetylacetone is higher than α-methylacetylacetone (in gas phase). In the later compound, there is much greater steric repulsion due to the presence of theαmethyl group. Thus, the α-methyl enol form has greater internal strain than the enol form of acetylacetone. H O
C
C Me
H O
O
C H 91 – 93%
Me
O C
C Me
C
Me
Me 43.5 – 44.5%
3. Nature of solvent: Any solvent that can form hydrogen bonds with the carbonyl group of the keto form will stabilize this form (by solvation). The enol form, however, since it forms an intramolecular bond, will be largely prevented from forming hydrogen bonds with the solvent i.e., solvation will be less. Thus the keto form is stabilized with respect to the enol form e.g.,
15
solvents such as water, methanol, acetic acid, etc. tend to reduce the enol content. On the other hand, in solvents such as hexane, benzene etc. the enol content will be larger, e.g., the enol content of acetylacetone in hexane is 92 per cent.
Synthesis of ethyl acetoacetate: the Claisen condensation Ethyl acetoacetate is the ethyl ester of acetoacetic acid (CH3COOH) and is widely used as a starting material for the synthesis of a variety of ketones and acids. It can be prepared by Claisen condensation of ethyl acetate.
The condensation of two molecules of an ester (e.g. ethyl acetate), or of two molecules of different esters, or of one molecule of an ester with one molecule of a ketone under the influence of sodium or sodium ethoxide, is termed Claisen condensation (1887), and is one of the best methods for preparing beta-ketonic esters like ethyl acetoace tate. Two molecules of ethyl acetate condense in the presence of sodium ethoxide to produce ethyl acetoacetate.
Claisen condensation may also be brought about by sodamide or tri-phenylmethylsodium etc. Mechanism: It is similar to aldol condensation. 1.Formation of carbanion O EtO C H3C
O
-
OEt
_ H2C
C OEt
+ EtOH pK a ca. 16
pK a ca. 24
2. Addition step:
EtO
O
O
C _ CH2 H3C
C
O OEt
O
_
C CH2 C EtO
CH3
OEt
3. Elimination step:
16
Evidence to support this mechanism: (i) Compounds containing an active methylene group undergo deuterium exchange with sodium ethoxide in the presence of EtOD. This can be explained by the reversible formation of αcarbanion. CH2 · CO
+ EtO –
EtOH +
–
CH · CO
EtOD
CHD · CO
+ EtO –
(ii) Optically active esters of the type R R ′CH ⋅ CO 2 Et are racemised by the ethoxide ion. The planar delocalized carbanion intermediate is expected to lead to racemisation. Alkylation of diethyl malonate and ethyl acetoacetate Acetic ester or ethyl acetoacetate (E.A.A.) is the ethyl ester of acetoacetic acid CH · CO · CH · CO H , a β-ketonic acid. 3 2 2
Malonic ester, CH 2 (CO 2 C 2 H 5 ) 2 , is the diethyl ester of malonic acid CH 2 (CO 2 H ) 2 .
Both these compounds contain two α-hydrogen atoms each, which are more acidic than those of simple aldehydes and ketones. These α -hydrogen atoms can be easily abstracted by the use of an appropriate base like sodium alkoxide. This followed by the reaction with an alkyl halide leads to alkylation of these compounds. 1. Alkylation of Ethyl acetoacetate : When treated with sodium ethoxide, acetoacetic ester forms sodioacetoacetic ester
Sodioacetioacetic ester so formed, readily reacts with primary and secondary alkyl halides to produce alkyl derivatives of acetoacetic ester in which the alkyl group is attached to carbon. Vinyl and aryl halides do not react. 17
Mechanism: The negative ion (II) (like enolate ion) is formed, which is a resonance hybrid, i.e., this ion is ambident.
The C-alkylation occurs usually by S N2 mechanism as shown below : CH3
C
O –
HC ·· R
CH3 X
CO2C2H5
C HC
O R + X –
CO2C2H5
The tendency for alkylation at the more electronegative atom (O-alkylation) of an ambident anion usually increases with the S N 1 character of the reaction. After one alkyl group has been introduced, the dialkyl derivative of acetoacetic ester may be produced by repeating the whole process.
A recent method gives one step preparation of the disubstituted derivatives of acetoacetic ester.
For example, Sandberg (1957) prepared ethyl β-acetotricarballylate form acetoacetic ester, ethyl bromoacetate and sodium hydride in benzene solution. CH3·CO·CH2·CO 2C2H5 + 2CH2Br · CO2C2H5
2NaH
CH2 · CO 2C2H5 CH3 · CO · C
CO2C2H5
(77%)
CH2 · CO 2C2H5
Potassium t-butoxide is usually best for preparing the metallo-acetoacetic ester compoun ds Amongst alkyl halides, generally alkyl iodides react faster than alkyl bromides.
Acetoacetic ester and its alkyl derivatives can undergo two types of hydrolysis with potassium hydroxide: (a) Ketonic hydrolysis: It is so called because a ketone is the chief product. It is carried ou t by boiling with dilute aqueous or ethanolic potassium hydroxide solution, e.g.,
The ketone obtained is acetone or its derivatives, and the latter always contain the group CH 3 . CO – . 18
Mechanism of decarboxylation:
(b) Acid hydrolysis: It is so called because an acid is the chief product, is carried out by boiling with concentrated ethanolic potassium hydroxide solution, e.g.,
The acid obtained is acetic acid or its derivatives as the potassium salt. The free acid is readily obtained from these salts by treatment with inorganic acids. Mechanism of the cleavage: O –
O Me
C
CHR
CO 2Et + EtO –
Me
C
CHR
CO 2Et
OEt Me · CO2Et + – CHR · CO2Et
EtOH
CH2R · CO2Et + EtO –
Applications: These alkylation reactions followed by ketonic hy drolysis or acidic hydrolysis are used for the synthesis of various ketones and acids.
1.Synthesis of Ketones : The formula of the ketone is written down, and provided it contains the group CH 3 . CO – , the ketone can be synthesized via acetoacetic ester as follows. The acetone nucleus is picked out, and the alkyl groups attached to it are then introduced into acetoacetic ester one at a time; this is followed by ketonic hydrolysis. It is usually better to introduce the larger group before the smaller (steric effect).
Reaction type: Nucleophilic substitution, then ester hydrolysis & finally decarboxylation (!)
For example,
i.
Butanone.
CH3 · CO · CH2 · CH3
19
C H ONa
CH I
5 3 ⎯2 ⎯ ⎯ ⎯ → [CH 3 · CO · CH · CO 2 C 2 H 5 ] – Na + ⎯ ⎯ ⎯ → CH 3 · CO · CH 2 · CO 2 C 2 H 5 ⎯ ketonic
⎯ ⎯ ⎯ → CH 3 · CO · CH 2 · CH 3 CH 3 · CO · CH (CH 3 ) · CO 2 C 2 H 5 ⎯ hydrolysis
ii.
3-Methylpentan-2-one. CH3 CH3 · CO · CH · CH2 · CH3
CH3·CO·CH2·CO2C2H5
C2H5ONa
CH3·CO·CH(C2H5)·CO2C2H5
[CH3·CO·CH·CO2C2H5] – Na+ C2H5ONa
C2H5I
[CH3·CO·C(C2H5)·CO2C2H5] – Na+
CH3·CO·C(CH3)(C2H5)·CO2C2H5
ketonic hydrolysis
CH3I
CH3·CO·CH·CH2·CH3 CH3
2. Synthesis of fatty acids: Here, the acetic acid nucleus is picked out, and the acetoacetic ester derivatives are subjected to acid hydrolysis. The acetoacetic ester acid synthesis is usually confined to the preparation of straight-chain acids or branched-chain acids where the branching occurs on the α-carbon atom. For example,
i.
n-Butyric acid.
CH3 · CH2 · CH2 · CO2H
ii.α-methyl-n-valeric acid:
3. Other synthesis: Sodioacetoacetic ester reacts with many other halogen compounds besides alkyl halides, and so may be used to synthesise a variety of compounds.
(i) 1, 3-Diketones. Here, the halogen compound used is an acid chloride. As acid chlorides react with ethanol, the reaction is not carried out in this solvent in the usual way. The reaction is
20
thus carried out by treating acetoacetic ester in benzene solution with magnesium and the acid chloride. For example, 1. pentane-2, 4-dione Mg
ketonic hydrolysis
CH 3 · CO · CH 2 · CO 2 C 2 H 5 + CH 3 · COCl ⎯ ⎯ ⎯ → (CH 3 · CO) 2 CH · CO 2 C 2 H 5 ⎯ ⎯ ⎯ ⎯ → CH 3 · CO · CH 2 · CO · CH 3
2. The O-acetyl derivative of acetoacetic ester, acetoxycrotonic ester, is obtained, if sodioacetoacetic ester or acetoacetic ester itself is treated with acetyl chloride in pyridine as solvent.
The first reaction occurs by the S N 2 mechanism and the latter by S N 1 . (ii) Dicarboxylic acids: These may be prepared by interaction of sodioacetoacetic ester and a halogen derivative of an ester. e.g., preparation of succinic acid from ethyl chloroacetate: [CH 3 · CO · CH · CO2C2H5] – Na+ + ClCH2 · CO2C2H5 CH2 · CO2C2H5 CH3 · CO · CH · CO2C2H5
iii.
CH2 · CO2H acid hydrolysis
CH2 · CO2H
Long chain fatty acids. It involves a combination of methods (i) and (ii) given above. (CH2)x · CO2C2H5
[CH3·CO·CH·CO2C2H5] – Na+
Br · (CH2)x · CO2C2H5
CH3·CO·CH·CO2C2H5
(i) C2HONa (ii) CH3 · (CH3)y · COCl
(CH2)x · CO2C2H5 CH3 · CO · C · CO2C2H5
graded hydrolysis
CH3·(CH2)y·CO·CH2·(CH2)x·CO2H
CO(CH2)y · CH3
These keto-acids are readily reduced to the corresponding fatty acid by means of the Clemmensen reduction.
2. Alkylation of Diethyl Malonate With sodium ethoxide, it forms a sodium derivative called as sodiomalonic ester. This reacts with compounds containing a reactive halogen atom, e.g., alkyl halides, acid chlorides, halogensubstituted esters, etc.
21
O C2H5O
C
CH2
C
O
C
OC2H5
C2H5ONa
C2H5O
C
O CH
O
O C2H5O
–
O
–
CH
C
C
OC2H5 Na+
O OC2H5 Na+
RX
C2H5O
C
O CHR
C
OC 2H5 + NaX
The process on repetition produces the disubstituted derivative of malonic ester. C H ONa
RX
5 ⎯ R · CH (CO 2 C 2 H 5 ) 2 ⎯ ⎯2 ⎯ ⎯ → [R · C(CO 2 C 2 H 5 ) 2 ] – Na + ⎯ ⎯ ⎯ → R R ′C(CO 2C 2 H 5 ) 2
These substituted derivatives of malonic ester can also be readily prepared in one step by treating the ester with two equivalents of sodium ethoxide and then with two equivalents of alkyl halide. This procedure is used only if two identical alkyl groups are to be introduced. (i ) 2EtO Na
CH 2 (CO 2 C 2 H 5 ) 2 ⎯ ⎯ ⎯ ⎯ ⎯ → R 2 C (CO 2 C 2 H 5 ) 2 + 2 NaX (ii ) 2 RX
Decarboxylation: Malonic acid and its derivatives eliminate a molecule of carbon dioxide when heated just above the melting point of the acid (between 150° and 200°) to form acetic acid or its derivatives CO2 H · CH2 · CO2 H ⎯ ⎯→ CH3 · CO2 H + CO2 CO2 H · CHR · CO2 H ⎯ ⎯→ R · CH 2 · CO2 H + CO2
Decarboxylation occurs faster if done by refluxing malonic acid or its derivatives in sulphuric acid solution. Applications: These alkylation reactions followed by decarboxylation are used for the synthesis of various higher acids called as fatty acids.
Reaction type: Nucleophilic substitution, then ester hydrolysis & finally decarboxylation (!)
1. Synthesis of fatty acids: Malonic ester is preferable to acetoacetic ester in synthesizing acids. The structural formula of the acid required is written down, the acetic acid nucleus picked out, and the required alkyl groups introduced into sodiomalonic ester. The substituted ester is then refluxed with potassium hydroxide solution, acidified with hydrochloric acid, and the precipitated acid dried and then heated just above its melting point. Alternatively, the potassium salt may be refluxed with sulphuric acid. 22
i.
n – Valeric acid
CH3 · CH2 · CH2 · CH2 · CO2H CH2(CO2C2H5)2
C2H5ONa
[CH(CO2C2H5)2] – Na+
C3H7 · CH(CO2K)2
HCl
C3H7Br
C3H7 · CH(CO2H)2
C3H7 · (CO2C2H5)2
150 – 200°
KOH
CH3 · CH2 · CH2 · CH · CO2H
CH3
ii.
Dimethylacetic acid.
CH3 · CH · CO2H
Alternatively, 2C H ONa
KOH, etc.
5 ⎯ 5 ⎯ → (CH ) C(CO C H ) ⎯ CH 2 (CO 2C 2 H 5 ) 2 ⎯ ⎯ ⎯ ⎯ ⎯ ⎯ ⎯ → (CH 3 ) 2 CH · CO 2 H 3 2 2 2 5 2 2CH 3 I
iii.
Aryl-substituted derivatives are prepared indirectly. Claisen condensation is followed by decarboxylation. e.g., ethyl phenylmalonate.
2.
Synthesis of dicarboxylic acids: Dicarboxylic acids of the type R R ′C(CO 2 H ) 2 are readily
prepared from malonic ester. For example,
i.
Adipic acid
CO 2H · CH 2 · CH 2 · CH 2 · CH 2 · CO 2H
(C 2 H 5 O 2 C) 2 CH ] – Na + + BrCH 2 · CH 2 Br + Na + [CH (CO 2 C 2 H 5 ) 2 ] – ⎯ ⎯→ (i ) KOH (C 2 H 5O 2 C) 2 CH · CH 2 · CH 2 · CH (CO 2 C 2 H 5 ) 2 ⎯ ⎯ ⎯ ⎯ → (ii ) HCl
150 – 200°
( HO 2C) 2 CH · CH 2 · CH 2 · CH(CO 2 H ) 2 ⎯ ⎯ ⎯ ⎯ ⎯ → CO 2 H· CH 2 · CH 2 · CH 2 · CH 2 · CO 2 H
23
Succinic acid.
ii.
CO2H · CH2 · CH2 · CO2H
(i) KOH
[CH (CO 2 C 2 H 5 ) 2 ] – Na + + ClCH 2 · CO 2 C 2 H 5 ⎯ ⎯→ (C 2 H 2 O 2 C) 2 CH · CH 2 · CO 2 C 2 H 5 ⎯ ⎯ ⎯ ⎯ → (ii ) HCl
150° – 200°
( HO 2 C) 2 CH · CH 2 · CO 2 H ⎯ ⎯ ⎯ ⎯ ⎯ → CO 2 H · CH 2 · CH 2 · CO 2 H
Alternatively, [(C 2 H 5O 2C) 2 CH] – Na + + I 2 + Na + [CH (CO 2 C 2 H 5 ) 2 ] – ⎯ ⎯→ (i) KOH
(C 2 H 5 O 2 C) 2 CH · CH(CO 2C 2 H 5 ) 2 ⎯ ⎯ ⎯ ⎯ → (HO 2 C) 2 CH· CH(CO 2 H ) 2 (ii ) HCl 150° – 200°
⎯ ⎯ ⎯ ⎯ ⎯ → CO 2 H · CH 2 · CH 2 · CO 2 H
3.
Synthesis of ketones
Synthesis of higher ketonic acids: Sodiomalonic ester is treated with the acid chloride-ester derivative of a dibasic acid, e.g., ε-ketoheptanoic acid: [(C 2 H 5 O 2 C) 2 CH] – Na + + COCl · (CH 2 ) 4 · CO 2 C 2 H 5 ⎯ ⎯→ (i ) KOH
150° − 200°
(C 2 H 5O 2 C) 2 CH · CO(CH 2 ) 4 · CO 2 C 2 H 5 ⎯ ⎯ ⎯ ⎯ → ( HO 2 C) 2 · CO(CH 2 ) 4 · CO 2 H ⎯ ⎯ ⎯ ⎯ ⎯ → (ii ) HCl
[CO 2 H · CH 2 · CO · (CH 2 ) 4 · CO 2 H] ⎯ ⎯→ CH 3 · CO · (CH 2 ) 4 · CO 2 H
Example
4. Synthesis of polybasic acids: CH2(CO2C2H5)
Br 2
CHBr(CO2C2H5)2 + [CH(CO2C2H5)2] – Na+ (C2H5O2C)2C
Br
(C2H5O2C)2C
Br
CHBr(CO2C2H5)2 NaBr + (C 2H5O2C)2CH·CH(CO2C2H5)2
2[CH(CO2C2H5)2] – Na+
(C2H5O2C)2C
CH(CO2C2H5)2
(C2H5O2C)2C
CH(CO2C2H5)2
Br 2
Alkylation of 1,3-dithianes Alcohols add to aldehydes and ketones via nucleophilic addition, producing cyclic acetals and cyclic ketals. For example,
24
Similarly, treatment of an aldehyde with a dithiol generates a cyclic thioacetal. The reaction here also is done in the presence of acids. Lewis acids are preffered.
This reaction is of synthetic interest because of the change in acidity of the aldehydic hydrogen that occurs when the aldehyde is converted to the corresponding cyclic thioacetal. While the pK a of an aldehydic proton is approximately 45, it drops to approximately 32 in the cyclic thioacetal. Hence, deprotonation of the cyclic thioacetal with LDA is essentially complete; K eq being 6 approximately 10 . This is due to the resonance stabilization which leads to the greater acidity of cyclic thioacetals.
Because sulfur has low lying empty 3d orbitals, the negative charge that initially resides on the carbon atom may be delocalized onto both adjacent sulfur atoms. This stabilizes the conjugate base, making deptotonation of the cyclic thioacetal feasible. A comparable acid-base reaction is not possible in cyclic acetals because the conjugate base is not stabilized by resonance; the oxygen atoms do not have d orbitals available to accomodate electron density. The electronic nature of the carbon atom has changed from being electrophilic in the aldehyde to being nucleophilic in the conjugate base of the cyclic thioacetal. This is called as Umpolung or polarity inversion. This refers to the chemical modification of a functional group with the aim of the reversal of polarity of that group.
25
This is noteworthy because the direct alkylation of aldehydes by the following reaction is not possible:
However, the above conversion may be accomplished indirectly by the 3-step sequence as follows.
The last step of this sequence, the work-up, involves hydrolysis of the thioacetal, a proce ss that is facilitated by the Lewis acid mercuric chloride. Examples:
26
Alkylation and acylation of enamines Primary amines react with aldehydes and ketones to produce imines. For example, the reaction of acetophenone with methyl amine.
In this reaction the initially formed tetrahedral intermediate, A, undergoes dehydration. The loss of the OH group in A could be accompanied by loss of a proton from either the NH group or the CH3 group. The former alternative is preferred because the C-N double bond is more stable than the C-C double bond that would be produced via the latter route, i.e. the more stable product is preferred. Also the hydrogen attached to nitrogen is more acidic as compared to carbon and in acid catalysed dehydration, the hydrogen attached to nitrogen gets lost. Note that the amine has to be primary, i.e. have two hydrogen atoms attached to the nitrogen, for the imine to form. On the other hand, reaction of a secondary amine initially follows the same course as that of a primary amine, but now the tetrahedral intermediate, B, cannot form an imine because the nitrogen does not have a second hydrogen atom to lose:
Consequently, intermediate B undergoes dehydration to form an alkene. (Note that the starting material must have at least one hydrogen attached to the α-carbon in order for this reaction to occur.) But this type of alkene is special. It is called an enamine. Imines and enamines may be converted into aldehydes and ketones by acid catalysed hydrolysis, i.e. by reaction with a large excess of water. Enamines, Enols and Enolate Ions Ketones exist in solution in equilibrium with their enol tautomers. Enolate ions exist as a resonance hybrid in which the negative charge resides primarily on the carbonyl oxygen and the α−carbon.
Similar charge delocalization occurs in enamines as well. The following diagram presents a comparison of the structural and chemical similarities between enols, enolates, an d enamines. 27
In all of these compounds a lone pair of electrons is conjugated to the pi system of the C-C double bond. This interaction lends nucleophilic character to the α-carbon atom as indicated by the resonance structures e1, e2, and e3, in which the α-carbons bear a formal negative charge. Note the structural similarity between e2 and e3; enamines may be regarded as synthetic equivalents of enolate ions. However, as we shall see, there are significant differences between these two types of nucleophilic reagents. The 3 Es
The synthetic utility of enamines In the case of unsymmetrical ketones, two enamines may be formed. For example, the reaction of cyclic secondary amine pyrrolidine with 2-methylcyclohexanone produces isomeric enamines.
The reaction produces a mixture of enamines in which the less substituted isomer predominates. Presumably a steric interaction between the methyl group of the cyclohexyl ring and the 28
methylene group of the pyrollidine ring, reduces the extent of conjugation between the lone pair of electrons on the nitrogen atom and the π- system of the double bond in the more substituted case. Keeping in mind the limitations implied by the above reactions, let's take a look at the reactions of enamines with electrophilic reagents. Alkylation of Enamines Enamines may be converted into aldehydes and ketones by acid catalysed hydrolysis, i.e. by reaction with a large excess of water. The following is a specific example of the 3-step process involved in the alkylation of aldehydes and ketones via enamines.
First step involves the formation of the enamine. In this case benzene is used as a solvent and the water that is formed is removed by azeotropic distillation. Steps 2 and 3 proceed without isolation of any intermediates. Compare step 3 to the reverse of the reaction outlined in Equation 2.
Since enamines are inherently less reactive than their enolate ion analogs, it is necessary to treat them with highly reactive alkylating agents in order to effect a reaction. For example,
29
The α-bromoketone is extremely reactive towards nucleophiles because of the orbital overlap between the π− system of the carbonyl group and the p orbital that develops as the hybridization 3 2 of the reaction center changes from sp to sp in order to accomodate the incoming nucleophile in the pentavalent transition state.
Although enamines are not as nucleophilic as their enolate ion equivalents, their relatively low reactivity makes them excellent partners for Michael additions. Thus, the enamine derived from 2-methylcyclohexanone reacts with acrylonitrile as shown below.
By contrast, direct alkylation of 2-methylcyclohexanone with acrylonitrile yields the regiosiomer as shown below.
Michael addition of enamines to unsaturated ketones may be coupled with intra molecular aldol condensations to produce cyclic ketones. This sequence of reactions is an alternative approach to traditional Robinson annulations. For example,
Acylation of Enamines Similar to alkylation, acylation can be done using acetyl chloride. For example,
30
