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Alkylation of active methylene compounds
Ref. books:
1. Some Modern Methods of Organic Synthesis - W. Carruthers
2. Synthetic Application of Organic Reactions - H. O. House
3. Organic Chemistry (Structure and Reactivity) - Seyhan Ege
Active methylene comound
An active methylene compound is a compound that has the following general structural formula.
E1, E2 = a functional group that withdraws electrons by resonance
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Active methylene compounds
Active methylene compound
The conjugate base of an active methylene compound is highly resonance stabilized.
Active methylene compounds are acidic and can be deprotonated for all practical purposes, irreversibly, using common strong bases, such as the hydroxide ion or alkoxide ions.
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Enols Enols are isomers of aldehydes or ketones having both a C=C (-ene) and an –OH (-ol) group which are directly attached to one another, i.e., in conjugation with each other.
Not all carbonyl compounds can form enols, but only those which have hydrogens of the alpha carbon.
Carbonyl group functionality reactive and also activates near by carbon-hydrogen bonds (specifically alpha hydrogens) to undergo a variety of substitution reactions.
Enols Enols can be formed either by acid or base catalysis in carbonyl compounds. The process of converting a carbonyl compound into its enol is called enolization.
Equilibrium between a carbonyl compound and its corresponding enol, the equilibrium lies well to the carbonyl side.
C=O function is much more stable than the C=C function.
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Enols
Acid-catalyzed enolization
Conjugate acid of carbonyl and enol
Back to the same conjugate acid as was formed by the protonation of the carbonyl form Note, this conjugate acid is the common conjugate acid of both the carbonyl compound and its enol form. Losing a proton from the oxygen, it goes to carbonyl compound and losing a proton from alpha carbon, it goes to the enol form
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Enols Base-catalyzed enolization
Both enols and enolate anions are nucleophiles and react with electrophile, such as halogens, alkyl halides, and carbonyl groups
Mechanism of acid-catalyzed bromination
Carbonyl compounds without alpha hydrogen do not react with bromine at all
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Mechanism of base-catalyzed bromination
Excess carbonyl present over both the enol and enolate, is essentially unreactive toward bromine.
Active methylene groups
There are three potentially important reactions of active methylene:
Alkylation by alkyl halides Conjugate addition to a,b-unsaturated carbonyls (Michael addition)
Loss of CO2 (decarboxylation)
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Alkylation by dihalide
Using a dihalide a cyclic system can be formed:
The enolates of active methylenes are easily prepared using a base (such as ethoxide, EtO-)
These enolates are good nucleophiles and react with alkyl
halides via SN2 type reactions. This allows alkyl groups to be introduced in the a-positions.
In principle both of the a-H can be replaced with alkyl groups
Mechanism of alkylation
1. An acid-base reaction. 2. The nucleophilic enolate attacks the alkyl halide at the electrophilic carbon carrying the halogen.
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Attacked by nucleophiles at C=O
In a conjugated carbonyl system, there is an extra resonance structure.
Attacked by nucleophiles at conjugated C=O a,b-unsaturated aldehydes and ketones can potentially react with nucleophiles at two sites: directly at the carbonyl C or the end of the conjugated system
Direct or 1,2-addition (kinetic product) Conjugate or 1,4-addition (thermodynamic product)
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Attacked by nucleophiles at conjugated C=O
The Nu attacks directly at the carbonyl C=O is usually faster but the product is less stable (i.e. it is the kinetic product). 1,4-addition is an enol that will tautomerize to the more stable carbonyl compound (thermodynamic product.)
Michael addition reactions of active methylene enolates
1. An acid-base reaction. 2. The nucleophilic enolate attacks the end of the conjugated system.
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Common features of Michael Addition reactions Reagents : common bases such as NaOH or KOH. The first step is the formation of the enolate. Enolates tend to react with a,b-unsaturated ketones via conjugate addition. Addition of enolates of carbonyl compounds to an a,b- unsaturated carbonyl compounds is known as the Michael reaction or Michael Addition.
Decarboxylation of b-carbonyl esters
(hydrolysis then elimination)
Loss of carbon dioxide is called decarboxylation. Esters or carboxylic acids with a carbonyl group at the 3- (or b-) position readily undergo thermal decarboxylation.
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Decarboxylation of b-ketoacids
Decarboxylation requires a carbonyl group at the 3- (or b-) position of the –COOH The decarboxylation reaction proceeds via a cyclic transition state giving an enol intermediate that tautomerizes to the carbonyl.
Umpolung Reversal of carbonyl group polarity
Carbon atom of the carbonyl group is electrophilic in nature and susceptible to nucleophilic attack.
Traditional approach
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Umpolung Reversal of carbonyl group polarity
A reversal of the positive polarity of the carbonyl group to formyl or acyl anion is called umpolung process.
Umpolung approach
Umpolung Reversal of carbonyl group polarity
Acyl anion (Benzoin condensation)
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Benzoin condensation
Mechanism
Umpolung (basic concepts) Carbonyl group is intimately involved in many reactions that create new carbon-carbon bonds. Carbonyl group is electrophilic at the carbon atom and hence is susceptible to attack by nucleophilic reagents. Reacts as a formyl cation or as an acyl cation. A reversal of the positive polarity of the carbonyl group acts as a fomyl or acyl anion and is synthetically very attractive.
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Umpolung
To achieve this, the carbonyl group is converted to a derivative whose carbon atom has the negative polarity. After its reaction with an electrophilic reagent, the carbonyl is regenerated. Reversal of polarity of a carbonyl group has been explored and systematized by Seebach. Umpolung synthesis usually requires extra steps. Can be achieved maximum advantage of the functionality already present in a molecule.
Carboxylic acids can be made by the addition of Grignard reagent to carbon dioxide.
Traditional approach to carboxylic acid
TM
Synthetic equivalent (SE) SE
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Carboxylic acids can also be made by nucleophilic displacement of halides by cyanides, then hydrolysis.
Umpolung approach to carboxylic acid
SE SE
Practice of synthesis Synthetic design involves two distinct steps:
1. Retrosynthetic analysis and 2. Subsequent translation of the analysis into a forward direction synthesis.
The construction of a synthetic tree by working backward from the target molecule (TM) is called retrosynthetic analysis or antithesis.
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Practice of synthesis
The symbol signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI). Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Also, reagents derived from inverting the polarity (IP) of synthons may serve as SEs.
Donar and acceptor synthons
Heterolytic retrosynthetic disconnection of a carbon-carbon bond in a molecule breaks the TM into an acceptor synthon, a carbocation, a donor synthon, a carbanion.
In a formal sense, the reverse reaction, the formation of a C-C bond, then involves the union of an electrophilic acceptor synthon a nucleophilic donor synthon
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Common acceptor synthons
Common donor synthons
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Consonant patterns
Positive charges are placed at carbon atoms bonded to the E class groups.
Dissonant patterns
One E class group is bonded to a carbon with a positive charge, whereas the other E class group resides on a carbon with a negative charge
Often, more than one disconnection is feasible: A & B One functional group
Analysis
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Synthesis (path a) Disconnection path a: leads readily available substrate with high yield using well-known methodologies.
Disconnection path b: Synthesis (path b) leads readily accessible substrates. But reconnection to furnish the TM requires more steps and involves two critical reaction attributes: 1. quantitative formation of the enolate ion 2. control of its monoalkylation by ethyl bromide.
Two functional groups in a 1,3-relationship
Analysis
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Synthesis (path a)
Path b is preferable since it does not require a selective functional group Synthesis (path b) interconversion (reduction).
Chemistry of enolates (C vs O alkylation)
In presence of base, alkyl halide and carbonyl compounds with α-hydrogens undergo a reaction to produce a mixture of C-alkylated or O-alkylated product. This happens due to the formation of enolate.
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Chemistry of enolates C-alkylation vs O-alkylation: A continuous challenge in the chemistry of enolates. Enolates form in two steps: 1. Formation of carbanion and 2. undergoes resonance stabilization and forms enolate
C-alkylation O-alkylation
Chemistry of enolates (C vs O alkylation) Products C- and O-alkylation depend on a number of factors: negative charge density solvation cation coordination strength of electrophile and product stability Often, in most reactions, a mixture is obtained and the ratios vary from reaction to reaction.
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(C vs O alkylation)
1. Trimethyl silyl chloride is a much stronger electrophile, O-Si bond is more favorable than C-Si bond. 2. Forms O-alkylation thermodynamically as well as kinetically. 1. Methyl iodide is a weak electrophile, there is strong attraction between Na+ and O– . 2. C-alkylated product forms more thermodynamically stable product.
Enolate ions are in equilibrium with carbonyl compounds
With relatively weak bases (e.g. HO–, RO–) only a small percentage of enolate is formed.
Acetone with ethoxide ion has a much higher concentration of acetone relative to enolate ion.
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Form an enolate using LDA
LDA, Lithium diisopropylamide (LiN(C3H7)2
functional group example pKa carboxylic acid CH3CO2H 5 O O
b-diketone CH3CCH2CCH3 9 O O
b-ketoester CH3CCH2COCH2CH3 11 O O
b-diester CH3OCCH2COCH3 13
alcohol CH3CH2OH 16 O
aldehyde CH3CH 17 O
ketone CH3CCH3 19
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Ideal base for alkylation: Strong basicity, weak nucleophilicity, soluble in non polar solvent
- - - Common bases: Ph3C (Me2CH)2N EtO - OH R3N The bases are used depending on the reactivity of the substrates
NaNH2, LiNH2, KNH2: strong bases, but insoluble in conventional organic solvents
Soluble secondary amine derived bases
Readily available, soluble; amine byproduct is low MWt, volatile, and easily removed. The anion is also non-nucleophilic (relatively hindered).
Other widely used bases
= Lithium isopropylcyclohexylamide (LICA) Very hindered base
= Lithium 2,2,6,6-tetramethylpiperidide (LTMP) very hindered
M = Li Lithium hexamethyldisilazide (LHMDS or LHDS) = Na Sodium hexamethyldisilazide (NaHMDS) = K Potassium hexamethyldisilazide (KHMDS)
= Lithium octayl-butylamide (LOBA)
= Lithium bis(2-adamantly)amide (LBAA)
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C vs O-alkylation
C-alkylation
O-alkylation
Since C is the more nucleophilic atom, the products are primarily C-alkylated ketone or aldehyde.
Enolate ions react with a variety of different substrates (Halogenation, Alkylation, and Condensation Reactions)
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Different reactions using LDA
Crossed aldol
Michael
Alkylation
Acylation
Keto–enol tautomerism
The enol tautomer can be stabilized by intramolecular hydrogen bonding
In phenol, the enol tautomer is aromatic
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Solvent effects
Common used polar aprotic solvent:
DMF, N,N-dimethylformamide HOCN(CH3)2
DMSO, Dimethyl sulfoxide CH3SOCH3
HMPA, hexamethylphosphoric triamide OP[N(CH3)2]3
Solvent effects on enolate structure and reactivity The rate of alkylation of enolate ions is strongly dependent on the solvent in which the reaction is carried.
Relative rates of reaction of the sodium enolate of diethyl n-butylmalonate with n-butyl bromide:
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,HMPA
Solvent effects Phenoxides undergo O-alkylation in solvent such as DMSO, DMF, ethers, and alcohols. However, water and trifluoroethanol form particularly strong hydrogen bonds with the oxygen atom of the phenolate anion and extensive C-alkylation occurs.
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The C-alkylation of phenol is favored: By the use of heterogeneous reaction condition. By the use of a protic solvent which can form hydrogen- bond with the oxygen atom of the anion.
Strong preference for O-alkylation in phenoxide ions because C-alkylation disrupts aromatic conjugation.
Phenoxides undergo O-alkylation in solvents such as DMSO, DMF, ethers and alcohols. In water and trifluoroethanol, extensive C-alkylation occurs, because of strong hydrogen bonding.
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Negative charge density
C-alkylated and O-alkylated products can be explained by the charge distribution in the intermediate enolate anion.
A more common example of usually predominant O-alkylation is the alkylation of phenol. O-alkylation competes significantly with C-alkylation only when active methylene compounds are involved in which the equilibrium concentration of the enol is relatively high (e.g. 1,3-dicarbonyl compounds and phenols).
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Substrate effect - Reactivity of alkylating reagent
(Soft Nu) (Hard Nu)
Cation coordination Polar aprotic solvents possess excellent metal cation coordination ability, so they can solvate and dissociate enolates and other carbanions from ion pairs and clusters.
Polar aprotic solvents are good cation solvators and poor anion solvators. Thus, these solvents provide a medium in which enolate- metal ion pairs are dissociated to give a less encumbered, more reactive enolate
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Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favourable, because they coordinate to both the metal cation and the enolate ion. Solvation of the enolate anion occurs through hydrogen bonding.
Enolates generated in polar protic solvents such as water, alcohols, or ammonia are therefore less reactive then the same enolate in polar aprotic solvent such as DMSO
Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product. First formed dominates.
In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative a-hydrogens. With the use of a bulky base, the less hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion. No equilibrium among alternative structures is set up.
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α-Alkylation of carbonyl compounds
Under kinetic conditions, the less substituted enolated is favored since the more accessible hydrogen is abstracted more rapidly. Under thermodynamic control enolate equilibrium is established (weaker base). The more substituted (more stable) enolate is the dominant species.
α-Alkylation of carbonyl compounds
Kinetic product Thermodynamic product Two different products can be formed if the ketone is not symmetrical The more highly substituted product is the thermodynamic product, the kinetic product results from substitution at the more accessible α-carbon.
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Alkylation at more substituted α-position
Stereoselectivity in ketone alkylation
Two issues: 1. Site of deprotonation 2. Geometry of enolate formed
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Enolate formation and geometry
Enolate formation and geometry
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Enolate formation and geometry
R1 R2 Z E Et Me LDA 23 77 Et Me LTMP 14 86 Et Me LTMP-LiBr 2 98 Pr Me LDA 37 63 Pr Me LTMP 33 67 Pr Me LTMP-LiBr 5 95
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Imine and enamine formation
RNH2 adds to C=O to form imines, R2C=NR (after loss of H2O).
R2NH yields enamines, R2N-CR=CR2 (after loss of H2O) (ene+ amine= unsaturated amine).
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Enamines formation
Formation of enamines
Enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone. The 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine. O
N N H H Pyrrolidine Morpholine
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Mechanism of enamine formation
Formation of enamines Examples:
+ + O H H + N N N OH -H2 O H An enamine
O O O O + + H H + N N OH -H O N 2 H An enamine
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Enamines – alkylation
The value of enamines is that the b-carbon is nucleophilic.
Enamines undergo SN2 reactions with methyl and 1° haloalkanes, a-haloketones, and a-haloesters. Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide.
O O
•• N N Br SN2 + Br
The morpholine 3-Bromopropene An iminium enamine of (Allyl bromide) bromide cyclohexanone (racemic)
Enamines - alkylation
Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.
O O O + - N Br + + - HCl/ H 2O N Cl H H 2-Allylcyclo- Morpholinium hexanone chloride
Overall process is to render the alpha carbons of ketone nucleophilic enough so that substitution reactions can occur.
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Enamines – alkylation
Enamines – acylation Enamines undergo acylation when treated with acid chlorides and acid anhydrides.
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1,3-dithiane (synthesis of aldehydes and ketones) 1,3-dithiane can be prepared from 1,3-dithiol and aldehyde
1,3-dithiane has two weakly acidic protons that can be removed and alkylation of the carbon is possible. Once alkylated, the 1,3-dithiane becomes a ‘protected’ carbonyl as it can be hydrolyzed to the corresponding carbonyl structure.
Mechanism of dithiane alkylation
Requires strong bases: RLi, NaNH2 Works with primary halides only, Cl, Br, I It is also possible to obtain ketones in this reaction simply by performing a second alkylation prior to the hydrolysis of the substituted dithiane.
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