15/12/2019 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 1 15/12/2019 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. 2 15/12/2019 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. 3 15/12/2019 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 4 15/12/2019 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 5 15/12/2019 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) 6 15/12/2019 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. 7 15/12/2019 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) 8 15/12/2019 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. 9 15/12/2019 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. 10 15/12/2019 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 11 15/12/2019 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) 12 15/12/2019 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. 13 15/12/2019 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 14 15/12/2019 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. 15 15/12/2019 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 16 15/12/2019 Common acceptor synthons Common donor synthons 17 15/12/2019 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 18 15/12/2019 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 19 15/12/2019 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. 20 15/12/2019 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. 21 15/12/2019 (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.