Chapter 17: Carbonyl Compounds II
Chapter 17: Carbonyl Compounds II Nomenclature of Aldehydes and Ketones • The systematic name of an aldehyde is obtained by replacing the final “e” on the name of the parent hydrocarbon with “al” (ethanal, 2-bromopropanal or methanal). • Terminal “e” is removed only to avoid two successive vowels (hexanedial, e isn’t removed). • If a compound has two functional groups, the one with the lower priority is indicated by a prefix and the one with the higher priority by a suffix. • The systematic name of a ketone is obtained by replacing the final “e” on the end of the name of the parent hydrocarbon with “one.” • The chain is numbered in the direction that gives the carbonyl carbon the smallest number (3-hexanone, 6-methyl-2-heptanone or acetone). • If the ketone has a second functional group of higher naming priority, the ketone oxygen is indicated by the prefix “oxo.” • Increasing Priority: Alkyl Halide < Ether < Alkane < Alkyne < Alkene < Amine < Alcohol < Ketone < Aldehyde < Nitrile < Amide < Ester < Carboxilic Acid Relative Reactivities of Carbonyl Compounds • Since a hydrogen is electron withdrawing compared to an alkyl group, an aldehyde is more reactive than a ketone toward nucleophilic attack (formaldehyde < aldehyde < ketone). • Steric factors also contribute to the greater reactivity of an aldehyde, making the carbonyl carbon of an aldehyde more accessible to the nucleophile than is the carbonyl carbon. • Relative Reactivities of Carbonyl Compounds: Acyl Halide > Acid Anhydride > Aldehyde > Ketone > Ester ~ Carboxylic Acid > Amide > Carboxylate Ion. • Aldehydes and ketones are not as reactive as carbonyl compounds in which Y- is a very weak base but more reactive in which Y- is a relatively strong base. How Aldehydes and Ketones React • Aldehydes and ketones do not undergo acyl substitution reactions. • Nucleophilic Addition Reaction: irreversible reaction when a nucleophile adds to the carbonyl group of an aldehyde or a ketone and nothing is expelled due to nucleophile being a strong base. • If the nucleophile is a relatively weak base, the product of the reaction will again be the tetrahedral compound but reversible. • Nucleophilic Addition-Elimination Reaction: if the attacking atom of the nucleophile has a lone pair and there is sufficient acid to protonate the OH group of the tetrahedral compound, water can be eliminated from the addition product (reversible). Reactions of Carbonyl Compounds with Grignard Reagents • Addition of a Grignard reagent to carbonyl compounds leads to the formation of a new C-C bond, with the Grignard reagent acting as a nucleophile that’s a strong base. • Aldehydes and ketones undergo nucleophilic addition reactions with Grignard reagents. • When a Grignard reagent (RMgX) reacts with formaldehyde, the addition product is a primary alcohol. • When a Grignard reagent (RMgX) reacts with an aldehyde other than formaldehyde, the addition product is a secondary alcohol.
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When a Grignard reagent (RMgX) reacts with a ketone, the addition product is a tertiary alcohol. In a Grignard reagent, the R group acts as a nucleophile attacking the C in C=O. A Grignard reagent can also react with carbon dioxide, giving a carboxylic acid as a product that has more than one carbon atom than the Grignard reagent. Class I carbonyl compounds (ester or acyl chloride) undergo two successive reactions with the Grignard reagent (nucleophilic acyl substitution reaction then a nucleophilic addition reaction). o Nucleophilic attack by the Grignard reagent forms a tetrahedral intermediate that is unstable because it has a group that can be expelled. o The tetrahedral intermediate expels methoxide ion, forming a ketone. The reaction doesn’t stop at the ketone stage because ketones are more reactive than esters toward nucleophilic attack. o Reaction of the ketone with a second molecule of the Grignard reagent, followed by protonation of the alkoxide ion, forms a tertiary alcohol. o The alcohol should have two identical alkyl groups bonded to the tertiary carbon.
Reactions of Carbonyl Compounds with Acetylide Ions • Terminal alkyne can be converted into an acetylide ion: CH3C≡ CH + NaNH2/NH3 CH3C≡ C-. • Acetylide ions are strong bases that react with a carbonyl compound to form a nucleophilic addition product (adds a new C-C bond), then a weak acid is added to the reaction mixture to protonate the alkoxide ion. Reactions of Carbonyl Compounds with Hydride Ion • A hydride ion is another strongly basic nucleophile that reacts with aldehydes and ketones to form nucleophilic addition products. • Mechanism for the reaction of an aldehyde or a ketone with hydride ion (NaBH4): o Addition of a hydride ion to an aldehyde or ketone form an alkoxide ion (the H- ion attacks the C in C=O). o Subsequent protonation by an acid produces an alcohol. The overall reaction adds H2 to the carbonyl group. o Reduction Reaction: addition of a hydrogen to a compound. • Mechanism for the reaction of an acyl chloride with hydride ion: o The acyl chloride undergoes a nucleophilic acyl substitution reaction because it has a group that can be replaced by hydride ion; produces an aldehyde. o The aldehyde undergoes a nucleophlic addition reaction with a second equivalent of hydride ion, forming an alkoxide ion, which, when protonated, gives a primary alcohol. • Lithium aluminum hydride (LiAlH4) is more reactive than sodium borohydride (NaBH4) so it reduces all carbonyl groups; sodium borohydride only reduces aldehydes and ketones. • Lithium aluminum hydride produces two alcohols, one corresponding to the acyl portion of the ester and one corresponding to the alkyl portion. • The mechanism for esters is the same as the mechanism for acyl chlorides but gives two alcohols as products. • Diisobutylaluminum Hydride (DIBALH): used as the hydride donor at a low temperature of -780C so the reaction can be stopped after the addition of one
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equivalent of hydride ion (converting esters into aldehydes). The reaction of a carboxylic acid with LiAlH4 forms a single primary alcohol. Mechanism for the reaction of a carboxylic acid with hydride ion: o In the first step, a hydride ion reacts with the acidic hydrogen of the carboxylic acid, forming H2 and a carboxylate ion. o We have seen that nucleophiles do not reacts with a carboxylic ion because of its negative charge. However, in this case, an electrophile (AlH3) is present that accepts the pair of electrons from the carboxylate ion and forms a new hydride donor. o Then, analogous to the reduction of an ester by LiAlH4, two successive additions of hydride ion takes place, with an aldehyde being formed as an intermediate on the way to the primary alcohol. Amides undergo two successive additions of hydride ion when they react with LiAlH4. The mechanism for amides is the same as the mechanism for carboxylic acids.
Reactions of Aldehydes and Ketones with Hydrogen Cyanide • Cyanohydrins: formed by adding hydrogen cyanide to aldehydes and ketones. • Mechanism for the reaction of an aldehyde or ketone with cyanide ion: o In the first step, the cyanide ion attacks the carbonyl carbon. o Alkoxide ion accepts a proton from an undissociated molecule of hydrogen cyanide. o Excess sodium cyanide is used in order to ensure that some cyanide ion is available to act as a nucleophile (weak base). • Because cyanide ion is a weak base, it can be eliminated from the addition product. • Cyanohydrins are stable: the OH group will not eliminate the cyano group because the transition state for that elimination reaction would be relatively unstable since the oxygen atom would bear a partial positive charge. • If the OH group loses its proton, the cyano group will be eliminated. • Cyanide ion doesn’t react with esters because the cyanide ion is a weaker base than an alkoxide ion, so the cyanide ion would be eliminated from the tetrahedral intermediate. Reactions of Aldehydes and Ketones with Amines and Derivatives of Amines • An aldehyde or a ketone reacts with a primary amine to form an imine. • Imine: a compound with a carbon-nitrogen double bond. • Schiff Base: imine obtained from the reaction of a carbonyl compound and a primary amine. • An aldehyde or ketone reacts with a secondary amine to form an enamine. • Enamine: α,β-unsaturated tertiary amine, a tertiary amine with a double bond in the α,β-position relative to the nitrogen atom. • Mechanism for imine formation: o The amine attacks the carbonyl carbon. o Gain of a proton by the alkoxide ion and loss of a proton by the ammonium ion forms a neutral tetrahedral intermediate. o The neutral tetrahedral intermediate (carbinolamine) is in equilibrium with two protonated forms because either the oxygen or the nitrogen can be protonated. o Elimination of water from the oxygen-protonated intermediate forms a protonated imine that loses a proton to yield the imine (reversible reaction).
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An imine undergoes acid-catalyzed hydrolysis to form a carbonyl compound and a primary amine. Mechanism for enamine formation: o The amine attacks the carbonyl carbon. o Gain of a proton by the alkoxide ion and loss of a proton by the ammonium ion forms a neutral tetrahedral intermediate. o The neutral tetrahedral intermediate is in equilibrium with two protonated forms because either the oxygen or the nitrogen can be protonated. o When a primary amine reacts with an aldehyde or ketone, the protonated imine loses a proton from nitrogen in the last step of the mechanism, forming a neutral imine. o However, when the amine is secondary, the positively charged nitrogen is not bonded to a hydrogen. In this case, a stable neutral molecule is obtained by loss of a proton from the α-carbon of the compound derived from the carbonyl compound. o An enamine undergoes acid-catalyzed hydrolysis to form a carbonyl compound and a secondary amine. Reductive Amination: the reaction of an aldehyde or a ketone with excess ammonia in the presence of a reducing agent (R2C=O + NH3 R2C=NH R2CH2NH2). Deoxygenation: an oxygen is removed from the reactant (Wolff-Kishner reduction). Mechanism for the Wolff-Kishner reduction: o Initially, the ketone reacts with hydrazine (NH2NH2) to form a hydrazone. o Hydroxide ion removes a proton from the NH2 group. The reaction requires heat because this proton is not easily removed. o The negative charge can be delocalized onto carbon, which abstracts a proton from water. o The last two steps are repeated to form the deoxygenated product and nitrogen gas.
Reactions of Aldehydes and Ketones with Water • The addition of water to an aldehyde or a ketone forms a hydrate. • Hydrate or Gem-Diols: a molecule with two OH groups on the same carbon. • An acid catalyst is needed to increase the rate of reaction but has no effect on the position of the equilibrium. • Formaldehyde will create 99.9% of hydrate, primary substituted aldehyde will create 58% of hydrate and ketones form 0.2% only; this is because ketones are more stable and more sterically hindering attack. o Electron-donating substituents and bulky substituents (methyl groups) decrease the percentage of hydrate present at equilibrium. o Electron-withdrawing substituents and small substituents (hydrogen) increase it. Reactions of Aldehydes and Ketones with Alcohols • Hemiacetal: the product formed when one equivalent of an alcohol adds to an aldehyde • Acetal: the product formed when a second equivalent of alcohol is added. • An alcohol, like water, is a poor nucleophile, so an acid catalyst is required for the reaction to take place at a reasonable rate. • When the carbonyl compound is a ketone instead of an aldehyde, the addition
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products are called hemiketal and ketal. Mechanism for acid-catalyzed acetal or ketal formation: o The acid protonates the carbonyl oxygen, making the carbonyl carbon more susceptible to nucleophilic attack. o Loss of proton from the protonated tetrahedral intermediate gives the hemiketal. o Because the reaction is carried out in an acidic solution, the hemiketal or hemiacetal is in equilibrium with its protonated form. The two oxygen atoms of the hemiketal or hemiacetal are equally basic so either one can be protonated. o Loss of water from the tetrahedral intermediate with a protonated OH group forms an O-alkylated intermediate that is very reactive because of its positively charged oxygen. Nucleophilic attack on this intermediate by a second molecule of alcohol, followed by loss of a proton, forms the acetal or ketal. The acetal or ketal can be hydrolyzed back to the aldehyde or ketone in an acidic aqueous solution.
Protecting Groups • If a compound has two functional groups that will react with a given reagent and you want only one of them to react, it is necessary to protect the other functional group from the reagent. • Protecting Group: a group that protects a functional group from a synthetic operation that it would not otherwise survive. • Acid and water will be used to kick off the protecting group, leaving us with the C=O bond. • Converting the carboxylic acid into an ester first can protect the OH GROUP of a carboxylic acid group. • An amino group can be protected by being converted into an amide. Addition of Sulfur Nucleophiles • Aldehydes and ketones react with thiols (CH3SH or HSCH2CH2CH2SH) to form thioacetals and thioketals. • Thioacetal or thioketal formation is useful in organic synthesis because a thioacetal or thioketal is desulfurized when it reacts with H2 and Raney nickel; desulfurization replaces the C-S bonds with C-H bonds. The Wittig Reaction Forms an Alkene • Wittig Reaction: an aldehyde or a ketone reacts with a phosphonium ylide to form an alkene. • Ylide: a compound that has opposite charges on adjacent covalently bonded atoms that have complete octets (it can be written in the double bonded form (C6H5)3P=CH2). • Mechanism for the Wittig reaction: o The nucleophilic carbon of the ylide attacks the carbonyl carbon while the carbonyl oxygen attacks the electrophilic phosphorus. o Elimination of triphenylphosphine oxide forms an alkene product. • If two sets of reagents are available for the synthesis of an alkene, the better choice is one that requires the less sterically hindered alkyl halide for synthesis of the ylide (better to use a three carbon alkyl halide than the five carbon one). • The Wittig reaction is the best way to make a terminal alkene. • Stabilized Ylides: have a group that can share carbon’s negative charge and forms primarily E or trans isomers.
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Unstabilized Ylides: do not have such a group and form primarily Z or cis isomers.
Nucleophilic Addition to α,β-Unsaturated Aldehydes and Ketones • If an aldehyde or ketone has a double bond in the α,β-position, a nucleophile can add either to the carbonyl carbon or to the β-carbon. • Direct Addition or 1,2-Addition: nucleophlic addition to the carbonyl carbon. • Conjugate Addition or 1,4-Addition: nucleophilic addition to the β-carbon. • After 1,4-addition has occurred, the product (enol) tautomerizes to a ketone so the overall reaction amounts to addition to the carbon-carbon double bond, with the nucleophile adding to the β-carbon and a proton from the reaction mixture adding to the α-carbon. • Weak bases (halide ion, cyanide ion, thiol, alcohol or amine) form conjugate addition products with the thermodynamic product as more stable. • Strong bases (Grignard reagents or hydride ion) form direct addition products with reactive carbonyl groups and conjugate addition products with less reactive carbonyl groups (hindrance is also taken into account; conjugate addition wins if sterically hindered). • Grignard reagents should be used when you want to add an alkyl group to the carbonyl carbon, whereas Gilman reagents (-R2CuLi) should be used when you want to add an alkyl group to the β-carbon. • Grignard reagent with highly polarized C-Mg bond prefers to react with the harder C=O bond, whereas a Gilman reagent with much less polarized C-Cu bond prefers to react with the softer C=C bond. Nucleophilic Addition to α,β-Unsaturated Carboxylic Acid Derivatives • They undergo nucleophilic acyl substitution rather than direct addition because the α,β-unsaturated carbonyl compound had a group that can be replaced by a nucleophile. • Nucleophlic acyl addition becomes nucleophilic acyl substitution if the carbonyl group is attached to a group that can be replaced by a nucleophile. • Conjugate addition products are formed from the reaction of nucleophlies with less reactive carbonyl groups, such as esters and amides.
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When a Grignard reagent (RMgX) reacts with a ketone, the addition product is a tertiary alcohol. In a Grignard reagent, the R group acts as a nucleophile attacking the C in C=O. A Grignard reagent can also react with carbon dioxide, giving a carboxylic acid as a product that has more than one carbon atom than the Grignard reagent. Class I carbonyl compounds (ester or acyl chloride) undergo two successive reactions with the Grignard reagent (nucleophilic acyl substitution reaction then a nucleophilic addition reaction). o Nucleophilic attack by the Grignard reagent forms a tetrahedral intermediate that is unstable because it has a group that can be expelled. o The tetrahedral intermediate expels methoxide ion, forming a ketone. The reaction doesn’t stop at the ketone stage because ketones are more reactive than esters toward nucleophilic attack. o Reaction of the ketone with a second molecule of the Grignard reagent, followed by protonation of the alkoxide ion, forms a tertiary alcohol. o The alcohol should have two identical alkyl groups bonded to the tertiary carbon.
Reactions of Carbonyl Compounds with Acetylide Ions • Terminal alkyne can be converted into an acetylide ion: CH3C≡ CH + NaNH2/NH3 CH3C≡ C-. • Acetylide ions are strong bases that react with a carbonyl compound to form a nucleophilic addition product (adds a new C-C bond), then a weak acid is added to the reaction mixture to protonate the alkoxide ion. Reactions of Carbonyl Compounds with Hydride Ion • A hydride ion is another strongly basic nucleophile that reacts with aldehydes and ketones to form nucleophilic addition products. • Mechanism for the reaction of an aldehyde or a ketone with hydride ion (NaBH4): o Addition of a hydride ion to an aldehyde or ketone form an alkoxide ion (the H- ion attacks the C in C=O). o Subsequent protonation by an acid produces an alcohol. The overall reaction adds H2 to the carbonyl group. o Reduction Reaction: addition of a hydrogen to a compound. • Mechanism for the reaction of an acyl chloride with hydride ion: o The acyl chloride undergoes a nucleophilic acyl substitution reaction because it has a group that can be replaced by hydride ion; produces an aldehyde. o The aldehyde undergoes a nucleophlic addition reaction with a second equivalent of hydride ion, forming an alkoxide ion, which, when protonated, gives a primary alcohol. • Lithium aluminum hydride (LiAlH4) is more reactive than sodium borohydride (NaBH4) so it reduces all carbonyl groups; sodium borohydride only reduces aldehydes and ketones. • Lithium aluminum hydride produces two alcohols, one corresponding to the acyl portion of the ester and one corresponding to the alkyl portion. • The mechanism for esters is the same as the mechanism for acyl chlorides but gives two alcohols as products. • Diisobutylaluminum Hydride (DIBALH): used as the hydride donor at a low temperature of -780C so the reaction can be stopped after the addition of one
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equivalent of hydride ion (converting esters into aldehydes). The reaction of a carboxylic acid with LiAlH4 forms a single primary alcohol. Mechanism for the reaction of a carboxylic acid with hydride ion: o In the first step, a hydride ion reacts with the acidic hydrogen of the carboxylic acid, forming H2 and a carboxylate ion. o We have seen that nucleophiles do not reacts with a carboxylic ion because of its negative charge. However, in this case, an electrophile (AlH3) is present that accepts the pair of electrons from the carboxylate ion and forms a new hydride donor. o Then, analogous to the reduction of an ester by LiAlH4, two successive additions of hydride ion takes place, with an aldehyde being formed as an intermediate on the way to the primary alcohol. Amides undergo two successive additions of hydride ion when they react with LiAlH4. The mechanism for amides is the same as the mechanism for carboxylic acids.
Reactions of Aldehydes and Ketones with Hydrogen Cyanide • Cyanohydrins: formed by adding hydrogen cyanide to aldehydes and ketones. • Mechanism for the reaction of an aldehyde or ketone with cyanide ion: o In the first step, the cyanide ion attacks the carbonyl carbon. o Alkoxide ion accepts a proton from an undissociated molecule of hydrogen cyanide. o Excess sodium cyanide is used in order to ensure that some cyanide ion is available to act as a nucleophile (weak base). • Because cyanide ion is a weak base, it can be eliminated from the addition product. • Cyanohydrins are stable: the OH group will not eliminate the cyano group because the transition state for that elimination reaction would be relatively unstable since the oxygen atom would bear a partial positive charge. • If the OH group loses its proton, the cyano group will be eliminated. • Cyanide ion doesn’t react with esters because the cyanide ion is a weaker base than an alkoxide ion, so the cyanide ion would be eliminated from the tetrahedral intermediate. Reactions of Aldehydes and Ketones with Amines and Derivatives of Amines • An aldehyde or a ketone reacts with a primary amine to form an imine. • Imine: a compound with a carbon-nitrogen double bond. • Schiff Base: imine obtained from the reaction of a carbonyl compound and a primary amine. • An aldehyde or ketone reacts with a secondary amine to form an enamine. • Enamine: α,β-unsaturated tertiary amine, a tertiary amine with a double bond in the α,β-position relative to the nitrogen atom. • Mechanism for imine formation: o The amine attacks the carbonyl carbon. o Gain of a proton by the alkoxide ion and loss of a proton by the ammonium ion forms a neutral tetrahedral intermediate. o The neutral tetrahedral intermediate (carbinolamine) is in equilibrium with two protonated forms because either the oxygen or the nitrogen can be protonated. o Elimination of water from the oxygen-protonated intermediate forms a protonated imine that loses a proton to yield the imine (reversible reaction).
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An imine undergoes acid-catalyzed hydrolysis to form a carbonyl compound and a primary amine. Mechanism for enamine formation: o The amine attacks the carbonyl carbon. o Gain of a proton by the alkoxide ion and loss of a proton by the ammonium ion forms a neutral tetrahedral intermediate. o The neutral tetrahedral intermediate is in equilibrium with two protonated forms because either the oxygen or the nitrogen can be protonated. o When a primary amine reacts with an aldehyde or ketone, the protonated imine loses a proton from nitrogen in the last step of the mechanism, forming a neutral imine. o However, when the amine is secondary, the positively charged nitrogen is not bonded to a hydrogen. In this case, a stable neutral molecule is obtained by loss of a proton from the α-carbon of the compound derived from the carbonyl compound. o An enamine undergoes acid-catalyzed hydrolysis to form a carbonyl compound and a secondary amine. Reductive Amination: the reaction of an aldehyde or a ketone with excess ammonia in the presence of a reducing agent (R2C=O + NH3 R2C=NH R2CH2NH2). Deoxygenation: an oxygen is removed from the reactant (Wolff-Kishner reduction). Mechanism for the Wolff-Kishner reduction: o Initially, the ketone reacts with hydrazine (NH2NH2) to form a hydrazone. o Hydroxide ion removes a proton from the NH2 group. The reaction requires heat because this proton is not easily removed. o The negative charge can be delocalized onto carbon, which abstracts a proton from water. o The last two steps are repeated to form the deoxygenated product and nitrogen gas.
Reactions of Aldehydes and Ketones with Water • The addition of water to an aldehyde or a ketone forms a hydrate. • Hydrate or Gem-Diols: a molecule with two OH groups on the same carbon. • An acid catalyst is needed to increase the rate of reaction but has no effect on the position of the equilibrium. • Formaldehyde will create 99.9% of hydrate, primary substituted aldehyde will create 58% of hydrate and ketones form 0.2% only; this is because ketones are more stable and more sterically hindering attack. o Electron-donating substituents and bulky substituents (methyl groups) decrease the percentage of hydrate present at equilibrium. o Electron-withdrawing substituents and small substituents (hydrogen) increase it. Reactions of Aldehydes and Ketones with Alcohols • Hemiacetal: the product formed when one equivalent of an alcohol adds to an aldehyde • Acetal: the product formed when a second equivalent of alcohol is added. • An alcohol, like water, is a poor nucleophile, so an acid catalyst is required for the reaction to take place at a reasonable rate. • When the carbonyl compound is a ketone instead of an aldehyde, the addition
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products are called hemiketal and ketal. Mechanism for acid-catalyzed acetal or ketal formation: o The acid protonates the carbonyl oxygen, making the carbonyl carbon more susceptible to nucleophilic attack. o Loss of proton from the protonated tetrahedral intermediate gives the hemiketal. o Because the reaction is carried out in an acidic solution, the hemiketal or hemiacetal is in equilibrium with its protonated form. The two oxygen atoms of the hemiketal or hemiacetal are equally basic so either one can be protonated. o Loss of water from the tetrahedral intermediate with a protonated OH group forms an O-alkylated intermediate that is very reactive because of its positively charged oxygen. Nucleophilic attack on this intermediate by a second molecule of alcohol, followed by loss of a proton, forms the acetal or ketal. The acetal or ketal can be hydrolyzed back to the aldehyde or ketone in an acidic aqueous solution.
Protecting Groups • If a compound has two functional groups that will react with a given reagent and you want only one of them to react, it is necessary to protect the other functional group from the reagent. • Protecting Group: a group that protects a functional group from a synthetic operation that it would not otherwise survive. • Acid and water will be used to kick off the protecting group, leaving us with the C=O bond. • Converting the carboxylic acid into an ester first can protect the OH GROUP of a carboxylic acid group. • An amino group can be protected by being converted into an amide. Addition of Sulfur Nucleophiles • Aldehydes and ketones react with thiols (CH3SH or HSCH2CH2CH2SH) to form thioacetals and thioketals. • Thioacetal or thioketal formation is useful in organic synthesis because a thioacetal or thioketal is desulfurized when it reacts with H2 and Raney nickel; desulfurization replaces the C-S bonds with C-H bonds. The Wittig Reaction Forms an Alkene • Wittig Reaction: an aldehyde or a ketone reacts with a phosphonium ylide to form an alkene. • Ylide: a compound that has opposite charges on adjacent covalently bonded atoms that have complete octets (it can be written in the double bonded form (C6H5)3P=CH2). • Mechanism for the Wittig reaction: o The nucleophilic carbon of the ylide attacks the carbonyl carbon while the carbonyl oxygen attacks the electrophilic phosphorus. o Elimination of triphenylphosphine oxide forms an alkene product. • If two sets of reagents are available for the synthesis of an alkene, the better choice is one that requires the less sterically hindered alkyl halide for synthesis of the ylide (better to use a three carbon alkyl halide than the five carbon one). • The Wittig reaction is the best way to make a terminal alkene. • Stabilized Ylides: have a group that can share carbon’s negative charge and forms primarily E or trans isomers.
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Unstabilized Ylides: do not have such a group and form primarily Z or cis isomers.
Nucleophilic Addition to α,β-Unsaturated Aldehydes and Ketones • If an aldehyde or ketone has a double bond in the α,β-position, a nucleophile can add either to the carbonyl carbon or to the β-carbon. • Direct Addition or 1,2-Addition: nucleophlic addition to the carbonyl carbon. • Conjugate Addition or 1,4-Addition: nucleophilic addition to the β-carbon. • After 1,4-addition has occurred, the product (enol) tautomerizes to a ketone so the overall reaction amounts to addition to the carbon-carbon double bond, with the nucleophile adding to the β-carbon and a proton from the reaction mixture adding to the α-carbon. • Weak bases (halide ion, cyanide ion, thiol, alcohol or amine) form conjugate addition products with the thermodynamic product as more stable. • Strong bases (Grignard reagents or hydride ion) form direct addition products with reactive carbonyl groups and conjugate addition products with less reactive carbonyl groups (hindrance is also taken into account; conjugate addition wins if sterically hindered). • Grignard reagents should be used when you want to add an alkyl group to the carbonyl carbon, whereas Gilman reagents (-R2CuLi) should be used when you want to add an alkyl group to the β-carbon. • Grignard reagent with highly polarized C-Mg bond prefers to react with the harder C=O bond, whereas a Gilman reagent with much less polarized C-Cu bond prefers to react with the softer C=C bond. Nucleophilic Addition to α,β-Unsaturated Carboxylic Acid Derivatives • They undergo nucleophilic acyl substitution rather than direct addition because the α,β-unsaturated carbonyl compound had a group that can be replaced by a nucleophile. • Nucleophlic acyl addition becomes nucleophilic acyl substitution if the carbonyl group is attached to a group that can be replaced by a nucleophile. • Conjugate addition products are formed from the reaction of nucleophlies with less reactive carbonyl groups, such as esters and amides.
