Carbonyl Compounds I
Carbonyl Compounds I Nomenclature of Carboxylic Acids and Carboxylic Acid Derivatives • Carbonyl Group: a carbon double bonded to oxygen. • Acyl Group: consists of a carbonyl group attached to an alkyl group or to an aryl group (Ar). • Carboxylic Acid Derivatives: differ from a carboxylic acid only in the nature of the group or atom that replaced the OH group of the carboxylic acid (amides, esters, acyl halides and acid anhydrides). • Weak bases are good leaving groups and strong bases are poor leaving groups because weak bases do not share their electrons (lower pKa, the stronger the acid and weaker its conjugate base). • Naming Carboxylic Acids: o Carboxylic acid is named by replacing the terminal “e” of alkane with “oic acid.” o The carbonyl carbon is always the C-1 carbon or α-carbon. o Carboxyl Group: the functional group of a carboxylic acid. o Carboxylic acids in which a carboxyl group is attached t a ring are named by adding “carboxylic acid” to the name of the cyclic compound. • Naming Acyl Halides: o Acyl Halides: have a Cl or Br in place of the OH group of a carboxylic acid. o Acyl halides are named by using the acid name and replacing “ic acid” with “yl chloride or yl bromide.” • Acid Anhydride: loss of water from two molecules of a carboxylic acid. o Symmetrical Anhydride: if the two carboxylic acid molecules forming the acid anhydride are the same; named by taking the acid name and replacing “acid” with “anhydride” (acetic anhydride). o Mixed Anhydride: if they are different; named by stating the names of both acids in alphabetical order followed by “anhydride” (acetic formic anhydride). • Naming Esters: o Ester: has an OR’ group in place of the OH group of a carboxylic acid. o The name of the group (R’) attached to the carboxyl oxygen is stated first, followed by the name of the acid, with “ic acid” replaced by “ate” (ethyl acetate). o Lactones: cyclic esters and are named as “2-oxacycloalkanones.” • Naming Amides: o Amide: has an NH2, NHR or NR2 group in place of the OH group of a carboxylic acid. o Amides are named by taking the acid name and replacing “oic acid,” “ic acid,” or “ylic acid” with “amide” (acetamide or benzamide). o If a substituent is bonded to the nitrogen, the name of the substituent is stated first, followed by the name of the amide; the name of each substituent is preceded by a capital N to indicate that the substituent is bonded to a nitrogen (N-cyclohexylpropanamide). o Lactams: cyclic amides; they are named as “2-azacycloalkanones.” • Naming Nitriles: o Nitriles: compounds that contain a C≡ N functional group (cyano group). o Nitriles are named by adding “nitrile” to the parent alkane name. o The triple-bonded carbon of the nitrile group is counted in the number of carbons in the longest continuous chain. o Nitriles are named by replacing “ic acid” of the carboxylic acid name
with “onitrile.” Structures of Carboxylic Acids and Carboxylic Acid Derivatives • Carbonyl Carbon: sp2 hybridized, it uses its three sp2 orbitals to form σ bonds to the carbonyl oxygen, α-carbon and a substituent (Y). • Carbonyl Oxygen: sp2 hybridized, one of its sp2 orbitals forms a σ bond with the carbonyl carbon and each of the other two sp2 orbitals contains a lone pair; the remaining p orbital of the carbonyl oxygen overlaps the remaining p orbital of carbonyl carbon to form a π bond. How Class I Carbonyl Compounds React • The carbonyl carbon is electron deficient due to the more electronegative oxygen so this will be attached by nucleophiles. • Tetrahedral Intermediate: the sp2 carbon in the reactant has become an sp3 carbon in the intermediate. • A compounds that has an sp3 carbon bonded to an oxygen atom will be unstable if the sp3 carbon is bonded to another electronegative atom. • The weaker the base, the better it is as a leaving group (Y- vs Z-). • Nucleophilic Acyl Substitution Reaction: a nucleophile (Z-) has replaced the substituent (Y-) that was attached to the acyl group in the reactant. • Acyl Transfer Reaction: an acyl group has been transferred from one group (Y-) to another (Z-). • Reaction Coordinate Diagram: o If the new group in the tetrahedral intermediate is a weaker base than the group that was attached to the acyl group in the reactant, the easier pathway (lower energy hill) is for the tetrahedral intermediate (Tl) to expel the newly added group and reform the reactants, so no reaction takes place. o If the new group in the tetrahedral intermediate is a stronger base than the group that was attached to the acyl group in the reactant, the easier pathway is for the tetrahedral intermediate to expel the group that was attached to the acyl group in the reactant and form a substituted product. o If both groups in the tetrahedral intermediate has similar basicities, the tetrahedral intermediate can expel either group with similar case; a mixture of reactant and substitution product will result. Relative Reactivities of Carboxylic Acids and Carboxylic Acid Derivatives • Relative Basicities of the Leaving Groups: Cl- < -OCR=O < -OR = -OH < -NH2 • Relative Reactivites of Carboxylic Acid Derivatives: acyl chloride > acid anhydride > ester = carboxylic acid > amide • A carboxylic acid derivative can be converted into a less reactive carboxylic acid derivative, but not into one that is more reactive (acyl chloride can be converted into an ester but not vice versa). General Mechanism for Nucleophilic Acyl Substitution Reactions • All carboxylic acid derivatives react by the same mechanism. o The nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. o The tetrahedral intermediate collapses, eliminating the weaker base. • Neutral Nucleophile: o The nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate.
o o
A proton is lost from the tetrahedral intermediate, resulting in a tetrahedral intermediate equivalent to the one formed by negatively charged nucleophile. This tetrahedral intermediate expels the weaker of the two bases, either the newly added group after it has lost a proto or the group that was attached to the acyl group in the reactant.
Reactions of Acyl Halides • Acyl halides react with carboxylate ions to form anhydrides. • Acyl halides react with alcohols to form esters. • Acyl halides react with water to form carboxylic acids. • Acyl halides react with amines to form amides. • The reaction of an acyl chloride with ammonia or with a primary or secondary amine forms an amide and HCl. o Acid generated in reaction will protonate unreacted ammonia or unreacted amine. o Since a protonated amine is not a nucleophile, it cannot react with the acyl chloride. o The reaction must be carried out with twice as much ammonia or amine as chloride. o Tertiary amines cannot form amides; an equivalent of a tertiary amine can be used instead of excess amine. Reactions of Acid Anhydrides • Acid anhydrides do not react with sodium chloride because the incoming halide ion is a weaker base than the departing carboxylate ion. • Acid anhydride reacts with an alcohol to form an ester and a carboxylic acid. • Acid anhydride reacts with water to form a carboxylic acid. • Acid anhydride reacts with an amine to form an amide and a carboxylate ion. • In the reaction of an amine, with an anhydride, two equivalents of the amine or one equivalent of the amine plus one equivalent of a tertiary amine must be used so sufficient amine will be present to react with both the carbonyl compound and the proton produced. Reactions of Esters • Esters do not react with halide ions or with carboxylate ions because these nucleophiles are much weaker bases than the RO- leaving group of the ester. • Esters react with water to form a carboxylic acid and an alcohol. • Hydrolysis Reaction: reaction with water that converts one compound into two compounds. • Esters react with an alcohol to form a new ester and a new alcohol. • Alcoholysis Reaction: reaction with an alcohol that converts one compound into two. • Transesterification Reaction: one ester is converted to another ester. • Hydrolysis and alcoholysis of an ester can be catalyzed by acids. • Esters react with amines to form amides; requires only one equivalent of amine. • Aminolysis: reaction with an amine that converts one compound into two compounds. • Phenyl esters are more reactive than alkyl esters. Acid-Catalyzed Ester Hydrolysis and Transesterification • In an acid-catalyzed reaction, all organic intermediates and products are positively charged or neutral; negatively charged organic intermediates and
products are not formed in acidic solutions. • In a reaction in which HO- is used to increase the rate of reaction, all organic intermediates and products are negatively charged or neutral; positively charged organic intermediates and products are not formed in basic solutions. • Mechanism: o The acid protonates the carbonyl oxygen. o The nucleophile (H2O) attacks the carbonyl carbon of the protonated carbonyl group, forming a protonated tetrahedral intermediate. o Protonated tetrahedral intermediate is in equilibrium with its nonprotonated form. o Once the nonprotonated tetrahedral intermediate has been formed, either the OH or the OR group of this intermediate can be protonated. o When tetrahedral intermediate collapses, it expels CH3OH rather than HO- and forms the carboxylic acid. o Removal of a proton from the protonated carboxylic acid or protonated ester forms the neutral carbonyl comounds. • Excess water will drive the reaction to the right, forming the carboxylic acid. • Excess CH3OH will drive the reaction to the left, reforming the ester. • Catalyst: substance that increases the rate of a reaction without being consumed or changed in the overall reaction. • An acid catalyst increases the reactivity of a carbonyl group. • An acid catalyst can make a group a better leaving group. • Mechanism for Hydrolysis of an Ester with a Tertiary Alkyl Group: o An acid protonates the carbonyl oxygen. o The leaving group departs, forming a tertiary carbocation. o A nucleophile reacts with the carbocation. o A base removes a proton from the strongly acidic protonated alcohol. Hydroxide-Ion-Promoted Ester Hydrolysis • Carrying out the reaction in a basic solution can increase the rate of hydrolysis of an ester. • Hydroxide ion is a better nucleophile than water. • The hydroxide-ion-promoted hydrolysis of an ester is not a reversible reaction, compared to the acid-catalyzed hydrolysis. Soaps, Detergents and Micelles • Fatty Acids: long-chain unbranched carboxylic acids. • When the ester groups of a fat or an oil are hydrolyzed in basic solution, glycerol and carboxylate ions are formed. • Soaps: sodium or potassium salts of fatty acids and are obtained when fats or oils are hydrolyzed under basic conditions. • Saponification: hydrolysis of an ester in a basic solution. • Micelles: long-chain carboxylate ions arrange themselves in spherical clusters. • Hydrophobic Interactions: attractive forces between hydrocarbon chains in water. • Because the surface of the micelle is negatively charged, the individual micelles usually repel each other instead of clustering to form larger aggregates. • Detergents: salts of benzene sulfonic acids; to prevent pollution, detergents should be made only with straight-chain alkyl groups due to it being biodegradable. Reactions of Carboxylic Acids • Carboxylic acids can undergo nucleophilic acyl substitution reactions only when
• • • • •
they are in their acidic forms. Relative Reactivities Toward Nucleophilic Acyl Substitution: RCOOH > RC=ONH2 > RCOOCarboxylic acids do not react with halide ions or with carboxylate ions. Carboxylic acids react with alcohols to form esters, in acidic solutions and excess alcohol must be used to drive it towards products. Fisher Esterification: an ester could be prepared by treating a carboxylic acid with excess alcohol in the presence of an acid catalyst. Carboxylic acids do not undergo nucleophilic acyl substitution reactions with amines; an acid/base reaction occurs resulting in a carboxylate salt as a product.
Reactions of Amides • Amides do not react with halide ions, carboxylate ions, alcohols or water because the incoming nucleophile is a weaker base than the leaving group of the amide. • Amides react with water and alcohols if the reaction mixture is HEATED in the presence of an acid. • Amide with an NH2 group can be dehydrated to a nitrile (R-C≡ N) using P2O5, POCl3 or SOCl2. The Hydrolysis of Amides Is Catalyzed by Acids • Mechanism: o The acid protonates the carbonyl oxygen, which increases the susceptibility of the carbonyl carbon to nucleophilic attack. o Nucleophilic attack by water on the carbonyl carbon leads to tetrahedral intermediate I, which is in equilibrium with its nonprotonated form, tetrahedral intermediate II. o Reprotonation can occur either on oxygen to reform tetrahedral intermediate I or on nitrogen to form tetrahedral intermediate III. o Protonation on nitrogen is favored because the NH2 group is a stronger base than the OH group. o Of the two possible leaving groups in tetrahedral intermediate III, NH3 is the weaker base, forming the carboxylic acid as the final product. o Since the reaction is carried out in an acidic solution, NH3 will be protonated after it is expelled from the tetrahedral intermediate; this prevents the reverse reaction from occurring, because +NH4 is not a nucleophile. • Amide cannot be hydrolyzed without a catalyst because the amide would not be protonated so water would have to attack a neutral amide that is less susceptible to nucleophilic attack than a protonated amide would be. • An amide reacts with an alcohol in the presence of acid for the same reason that it reacts with water in the presence of acid. The Hydrolysis of Nitriles • Mechanism: o The acid protonates the nitrogen of the cyano group (C≡ N), making it easier for water to attack the carbon of the cyano group. o Nucleophilic attack by water on the protonated cyano group is analogous to nucleophlic attack by water on a protonated carbonyl group. o Because nitrogen is a stronger base than oxygen, oxygen loses a proton and nitrogen gains a proton, resulting in a protonated amide.
The amide is immediately hydrolyzed to a carboxylic acid by means of acid-catalyzed mechanism. Nitriles can be prepared from an Sn2 reaction of alkyl halide with cyanide ion then to a carboxylic acid (HCl, H2O). A nitrile can be reduced to a primary amine by the same reagent that reduces an alkyne to an alkane (H2, Pt/C). o
• •
Designing a Synthesis V: The Synthesis of Cyclic Compounds • Cyclic compounds are formed from INTRAMOLECULAR reactions; the two reacting groups are in the same molecule. • A cyclic ester or lactone can be prepared from a reactant that has a carboxylic acid group and an alcohol group in the same molecule (HOCH2CH2CH2CH2COOH with HCl). • A compound with a ketone group attached to a benzene ring can be prepared using a Friedel-Crafts acylation reaction and a cyclic ketone will result if a Lewis acid (AlCl3) is added to a compound that contains both a benzene ring and an acyl chloride group. • A cyclic ether can be prepared by an intramolecular Williamson ether syntheses. • A cyclic ether can also be prepared by an intramolecular electrophilic addition reaction. How Chemists Activate Carboxylic Acids • Organic chemists activate carboxylic acids by converting them into acyl halides. • A carboxylic acid can be converted into an acyl chloride by being heated either with thionyl chloride (SOCl2) or with phosphorus trichloride (PCl3). • Acyl bromides can be synthesized by using phosphorus tribromide (PBr3). • All these reagents convert the OH group of a carboxylic acid into a better leaving group than the halide ion. • As a result, when the halide ion attacks the carbonyl carbon and forms a tetrahedral intermediate, the halide ion is not the group that is eliminated (SOCl, PCl2 or PBr2 is). • Carboxylic acids can also be activated for nucleophlic acyl substitution reactions by being converted into anhydrides; treating a carboxylic acid with a strong dehydrating agent (P2O5) yields an anhydride. Dicarboxylic Acids and Their Derivatives • Although the two carboxyl groups of a dicarboxylic acid are identical, the two pKa values are different because the protons are lost one at a time and therefore leave from different species (first from a neutral molecule and second from a negatively charged ion). • A COOH group withdraws electrons and therefore increases the stability of the conjugate base formed when the first COOH group loses a proton, thereby increasing its acidity. • The pKa values of the dicarboxylic acids show that the acid-strengthening effect of the COOH group decreases as the separation between the two carboxyl groups increases (pKa2 > pKa1 more acidic to less acidic or more basic when deprotonated). • Cyclic anhydrides are more easily prepared if the dicarboxylic acid is heated in the presence of acetyl chloride or acetic anhydride or P2O5. • Carbonic acid, a compound with two OH groups bonded to the carbonyl carbon,
is unstable and readily breaks down to CO2 and H2O (reversible reaction).
with “onitrile.” Structures of Carboxylic Acids and Carboxylic Acid Derivatives • Carbonyl Carbon: sp2 hybridized, it uses its three sp2 orbitals to form σ bonds to the carbonyl oxygen, α-carbon and a substituent (Y). • Carbonyl Oxygen: sp2 hybridized, one of its sp2 orbitals forms a σ bond with the carbonyl carbon and each of the other two sp2 orbitals contains a lone pair; the remaining p orbital of the carbonyl oxygen overlaps the remaining p orbital of carbonyl carbon to form a π bond. How Class I Carbonyl Compounds React • The carbonyl carbon is electron deficient due to the more electronegative oxygen so this will be attached by nucleophiles. • Tetrahedral Intermediate: the sp2 carbon in the reactant has become an sp3 carbon in the intermediate. • A compounds that has an sp3 carbon bonded to an oxygen atom will be unstable if the sp3 carbon is bonded to another electronegative atom. • The weaker the base, the better it is as a leaving group (Y- vs Z-). • Nucleophilic Acyl Substitution Reaction: a nucleophile (Z-) has replaced the substituent (Y-) that was attached to the acyl group in the reactant. • Acyl Transfer Reaction: an acyl group has been transferred from one group (Y-) to another (Z-). • Reaction Coordinate Diagram: o If the new group in the tetrahedral intermediate is a weaker base than the group that was attached to the acyl group in the reactant, the easier pathway (lower energy hill) is for the tetrahedral intermediate (Tl) to expel the newly added group and reform the reactants, so no reaction takes place. o If the new group in the tetrahedral intermediate is a stronger base than the group that was attached to the acyl group in the reactant, the easier pathway is for the tetrahedral intermediate to expel the group that was attached to the acyl group in the reactant and form a substituted product. o If both groups in the tetrahedral intermediate has similar basicities, the tetrahedral intermediate can expel either group with similar case; a mixture of reactant and substitution product will result. Relative Reactivities of Carboxylic Acids and Carboxylic Acid Derivatives • Relative Basicities of the Leaving Groups: Cl- < -OCR=O < -OR = -OH < -NH2 • Relative Reactivites of Carboxylic Acid Derivatives: acyl chloride > acid anhydride > ester = carboxylic acid > amide • A carboxylic acid derivative can be converted into a less reactive carboxylic acid derivative, but not into one that is more reactive (acyl chloride can be converted into an ester but not vice versa). General Mechanism for Nucleophilic Acyl Substitution Reactions • All carboxylic acid derivatives react by the same mechanism. o The nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. o The tetrahedral intermediate collapses, eliminating the weaker base. • Neutral Nucleophile: o The nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate.
o o
A proton is lost from the tetrahedral intermediate, resulting in a tetrahedral intermediate equivalent to the one formed by negatively charged nucleophile. This tetrahedral intermediate expels the weaker of the two bases, either the newly added group after it has lost a proto or the group that was attached to the acyl group in the reactant.
Reactions of Acyl Halides • Acyl halides react with carboxylate ions to form anhydrides. • Acyl halides react with alcohols to form esters. • Acyl halides react with water to form carboxylic acids. • Acyl halides react with amines to form amides. • The reaction of an acyl chloride with ammonia or with a primary or secondary amine forms an amide and HCl. o Acid generated in reaction will protonate unreacted ammonia or unreacted amine. o Since a protonated amine is not a nucleophile, it cannot react with the acyl chloride. o The reaction must be carried out with twice as much ammonia or amine as chloride. o Tertiary amines cannot form amides; an equivalent of a tertiary amine can be used instead of excess amine. Reactions of Acid Anhydrides • Acid anhydrides do not react with sodium chloride because the incoming halide ion is a weaker base than the departing carboxylate ion. • Acid anhydride reacts with an alcohol to form an ester and a carboxylic acid. • Acid anhydride reacts with water to form a carboxylic acid. • Acid anhydride reacts with an amine to form an amide and a carboxylate ion. • In the reaction of an amine, with an anhydride, two equivalents of the amine or one equivalent of the amine plus one equivalent of a tertiary amine must be used so sufficient amine will be present to react with both the carbonyl compound and the proton produced. Reactions of Esters • Esters do not react with halide ions or with carboxylate ions because these nucleophiles are much weaker bases than the RO- leaving group of the ester. • Esters react with water to form a carboxylic acid and an alcohol. • Hydrolysis Reaction: reaction with water that converts one compound into two compounds. • Esters react with an alcohol to form a new ester and a new alcohol. • Alcoholysis Reaction: reaction with an alcohol that converts one compound into two. • Transesterification Reaction: one ester is converted to another ester. • Hydrolysis and alcoholysis of an ester can be catalyzed by acids. • Esters react with amines to form amides; requires only one equivalent of amine. • Aminolysis: reaction with an amine that converts one compound into two compounds. • Phenyl esters are more reactive than alkyl esters. Acid-Catalyzed Ester Hydrolysis and Transesterification • In an acid-catalyzed reaction, all organic intermediates and products are positively charged or neutral; negatively charged organic intermediates and
products are not formed in acidic solutions. • In a reaction in which HO- is used to increase the rate of reaction, all organic intermediates and products are negatively charged or neutral; positively charged organic intermediates and products are not formed in basic solutions. • Mechanism: o The acid protonates the carbonyl oxygen. o The nucleophile (H2O) attacks the carbonyl carbon of the protonated carbonyl group, forming a protonated tetrahedral intermediate. o Protonated tetrahedral intermediate is in equilibrium with its nonprotonated form. o Once the nonprotonated tetrahedral intermediate has been formed, either the OH or the OR group of this intermediate can be protonated. o When tetrahedral intermediate collapses, it expels CH3OH rather than HO- and forms the carboxylic acid. o Removal of a proton from the protonated carboxylic acid or protonated ester forms the neutral carbonyl comounds. • Excess water will drive the reaction to the right, forming the carboxylic acid. • Excess CH3OH will drive the reaction to the left, reforming the ester. • Catalyst: substance that increases the rate of a reaction without being consumed or changed in the overall reaction. • An acid catalyst increases the reactivity of a carbonyl group. • An acid catalyst can make a group a better leaving group. • Mechanism for Hydrolysis of an Ester with a Tertiary Alkyl Group: o An acid protonates the carbonyl oxygen. o The leaving group departs, forming a tertiary carbocation. o A nucleophile reacts with the carbocation. o A base removes a proton from the strongly acidic protonated alcohol. Hydroxide-Ion-Promoted Ester Hydrolysis • Carrying out the reaction in a basic solution can increase the rate of hydrolysis of an ester. • Hydroxide ion is a better nucleophile than water. • The hydroxide-ion-promoted hydrolysis of an ester is not a reversible reaction, compared to the acid-catalyzed hydrolysis. Soaps, Detergents and Micelles • Fatty Acids: long-chain unbranched carboxylic acids. • When the ester groups of a fat or an oil are hydrolyzed in basic solution, glycerol and carboxylate ions are formed. • Soaps: sodium or potassium salts of fatty acids and are obtained when fats or oils are hydrolyzed under basic conditions. • Saponification: hydrolysis of an ester in a basic solution. • Micelles: long-chain carboxylate ions arrange themselves in spherical clusters. • Hydrophobic Interactions: attractive forces between hydrocarbon chains in water. • Because the surface of the micelle is negatively charged, the individual micelles usually repel each other instead of clustering to form larger aggregates. • Detergents: salts of benzene sulfonic acids; to prevent pollution, detergents should be made only with straight-chain alkyl groups due to it being biodegradable. Reactions of Carboxylic Acids • Carboxylic acids can undergo nucleophilic acyl substitution reactions only when
• • • • •
they are in their acidic forms. Relative Reactivities Toward Nucleophilic Acyl Substitution: RCOOH > RC=ONH2 > RCOOCarboxylic acids do not react with halide ions or with carboxylate ions. Carboxylic acids react with alcohols to form esters, in acidic solutions and excess alcohol must be used to drive it towards products. Fisher Esterification: an ester could be prepared by treating a carboxylic acid with excess alcohol in the presence of an acid catalyst. Carboxylic acids do not undergo nucleophilic acyl substitution reactions with amines; an acid/base reaction occurs resulting in a carboxylate salt as a product.
Reactions of Amides • Amides do not react with halide ions, carboxylate ions, alcohols or water because the incoming nucleophile is a weaker base than the leaving group of the amide. • Amides react with water and alcohols if the reaction mixture is HEATED in the presence of an acid. • Amide with an NH2 group can be dehydrated to a nitrile (R-C≡ N) using P2O5, POCl3 or SOCl2. The Hydrolysis of Amides Is Catalyzed by Acids • Mechanism: o The acid protonates the carbonyl oxygen, which increases the susceptibility of the carbonyl carbon to nucleophilic attack. o Nucleophilic attack by water on the carbonyl carbon leads to tetrahedral intermediate I, which is in equilibrium with its nonprotonated form, tetrahedral intermediate II. o Reprotonation can occur either on oxygen to reform tetrahedral intermediate I or on nitrogen to form tetrahedral intermediate III. o Protonation on nitrogen is favored because the NH2 group is a stronger base than the OH group. o Of the two possible leaving groups in tetrahedral intermediate III, NH3 is the weaker base, forming the carboxylic acid as the final product. o Since the reaction is carried out in an acidic solution, NH3 will be protonated after it is expelled from the tetrahedral intermediate; this prevents the reverse reaction from occurring, because +NH4 is not a nucleophile. • Amide cannot be hydrolyzed without a catalyst because the amide would not be protonated so water would have to attack a neutral amide that is less susceptible to nucleophilic attack than a protonated amide would be. • An amide reacts with an alcohol in the presence of acid for the same reason that it reacts with water in the presence of acid. The Hydrolysis of Nitriles • Mechanism: o The acid protonates the nitrogen of the cyano group (C≡ N), making it easier for water to attack the carbon of the cyano group. o Nucleophilic attack by water on the protonated cyano group is analogous to nucleophlic attack by water on a protonated carbonyl group. o Because nitrogen is a stronger base than oxygen, oxygen loses a proton and nitrogen gains a proton, resulting in a protonated amide.
The amide is immediately hydrolyzed to a carboxylic acid by means of acid-catalyzed mechanism. Nitriles can be prepared from an Sn2 reaction of alkyl halide with cyanide ion then to a carboxylic acid (HCl, H2O). A nitrile can be reduced to a primary amine by the same reagent that reduces an alkyne to an alkane (H2, Pt/C). o
• •
Designing a Synthesis V: The Synthesis of Cyclic Compounds • Cyclic compounds are formed from INTRAMOLECULAR reactions; the two reacting groups are in the same molecule. • A cyclic ester or lactone can be prepared from a reactant that has a carboxylic acid group and an alcohol group in the same molecule (HOCH2CH2CH2CH2COOH with HCl). • A compound with a ketone group attached to a benzene ring can be prepared using a Friedel-Crafts acylation reaction and a cyclic ketone will result if a Lewis acid (AlCl3) is added to a compound that contains both a benzene ring and an acyl chloride group. • A cyclic ether can be prepared by an intramolecular Williamson ether syntheses. • A cyclic ether can also be prepared by an intramolecular electrophilic addition reaction. How Chemists Activate Carboxylic Acids • Organic chemists activate carboxylic acids by converting them into acyl halides. • A carboxylic acid can be converted into an acyl chloride by being heated either with thionyl chloride (SOCl2) or with phosphorus trichloride (PCl3). • Acyl bromides can be synthesized by using phosphorus tribromide (PBr3). • All these reagents convert the OH group of a carboxylic acid into a better leaving group than the halide ion. • As a result, when the halide ion attacks the carbonyl carbon and forms a tetrahedral intermediate, the halide ion is not the group that is eliminated (SOCl, PCl2 or PBr2 is). • Carboxylic acids can also be activated for nucleophlic acyl substitution reactions by being converted into anhydrides; treating a carboxylic acid with a strong dehydrating agent (P2O5) yields an anhydride. Dicarboxylic Acids and Their Derivatives • Although the two carboxyl groups of a dicarboxylic acid are identical, the two pKa values are different because the protons are lost one at a time and therefore leave from different species (first from a neutral molecule and second from a negatively charged ion). • A COOH group withdraws electrons and therefore increases the stability of the conjugate base formed when the first COOH group loses a proton, thereby increasing its acidity. • The pKa values of the dicarboxylic acids show that the acid-strengthening effect of the COOH group decreases as the separation between the two carboxyl groups increases (pKa2 > pKa1 more acidic to less acidic or more basic when deprotonated). • Cyclic anhydrides are more easily prepared if the dicarboxylic acid is heated in the presence of acetyl chloride or acetic anhydride or P2O5. • Carbonic acid, a compound with two OH groups bonded to the carbonyl carbon,
is unstable and readily breaks down to CO2 and H2O (reversible reaction).
