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Carboxylic Acids and Carboxylic Acid Deriva3ves Nucleophilic Acyl Subs0tu0on (Addi0on-­‐Elimina0on) Carboxylic Compounds • Acyl group bonded to X, an electronega3ve atom or leaving group • Includes: X = halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates) General Reac3on PaMern • Nucleophilic acyl subs3tu3on Why this Chapter? • Carboxylic acids (deriva3ves) are among the most widespread of molecules. • A study of them and their primary reac3on “nucleophilic acyl subs3tu3on” is fundamental to understanding organic chemistry Nomenclature of Carboxylic Acids In systema3c nomenclature, the carbonyl carbon is C-­‐1. In common nomenclature, the carbon next to the carbonyl is the alpha-carbon. Nomenclature of Carboxylic Acids Nomenclature of Acyl Halides (Acyl Chlorides and Acyl Bromides) Nomenclature of Acid Anhydrides Nomenclature of Esters and Carboxylate Ion Salts state the subs3tuent aMached to the O delete “ic acid” add “ate” Nomenclature of Lactones (Cyclic Esters) Nomenclature of Amides Nomenclature of Lactams (Cyclic Amides) Nomenclature of Nitriles Deriva3ves of Carbonic Acid Resonance Contributors Esters, carboxylic acids, and amines have two resonance contributors. Physical Proper3es Amides and Nitriles Have Rela3vely High Boiling Points A Nucleophilic Acyl Subs3tui3on Addi3on–Elimina3on Reac3on If the Incoming Nucleophile (Z) is a Stronger Base Than the Base in the Reactant (Y) The weakest base is eliminated from the tetrahedral intermediate. If the incoming nucleophile (Z) is a stronger base than the base in the reactant (Y), a new product will be formed. If the Incoming Nucleophile (Z) is a Weaker Base Than the Base in the Reactant (Y) The weakest base is eliminated from the tetrahedral intermediate. If the incoming nucleophile (Z) is a weaker base than the base in the reactant (Y), the reactants will be reformed. If the Two Groups Have Similar Basici3es A mixture of reactants and products is obtained. Reac3on Coordinate Diagrams The Class to which a Carbonyl Group Belongs Depends on the Basicity of the Group AMached to the Acyl Group The Rela3ve Reac3vi3es Depend on the Basicity of the Subs3tuent AMached to the Leaving Group Rela3ve Reac3vity of Carboxylic Acid Deriva3ves • Nucleophiles react more readily with unhindered carbonyl groups • More electrophilic carbonyl groups are more reac3ve to addi3on (acyl halides are most reac3ve, amides are least) • The intermediate with the best leaving group decomposes fastest Subs3tu3on in Synthesis • We can readily convert a more reac3ve acid deriva3ve into a less reac3ve one • Reac3ons in the opposite sense are possible but require more complex approaches General Reac3ons of Carboxylic Acid Deriva3ves • • • • • Water is a reagent used to make carboxylic acids Alcohols is a reagent used to make esters ammonia or an amine are used to make an amide hydride source is used to make an aldehyde or an alcohol Grignard reagent is used to make a ketone or an alcohol Nucleophilic Acyl Subs3tu3on Reac3ons of Carboxylic Acids • Must enhance reac3vity • Convert –OH into a beMer leaving group • Specific reagents can produce acid chlorides, anhydrides, esters, amides Conversion of Carboxylic Acids into Acid Chlorides • Reac3on with thionyl chloride, SOCl2 Mechanism of Thionyl Chloride Reac3on • Nucleophilic acyl subs3tu3on pathway • Carboxylic acid is converted into a chlorosulfite which then reacts with chloride Conversion of Carboxylic Acids into Acid Anhydrides • Acid anhydrides can be derived from two molecules of carboxylic acid by strong hea3ng to remove water Ac3va3ng Carboxylic Acids by Conver3ng Them to Acid Anhydrides Conversion of Carboxylic Acids into Esters • Methods include reac3on of a carboxylate anion with a primary alkyl halide Fischer Esterifica3on • Hea3ng a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid Mechanism of the Fischer Esterifica3on • The reac3on is an acid-­‐
catalyzed, nucleophilic acyl subs3tu3on of a carboxylic acid • When 18O-­‐labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-­‐
labeled but the water produced is unlabeled Reac3on of a Carboxylic Acid with an Amine A carboxylic acid is an acid and an amine is a base, so an acid-­‐base reac3on occurs. Hea3ng the Product of the Acid–Base Reac3on Forms an Amide Mechanism of Amide Forma3on from Carboxylic Acids Dicarboxylic Acids The Two pKa Values of Dicarboxylic are Different Why? The neighboring COOH group withdraws electrons and lowers the first pKa. Electrosta3c interac3on between like charges raises the second pKa. Dicarboxylic Acids Lose Water When Heated if They Can Form a Five-­‐ or Six-­‐Membered Ring Ace3c Anhydride (or Acetyl Chloride) Catalyzed Anhydride Forma3on Chemistry of Acid Halides • Acid chlorides are prepared from carboxylic acids by reac3on with SOCl2 • Reac3on of a carboxylic acid with PBr3 yields the acid bromide Reac3ons of Acid Halides • • • • Nucleophilic acyl subs3tu3on Halogen replaced by –OH, by –OR, or by –NH2 Reduc3on yields a primary alcohol Grignard reagent yields a ter3ary alcohol Reac3ons of Acyl Chlorides Hydrolysis: Conversion of Acid Halides into Acids • Acid chlorides react with water to yield carboxylic acids • HCl is generated during the hydrolysis: a base is added to remove the HCl Conversion of Acid Halides to Esters • Esters are produced in the reac3on of acid chlorides with alcohols in the presence of pyridine or NaOH. This is called Alcoholysis • The reac3on is beMer with less steric bulk Two Equivalents of Amine are Required Conversion of Acid Halides into Amides: Aminolysis • Amides result from the reac3on of acid chlorides with NH3, primary (RNH2) and secondary amines (R2NH) • The reac3on with ter3ary amines (R3N) gives an unstable species that cannot be isolated • HCl is neutralized by the amine or an added base Reduc3on: Conversion of Acid Chlorides into Alcohols • LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols Reac3on of Acid Chlorides with Organometallic Reagents • Grignard reagents react with acid chlorides to yield ter3ary alcohols in which two of the subs3tuents are the same Forma3on of Ketones from Acid Chlorides • Reac3on of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu-­‐ • Addi3on produces an acyl diorganocopper intermediate, followed by loss of Rʹ′Cu and forma3on of the ketone Chemistry of Acid Anhydrides • Prepared by nucleophilic acyl subs3tu3on of a carboxylate with an acid chloride An Acid Anhydride is Formed When Water is Lost from Two Molecules of a Carboxylic Acid Reac3ons of Acid Anhydrides The Mechanism Reac3ons of Acid Anhydrides • Similar to acid chlorides in reac3vity Acetyla3on • Ace3c anhydride forms acetate esters from alcohols and N-­‐subs3tuted acetamides from amines Chemistry of Esters • Many esters are pleasant-­‐smelling liquids: fragrant odors of fruits and flowers • Also present in fats and vegetable oils Prepara3on of Esters • Esters are usually prepared from carboxylic acids Reac3ons of Esters • Less reac3ve toward nucleophiles than are acid chlorides or anhydrides • Cyclic esters are called lactones and react similarly to acyclic esters Hydrolysis: Conversion of Esters into Carboxylic Acids • An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol Mechanism of Ester Hydrolysis • Hydroxide catalysis via an addi3on intermediate Aminolysis of Esters • Ammonia reacts with esters to form amides Reduc3on: Conversion of Esters into Alcohols • Reac3on with LiAlH4 yields primary alcohols Mechanism of Reduc3on of Esters • Hydride ion adds to the carbonyl group, followed by elimina3on of alkoxide ion to yield an aldehyde • Reduc3on of the aldehyde gives the primary alcohol Reac3on of Esters with Grignard Reagents • React with 2 equivalents of a Grignard reagent to yield a ter3ary alcohol Chemistry of Amides • Amides are abundant in all living organisms… proteins, nucleic acids, and other pharmaceu3cals have amid func3onal groups Prepara3on of Amides • Prepared by reac3on of an acid chloride with ammonia, monosubs3tuted amines, or disubs3tuted amines Reac3ons of Amides • Hea3ng in either aqueous acid or aqueous base produces a carboxylic acid and amine • Acidic hydrolysis by nucleophilic addi3on of water to the protonated amide, followed by loss of ammonia Basic Hydrolysis of Amides • Addi3on of hydroxide and loss of amide ion Reduc3on: Conversion of Amides into Amines • Reduced by LiAlH4 to an amine rather than an alcohol • Converts C=O → CH2 Mechanism of Reduc3on • Addi3on of hydride to carbonyl group • Loss of the oxygen as an aluminate anion to give an iminium ion intermediate which is reduced to the amine Uses of Reduc3on of Amides • Works with cyclic and acyclic • Good route to cyclic amines Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Deriva3ves • Nucleophilic carboxyl subs3tu3on in nature ojen involves a thioester or acyl phosphate • Acetyl CoA’s are most common thioesters in nature Polyamides and Polyesters: Step-­‐Growth Polymers • Reac3ons occur in dis3nct linear steps, not as chain reac3ons • Reac3on of a diamine and a diacid chloride gives an ongoing cycle that produces a polyamide • A diol with a diacid leads to a polyester Polyamides (Nylons) • Hea3ng a diamine with a diacid produces a polyamide called Nylon® • Nylon 66® is from adipic acid and hexamethylene-­‐diamine at 280°C Polyesters • The polyester from dimethyl terephthalate and ethylene glycol is called Dacron® and Mylar® to make fibers Synthesis of Nitrile Na CN
+
R
+
RCN
Br
NaBr
O
Cl
S
Cl
O
:O:
O
H
R
N
H
R
S
N
H
O
Cl
H
O
B
R
S
O
Cl
B
N
H
R
C
N:
+
S
O
+
Cl
Synthesis of a Carboxylic Acid Acid-­‐Catalyzed Hydrolysis of a Nitrile The Mechanism O
R
C
N:
+
C
OH
R
H
O
H
N:
O
C
H
R
(Why, can it be? It's...
it's...it's REGENERATION
of the CATALYST!!!!)
:O:
H3O
H
N:
O
H
H (Can you say,
"Tautomerize?")
H
:O: CORRESPONDING CARBOXYLIC ACIDS: The
HYDROLYSIS OF NITRILES TO THE
R
mechanism for the acid-catalyzed conversion
of nitriles into carboxylic
acids has already been given.
OH
R
NH
However, the use of the base-catalyzed conversion of nitriles into carboxylic acids still does not tolerate the
presence of acid-sensitive functional groups because the final step in this sequence is the acid-catalyzed
hydrolysis of the primary amide formed by the initial base-catalyzed process.
2
O
R
C
N:
+
OH
R
C
H
H
N:
:O:
R
O
O
C
H
R
(Why, can it be? It's...
it's...it's REGENERATION
of the CATALYST!!!!)
:O:
H3 O
OH
R
H
N:
H
NH2
O
H
H (Can you say,
"Tautomerize?")
Reduc3on of Nitrile R
C
N:
+
1) H
2) H3O
:N:
H
R
C
H
R
NH2
:O:
H2O
R
H
Synthesis of Ketone :N:MgBr
R
C
N:
+
R' MgBr
R
C
R'
:O:
H3 O
+
R
R'
NH3