Nomenclature of Carboxylic Acid Derivatives
Acid Halides; Y = halogen, X;  RCOX
Change the -ic to -yl followed by the halide (e.g., acetyl chloride).

Acid Anhydrides; Y = acyl group;  RCO₂COR
Symmetrical anhydrides of unsubstituted monocarboxylic acids and cyclic anhydrides of dicarboxylic acids are named by replacing the word acid with anhydride (e.g., acetic anhydride).
If the anhydride is derived from a substituted monocarboxylic acid, it is named by adding the prefix bis- (meaning two) to the acid name.   Unsymmetrical (mixed): give the name of the two acids followed by anhydride as a third word.

Amides; Y = NH₂, NHR, or NR₂;   RCONH₂
Unsubstituted amides are named by replacing -oic with -amide or by replacing -carboxylic acid with -carboxamide.  Substituted nitrogen atoms are named by first identifying the substituent groups and then the parent amide name.  Nitrogen substituents are preceded by the letter N to identify them as bonded directly to nitrogen.

Esters, Y = OR;  RCO₂R’
Using two separate words, identify the alkyl group attached to the oxygen and then the carboxylic acid, with the -ic ending replaced with -ate.

Nitriles,  RCN
Simple acyclic nitriles are named by adding -nitrile as a suffix to the alkane name, with the nitrile carbon number C1.

Nucleophilic Acyl Substitution Reactions
Nucleophilic acyl substitution reactions take place in two steps:
    1. Addition of the nucleophile (Nu:) to form a tetrahedral intermediate.
    2. Reformation of carbonyl and loss of the leaving group (-Y).
The outcome of nucleophilic acyl substitution is the replacement of Y by Nu:  Nu:  + RC=OY ----> RC=ONu + -Y

The order of reactivity of carboxylic derivatives toward nucleophilic acyl substitution is:
Acid chloride >  Anhydride >  Ester > Amide
More reactive                              Less reactive

The general order of reactivity of acid derivatives can be explained by taking into account the basicity of the leaving groups.
Weak bases are good leaving groups.
Derivative       Leaving group
acyl chlorides     chloride ion   ( Cl^1- )
anhydrides         carboxylic acid or a carboxylate ion (RCO₂^1-)
esters                   alcohol (ROH)
amides                 amine or ammonia (NH₃)
The order of basicity is:  NH₃/Amines >  ROH > RCO₂^1-  >  Cl^1-
The order of leaving group is:    Cl^1- >  RCO₂^1-  > ROH  >  NH₃/Amines

Steric Factors influence reactivity.  Within a series of the same acid derivatives, the unhindered accessible carbonyl group react with nucleophiles more readily than do sterically hindered groups.
Electronic Factors influence reactivity.  Strongly polarized carboxylic acid derivatives are attacked more readily than less polar.
It is usually possible to transform a more reactive acid derivative into a less reactive one.
In general, less reactive acyl compounds can be synthesized from more reactive ones, but the reverse is usually difficult and, when possible, requires special reagents.

Nucleophilic Acyl Substitution Reactions of Carboxylic Acids
A.    Conversion of Carboxylic Acids into Acid Chlorides:   RCO₂H ----> RCOCl
    A1.     RCO₂H + SOCl₂ in CHCl₃ ---> RCOCl + HCl + SO₂
                        Thionyl chloride
    A2.     3 RCO₂H + PCl₃ ---> 3 RCOCl + H₃PO₃
                        Phosphorus trichloride is the acid chloride of phosphorus acid.
    A3.     RCO₂H + PCl₅ ---> RCOCl + POCl₃ + HCl
                            Phosphorus pentachloride is the acid chloride of phosphoric acid.
B.    Conversion of Carboxylic Acids into Acid Anhydrides:  RCO₂H ----> RCO₂COR
        Acyclic anhydrides are difficult to prepare directly from the corresponding acids.
        Acetic anhydride is commonly used.       Acetic acid + CH₂=C=O (ketene) ----> CH₃CO₂COCH₃
C.    Conversion of Carboxylic Acids into Esters:  RCO₂H ----> RCO₂R
    C1.     S_N2 reaction between carboxylate anion and a primary alkyl halide.
               Sodium butanoate + Methyl iodide --> Methyl butanoate
    C2.     Nucleophilic Acyl Substitution By Alcohol.
               Fischer esterification reaction. Methyl, ethyl, and propyl ester esters are most commonly synthesized.
               Salicylic acid + methanol ----> methyl salicylate + water
D.    Conversion of Carboxylic Acids into Amides:  RCO₂H ----> RCONH₂
Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their corresponding anions.
        RCO₂H + NH₃ ----> RCO₂^1- + NH₄¹⁺

Kinds of Nucleophilic Acyl Substitution Rxns:  An Overview Of Carboxylic Acid Derivative Rxns
1.    Hydrolysis: Reaction with water to yield a carboxylic acid.
            RCOY + H₂O ----> RCO₂H
2.    Alcoholysis: Reaction with an alcohol to yield an ester.
            RCOY + R’OH ----> RCO₂R’
3.    Aminolysis: Reaction with ammonia or an amine to yield an amide.
            RCOY + NH₃ ----> RCONH₂
4.    Reduction: Reaction with a hydride reducing agent to yield an aldehyde or alcohol.
            RCOY + [H] ----> RCHO + [H] ----> RCH₂OH
5.    Grignard: Reaction with an organometallic reagent to yield a ketone or an alcohol.
            RCOY + R’MgX ----> RCOR’ + R’MgX ----> RCOH(R’)₂

Synthesis of Acid Halides
A.    Preparation of Acid Halides
        A1.     RCO₂H + SOCl₂ ---> RCOCl
        A2.     3 RCO₂H + PBr₃/ether ---> 3 RCOBr
        A3.     RCO₂H + PCl₅ ---> RCOCl + POCl₃ + HCl

Reactions Of Acid Halides
A.    Friedel-Crafts  Preparation of aryl alkyl ketones
        RCOCl + Ar-H + AlCl₃ ---> RCOAr + HCl
B.    Hydrolysis: Conversion of Acid Halides into Acids
        RCOX + H₂O ----> RCO₂H
C.    Alcoholysis: Conversion of Acid Halides into Esters
        RCOX + R’OH ----> RCO₂R’
D.    Aminolysis: Conversion of Acid Halides into Amides
        RCOX + NH₃ ----> RCONH₂
E.    Reduction: Conversion of Acid Halides into Alcohols
        RCOX + [H] ----> RCH₂OH
F.    Reaction with an organometallic reagent to yield a ketone or an alcohol
        F1.    Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same.
                RCOCl + 2R'MgX  (1) ether solvent (2) H⁺¹ --> RC(R'O₂)OH
        F2.    Diorganocopper (Gilman) reagents  react with acid chlorides to form ketones .
                Acids, esters, anhydrides and amides are inert to diorganocopper reagents.
                RCOCl +  R'₂CuLi / ether solvent  ----> RCOR'

Synthesis of Acid Anhydrides
Nucleophilic acyl substitution reaction of an acid chloride with the carboxylate anion is the most common. Both symmetrical and unsymmetrical anhydrides can be prepared this way.
RCO₂H + R'COCl / Pyridine ----> RCOOCR'

Reactions of Acid Anhydrides
A.    Hydrolysis: Conversion of Acid Anhydrides into Acids
        RCO₂COR + H₂O ----> 2 RCO₂H
B.    Alcoholysis: Conversion of Acid Anhydrides into Esters
        RCO₂COR + R'OH ----> RCO₂R' +  RCO₂H
C.    Aminolysis: Conversion of Acid Anhydrides into Amides
        RCO₂COR + 2 NH₃ ----> RCONH₂  +  RCO₂^-NH₄⁺
D.    Reduction: Conversion of Acid Anhydrides into 1^o Alcohols
        RCO₂COR' + [H] ----> 2 RCH₂OH

Synthesis of Esters
A.    Carboxylate anion + 1^o alkyl halide ---> ester
                        1.  NaOH
         RCO₂H  -------------> RCO₂R'
                        2.  R'X
B.    Fischer Esterification (limited to simple alcohols)
        RCO₂H + R'OH/HCl ---> RCO₂R'
C.    Acid chloride + Alcohol {Most widely used.}
        RCOCl + R'OH/Pyridine ---> RCO₂R'

Reactions of Esters
A.    Hydrolysis: Conversion of Esters into Carboxylic Acids
        RCO₂R + H₂O ----> RCO₂H
        A1.    Esters are hydrolyzed aqueous acid to yield carboxylic acids plus alcohols.
        RCO₂R' + H₃O¹⁺ <====> RCO₂H + R'OH
        A2.    Saponification - Ester are hydrolyzed in basic solution is called saponification, after the Latin sapo, meaning "soap".
        RCO₂R' + NaOH ---> RCO₂^1-Na¹⁺ + R'OH
B.    Aminolysis: Conversion of Esters into Amides
        RCO₂R' + NH₃   ----> RCONH₂ + R'OH
C.    Reduction:
        C1.    Reduction of Esters to Alcohols
                                     1.  LiAlH₄ , Et₂O
                   RCO₂R'  ------------------------> RCH₂OH + R'OH
                                     2. H₃O⁺

                   Lactone + LiAlH₄ ---> Primary dialcohol

        C2.    Reduction of Esters to Aldehydes
                                     1.  DIBAH, Toluene
                   RCO₂R'  --------------------------------->RCHO + R'OH
                                     2. H₃O⁺
D.    Reaction of Esters with Grignard Reagents to yield 3^o Alcohols
                                     1.  2 R''MgX, Et₂O
                   RCO₂R'  --------------------------------->RC(R'')₂OH + R'OH
                                     2. H₃O⁺
Synthesis of Amides
Aminolysis: Conversion of Acid Halides into Amides
        RCOX + NH₃ ----> RCONH₂
         Ammonia, mono- and disubstituted amines all undergo this reaction.

Reactions of Amides
A.    Hydrolysis: Conversion of Amides into Carboxylic Acids
                           H₃O⁺  or   NaOH, H₂O
        RCONH₂ --------------------------------> RCO₂H + NH₃
B.    Reduction of Amides to Amines
                                        1.  LiAlH₄ , Et₂O
                   RCONH₂  ------------------------> RCH₂NH₂
                                       2. H₃O⁺
C.    Dehydration of 1^o Amides to yield Nitriles
        RCONH₂  + SOCl₂ -----------> RCN + SO₂ + HCl
Synthesis of Nitriles
Nitriles are not related to carboxylic acids in the same sense that acid derivatives are, but the structures and reactions of nitriles and carboxylic acids are nevertheless similar.  Both kinds of compounds have a carbon atom with three bonds to an electronegative atom, and both contain a Pi bond.
A.    S_N2 reaction of cyanide ion with a primary alkyl halide.
         Steric constraints of  S_N2 rxns limit this method to the synthesis of a-unsubstituted nitriles, RCH₂CN.
            RCH₂Br + NaCN/DMSO ---> RCH₂CN + NaBr
B.     Dehydration of a primary amide by dehydrating agents such as SOCl₂, P₂O₅, POCl₃, and acetic anhydride.
            2-methylpropanamide + SOCl₂/Benzene ---> 2-methylpropaneitrile
Reactions of Nitriles
A.    Hydrolysis of Nitriles to Carboxylic Acids with one more carbon than the parent alkyl compound.
        RCN ----> RCO₂H + NH₃
B.    Reduction: Conversion of Nitriles into 1^o Amines and Aldehydes
    B1.    LiAlH₄ reduces nitrile to 1^o amines.
                               1.  2 LiAlH₄ , Et₂O
                   RCN  ------------------------> RCH₂NH₂
                              2. H₃O⁺

    B2.    DIBAH reduces nitrile to an aldehyde.
                               1.  DIBAH/toluene, –78^oC
                   RCN  -------------------------------------> RCHO + NH₃
                              2. H₃O⁺

C.    Nitriles react with Grignard reagents to yield Ketones.
                                     1.  R'MgX, Et₂O
                   RCN  -------------------------------------> RCOR' + NH₃
                              2. H₃O⁺

CH₃-CH₂-CH₂-CH₂-CH₂-CH=O
e       d       g       b      a
Pentanal

Hydrogen substituents are given the same Greek letter as the carbon to which they are bonded. In the example of pentanal, there are two a hydrogens, two b hydrogens, two g hydrogens, two d hydrogens and three e hydrogens. In 3,3-dimethyl butanone, there are two different a carbons but only one of these has a hydrogens. This same molecule has three different b carbons.

As the name suggests, alpha substitution rxns occur at the alpha carbon of a carbonyl compound.  In this type of rxn, an alpha hydrogen is replaced by an electrophile (Y) through either an enol or enolate ion intermediate.

Keto-Enol Tautomerism
Carbonyl compounds with one or more hydrogens on their a carbons rapidly interconvert with their corresponding enols.
Keto enol tautomerism is catalyzed by acid or base.    Enols act as nucleophiles due to their electron rich double bond.
 

Alpha Halogenation of Ketones and Aldehydes
Ketones and aldehydes can be halogenated at the a positions by reaction of Cl₂, Br₂, or I₂ in acidic solution.
Bromine is most often used, and acetic acid is often employed as solvent.

PhCOCH₃ + Br₂ ---> PhCOCH₂Br + HBr
Acetophenone         a-Bromoacetophenone

The Hell-Volhard-Zelinskii Reaction (HVZ):  Alpha Bromination of Carboxylic Acids
In the Hell-Volhard-Zelinskii (HVZ) reaction, carboxylic acids are brominated at the alpha position by using a mixture of Br₂ and PBr₃ followed by water, .  The overall result of the HVZ rxn is the transformation of an acid into an a-bromo acid.
                             1.  Br₂/PBr₃
Heptanoic acid -------------------> 2-Bromoheptanoic acid
                             2. H₂O

Enolate Ion Formation
Strong bases are required to form enolates.   Sodium ethoxide, causes only 0.1% ionization of acetone.   Sodium hydride, NaH,  or lithium diisopropylamide (LDA), LiN(i-C₃H₇)₂, the lithium salt of diisopropyl amine, are more powerful bases and can completely convert the carbonyl compound into its enolate ion.

                                          THF
Cyclohexanone + LDA -------------> Cyclohexanone enolate (100%)

Dicarbonyl compounds with a hydrogens on a carbon flanked by the two carbonyl are readily converted to the enol or enolate ion.  Examples include of such dicarbonyls are 1,3 diketones (a-diketones),  3-oxo esters (a-keto esters), and 1,3 diesters.

Halogenation of Enolate Ions: The Haloform Rxn
The haloform reaction converts methyl ketones into a carboxylic acid and a haloform.  Base-promoted halogenation requires only a small amount of enolate generated. Therefore, weak bases can be used.  Base-promoted halogenation of methyl ketones is difficult to stop the reaction at the monosubstituted product.  An a-halogenated ketone is generally more acidic than the starting material because of the electron-withdrawing inductive effect of the halogen atom.  Thus, monohalogenated products are themselves rapidly turned into enolate ions and are further halogenated.   The haloform reaction converts methyl ketones into a carboxylic acid and a haloform and is used as a qualitative test for methyl ketones.

                     Br₂ / NaOH(aq)
PhCOCH₃  ------------------------>  PhCO₂^- + CHBr₃

Alkylation of Enolate Ions
The general scheme for the Malonic Ester Synthesis & Acetoacetic Ester Synthesis is:

Monosubstitution 1.    Generate enolate 2.    Alkylate 3.    Decarboxylate

Disubstitution 1.     Generate enolate 2.     Alkylate 3.     Generate enolate 4.     Alkylate 5.     Decarboxylate

The Malonic Ester Synthesis
The malonic ester synthesis is used to prepare a substituted acetic acid from an alkyl halide.   Overall effect of the Malonic Ester Synthesis is to convert an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms.

R-X ---> R-CH₂CO₂H (a-substituted acetic acid)

Diethyl propanedioate (Et-CO₂CH₂CO₂-Et), diethyl malonate or malonic ester is more acidic than monocarbonyl compounds because the a hydrogens are flanked by two carbonyls.

                                    1. Sodio diethylmalonate
CH₃(CH₂)₂CH₂Br -----------------------------------------> CH₃(CH₂)₄CO₂H
1-Bromobutane       2. H⁺ / Heat Hexanoic acid
 

A second alkylation can be carried out with a different alkyl halide.

                                    1. Sodio diethylmalonate
CH₃(CH₂)₂CH₂Br ------------------------------> CH₃(CH₂)₃CH₂(CH₃)CO₂H
1-Bromobutane        2. NaOEt                            2-Methylhexanoic acid
                                   3. CH₃I
                                  4. H⁺ / Heat

The malonic ester synthesis can also be used to prepare cycloalkane-carboxylic acids.

The Acetoacetic Ester Synthesis
The acetoacetic ester synthesis is a method for preparing a-substituted acetone derivatives from alkyl halides in the same way that the malonic ester synthesis is a method for preparing a-substituted acetic acids.

R-X ---> R-CH₂COCH₃ (a-substituted acetone)

Ethyl 3-oxobutanoate (CH₃COCH₂CO₂Et), commonly called ethyl acetoacetate or acetoacetic ester, is much like malonic ester in that its a hydrogens are flanked by two carbonyl groups.   It is therefore readily converted into its enolate ion, which can be alkylated or dialkylated.

                                                                  1. NaOEt
1-Bromobutane + Acetoacetic ester --------------------------> 2-Heptanone
                                                                 2. NaOH
                                                                 3. H₃O¹⁺/Heat

THREE-STEP Sequence is applicable to all a-keto esters with acidic a hydrogens.
    1.    Enolate formation
    2.    Alkylation
    3.    Hydrolysis / Decarboxylation

Direct Alkylation of Ketones, Esters, and Nitriles
It is also possible to alkylate directly at the singly activated a position of monoketones, monoesters, or nitriles.   A strong, sterically hindered base is needed, so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used.   The temperature of –78^oC is critical!   Ketones, esters, and nitriles can be alkylated by using LDA (lithium diisopropylamide) or related dialkylamide bases in THF as the enolate generating agent.

LDA = Lookout for Direct Alkylation

Butyrolactone + LDA/THF + CH₃I ---> 2-Methylbutyrolactone

(CH₃)₂CHCO₂Et + LDA/THF + CH₃I ---> (CH₃)₃CCO₂Et

PhCH₂CN + LDA/THF + CH₃I ---> CH₃CHPhCN

In general, the major product of the alkylation of an unsymmetrical ketone involves the less hindered position product.

Suggested problems for Chapter 22 Carbonyl Alpha-Substitution Rxns
22.20; 22.21; 22.22; 22.26; 22.28; 22.29; 22.30; 22.31; 22.35