Derivatives of Carboxylic Acids Nucleophilic Acyl Substitution

Derivatives of Carboxylic Acids Made Directly from Acids

Preparation of Acid Chlorides Directly from Acids

Preparation of Acid Anhydrides Directly from Acids Good for acetic and 5- and 6-membered ring anhydrides + H 2 O

Preparation of Esters Directly from Acids + H 2 O

Preparation of Amides Directly from Acids (not generally useful, however, due to high temperature needed)

Overview of Reactions of Derivatives of Acids:

All have a Common Mechanism! 2-step Acyl Substitution: 1. Addition to C=O (to create a tetrahedral C) 2. Elimination of the best L to reform the C=O (gem diol-like intermediate; unstable w/r to reformation of the carbonyl group & displacement of the best leaving group)

Relative Reactivity Acid Chlorides > Acid Anhydrides > Thioesters > Esters > Acids > Amides (inversely related to basicity of leaving group)

Reactions of Acid Chlorides w/ LiAlH(t-OBu) 3 w/ LiAlH 4 w/ R 2 CuLi or 2

Application: Synthesis of Nylon n

Reactions of Anhydrides w/ LiAlH 4 w/ Na 2 Fe(CO) 4 ( low T)

Applications: Synthesis of Analgesics

Reactions of Esters w/ LiAlH 4 w/ DIBAH; AlH(i-Bu) 2 ( low T)

Application: Synthesis of Polyethyleneterephthalate (PET)

Review: Oxidation at Benzylic Position, Esterification

Reactions of Amides (unreactive) ROH RNH 2

Reactions of Nitriles The nitrile is an anhydride of an amide; the CN group is a polar group; nucleophiles add to the CN triple bond as they add to a carbonyl group.

Thiol Esters (thioesters) Intermediate in reactivity between anhydrides and esters...ideal for biological acylation reactions: stable to hydrolysis, yet reasonably reactive

Summary of Reactions of Derivatives of Acids DerivativeH 2 OROH NH 3 [H] RMgX Acid Chlorideacidesteramide (ald)/alc (ket)/alc Anhydrideacidesteramide (ald)/alc (ket)/alc Esteracidesteramide (ald)/alc (ket)/alc Amideacid (NR) (NR) amine (NR) Nitrile amideester (NR) amine/ ketone /acid (ald)

IR Spectroscopy of Carbonyl- Containing Compounds RCOOCOR(anhydride)~1820 & 1760 cm -1 RCOCl (acid chloride)~1800 cm -1 RCO 2 R’(ester)~1740 cm -1 RCHO(aldehyde)~1730 cm -1 RCOR’(ketone)~1715 cm -1 RCO 2 H(acid...dimer)~1710 cm -1 RCONH 2 (1 o amide)~1690 cm -1 RCONR 2 (3 o amide)~1650 cm -1

Explanation of Carbonyl Stretching Frequency The polarity of the C-Cl bond increases the positive charge on the carbon in the dipolar resonance form. This raises its energy, resulting in a resonance hybrid with little C-O (single) bond character. The result is mostly C=O (double) bond character and a high C=O bond stretching frequency.

Explanation of Carbonyl Stretching Frequency... Amide resonance results in an additional resonance form. Two of the resonance forms have C-O single bond character. The result is a lower C=O bond stretching frequency.

C=O (2) 1822 & 1756 cm -1

C=O 1792 cm -1

C=O 1739 cm -1 C-O 1189 cm -1

C=O 1716 cm -1 C-O 1240 cm- 1 O-H cm -1

C=O 1690 cm -1 N-H (2) 3363 & 3192 cm-1

C=O 1669 cm -1

CN 2248 cm -1