Carboxylic Acids (Chapter 19) Flashcards

Question

Nitrile ⟶ Carboxylic Acid | **Nitrile =** —CN

Answer 1

Nitrile Hydrolysis

Answer 2

SN2 Addition of CN^– to Alkyl Halide ## Footnote **NaCN =** CN^–

Answer 3

1. NaOH, Δ 2. H₃O⁺ ## Footnote **Alternative:** H₂SO₄, H₂O, Δ

Answer 4

SN2-mediated nitrile synthesis CANNOT occur with *3° alkyl halides*, *phenyl halides*, or *alkenyl halides*. ## Footnote SN2-mediated nitrile synthesis can ONLY occur with 2°/1°/0° alkyl halides.

Answer 5

2-Hydroxyl Carboxylic Acid Synthesis

Answer 6

A compound containing a *cyanide group* (—CN) and an *alcohol group* bonded to the *same* sp³-hybridized carbon atom.

Answer 7

1. NaCN, H₂SO₄ 2. H₂SO₄, H₂O, Δ

Answer 8

* **Jones Oxidation** (Alcohol Intermediate) * **Nitrile Synthesis-Hydrolysis** (Nitrile Intermediate) * **Organometallic Addition** (Carboxylate Intermediate) ## Footnote * The *Jones Oxidation* product contains the **same number** of carbons as the alkyl halide reagent. * The *Nitrile Synthesis-Hydrolysis* and *Organometallic Addition* products contain **one more** carbon than the alkyl halide reagent.

Answer 9

* Acyl Halide * Anhydride * Ester * Amide

Answer 10

Fischer Esterification | Reversible ## Footnote * A catalytic acid (i.e. H₂SO₄, HCl) *must* be present for Fischer Esterification to occur. * The esterification process yields one molecule of byproduct H₂O.

Answer 11

R—OH (Large Excess), H₂SO₄, Δ

Answer 12

Acid-Catalyzed Ester Hydrolysis | Reversible

Answer 13

H₂O, H₂SO₄, Δ

Answer 14

The carbonyl Oxygen (of the carboxylic acid) must be protonated (by the acid catalyst) to increase the electrophilicity of the carboxylic acid compound. ## Footnote The unprotonated carboxylic acid compound is NOT sufficiently electrophilic to be attacked by the alcohol nucleophile.

Answer 15

1. Protonation of Carbonyl Oxygen 2. Attack of Alcohol at Carbonyl Carbonyl 3. Elimination of Water ## Footnote The nucleophilic attack of the alcohol at the carbonyl Carbon results in an sp³-hybridized tetrahedral intermediate.

Answer 16

A carboxylic acid compound containing one (or more) hydroxyl groups.

Answer 17

Intramolecular Esterification | Reversible

Answer 18

Cyclic Ester ## Footnote Lactone are formed via the *intramolecular esterification* reaction.

Answer 19

Entropic Effects ## Footnote The hydroxycarbonic acid reagent is converted to a lactone compound *and* a water molecule.

Answer 20

H₂O, H₂SO₄

Answer 21

Lactone Hydrolysis | Reversible

Answer 22

High-Temperature Amine Addition | Reversible ## Footnote The high-temperature amine addition reaction is an *addition-elimination mechanism* (that occurs slowly).

Answer 23

Low-Temperature Amine Addition | Reversible ## Footnote The low-temperature amine addition reaction is an *acid-base mechanism* (that occurs rapidly).

Answer 24

* **Ammonium-Salt Synthesis:** Rapid Acid-Base Mechanism * **Amide Synthesis:** Slow Addition-Elimination Mechanism ## Footnote * The *ammonium salt* product is favored (i.e. the major product) at *low* reaction temperatures. * The *amide* product is favored (i.e. the major product) at *high* reaction temperatures.

Answer 25

Amine at 0°C–100°C | Low Temperature

Answer 26

Amine at >100°C | High Temperature

Answer 27

* High reaction temperatures create dangerous laboratory conditions. * Presence of competing reactions to form ammonium carboxylate salt.

Answer 28

The imide synthesis mechanism requires the **double deprotonation** of the amine.

Answer 29

Imide Synthesis ## Footnote * The imide synthesis reaction requires the input of **heat**. * Imide Synthesis is *only* possible with **0°/1° amines**. (The synthesis processes requires the double deprotonation of the amine.)

Answer 30

2 NH₃, Δ ## Footnote **Alternative:** 2 NRH₂, Δ

Answer 31

Cyclic Amide

Answer 32

Lactam Synthesis ## Footnote * The *lactam synthesis* reaction involves the cyclization of an amino acid. * **Heat** is required for the cyclization reaction to occur.

Answer 33

1. Low Temperature 2. Δ

Answer 34

* **3-Membered Ring:** α-Lactone * **4-Membered Ring:** β-Lactone * **5-Membered Ring:** γ-Lactone * **6-Membered Ring:** δ-Lactone

Answer 35

SOCl₂-Faciliated Chloride Substitution ## Footnote The *hydroxyl group* (of the carboxylic acid) is substituted for a *chloride* to yield an acyl chloride.

Answer 36

PBr₃-Faciliated Bromide Substitution ## Footnote The *hydroxyl group* (of the carboxylic acid) is substituted for a *bromide* to yield an acyl bromide.

Answer 37

1. Nucleophilic Attack of SOCl₂ to Yield Inorganic Ester 2. Protonation by H—Cl to Yield Oxocarbenium Intermediate 3. Nucleophilic Attack of Cl^– to Yield Tetrahedral Intermediate 4. π-Electron Rearrangement to Eliminate SO₂ and Cl^–

Answer 38

1. Nucleophilic Attack of PBr₃ to Yield Inorganic Ester 2. Protonation by H—Br to Yield Oxocarbenium Intermediate 3. Nucleophilic Attack of Br^– to Yield Tetrahedral Intermediate 4. π-Electron Rearrangement to Eliminate PBr₂OH

Answer 39

* **SOCl₂ Substitution:** SOCl₂, Δ * **PBr₃ Substitution:** PBr₃

Answer 40

* **SOCl₂ Substitution:** Hydroxyl oxygen π-electron rearrangement eliminates SO₂ and Cl^– *without additional protonation*. * **PBr₃ Substitution:** *Protonation of ether oyxgen* is required for hydroxyl oxygen π-electron rearrangement to eliminate PBr₂OH.

Answer 41

* The acid catalyst could potentially protonate the amine nucleopile, which would *eliminate the amine's nucleophilic character*.

Answer 42

LiAlH₄ Reduction ## Footnote The reduction of carboxylic acids to 1° alcohols can occur ONLY with LiAlH₄. (NaBH₄ is a *weaker reductant* than LiAlH₄, so it cannot reduce carboxylic acids.)

Answer 43

1. LiAlH₄ 2. H₃O⁺

Answer 44

* Magnitude of Partial Positive Charge on Carbonyl Carbon. * Stabiity of Leaving Group (i.e. Strength of C—LG Bond). | **LG =** Leaving Group

Answer 45

As the carbonyl carbon becomes *more partially positive*, the carboxylic acid derivative becomes *more reactive*. ## Footnote A *greater* partial positive charge on the carbonyl carbon *increases* the derivative's susceptibility to nucleophilic attack.

Answer 46

As the stability of the leaving group *increases*, the carboxylic acid derivative becomes *more reactive*. ## Footnote A *more stable* leaving group denotes a *weaker* (i.e. more easily broken) C—LG bond.

Answer 47

The *extent of conjugation* between the carbonyl group and the adjacent heteroatom. ## Footnote If the adjacent heteroatom is a *weaker π-electron donor*, the C—LG bond is *weaker* (due to a lower degree of conjugation between the carbonyl group and heteroatom).

Answer 48

The C^Carbonyl—X bond is *weaker* due to the halogen being a *weak π-electron donor*. ## Footnote The *weak conjugation* between the carbonyl group and the halogen atom *increases* reactivity of the acyl halide.

Answer 49

The C^Carbonyl—N bond is *stronger* due to the nitrogen being a *strong π-electron donor*. ## Footnote The *strong conjugation* between the carbonyl group and the nitrogen atom *decreases* reactivity of the amide.

Answer 50

Acyl halides are *highly reactive* due to the (1) the halide's electron-withdrawing character and (2) the *weak* C^Carbonyl—X bond.

Answer 51

Amides are relatively *unreactive* due to the (1) the nitrogen's electron-donating character and (2) the *strong* C^Carbonyl—N bond.

Answer 52

Conjugation between the carbonyl group and the nitrogen atom *increases the strength* of the C^Carbonyl—N bond.

Answer 53

Rotation about the C^Carbonyl—N bond requires breaking the carbonyl-nitrogen conjugation across the amide, which is highly *enthalpically unfavorable* (at room temperature).

Answer 54

Stability of the (Derivative's) Conjugate Acid

Answer 55

Stability of the (Derivative's) Conjugate Base

Answer 56

* Positive-Charge Density of Conjugate Acid * Positive-Charge Compatibility in Conjugate Acid ## Footnote * If there is a *smaller* positive charge on the conjugate acid's hydroxyl oxygen, the derivative is *more basic*. * If the conjugate acid's resonance structures place the positive charge on *less electronegative* atoms, the derivative is *more basic*.

Answer 57

Negative-Charge Density of Base ## Footnote If there is a *smaller* negative charge on the conjugate base's α-Carbon, the derivative is *more acidic*.

Answer 58

Increased Acidity ## Footnote EWGs delocalize the negative charge of the enolate conjugate base, which results in a *more stable* anionic compound.

Answer 59

Decreased Basicity ## Footnote EWGs concentrate the positive charge on the conjugate acid's hydroxyl oxygen, which results in a *less stable* cationic compound.

Answer 60

Decreased Acidity ## Footnote EDGs concentrates the negative charge of the enolate conjugate base, which results in a *less stable* anionic compound.

Answer 61

Increased Acidity ## Footnote EDGs delocalize the positive charge on the conjugate acid's hydroxyl oxygen, which results in a *more stable* cationic compound.

Answer 62

* **Same # of Carbons:** Jones Oxidation * **One Additional Carbon:** [Grigard + CO₂] OR [Nitrile Hydrolysis]

Answer 63

1. Initial Protonation to "Activate" Carbonyl Carbon 2. Proton Transfer to Form Neutral Tetrahedral Intermediate 3. Proton Acquisition to Eliminate H₂O 4. Deprotonation of Carbonyl Oxygen to Yield Neutral Carbonyl ## Footnote * In Carboxylic Acid Esterification, the proton transfer processes involve external-internal exchanges (due to the presence of an **acid catalyst**). * In Carboxylic Acid Amidification, the proton transfer processes involve intramolecular exchanges (due to there being **no** acid catalyst).