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Organic Chemistry 2 > Carboxylic Acids (Chapter 19) > Flashcards

Carboxylic Acids (Chapter 19) Flashcards

1
Q

Why are carboxylic acid groups planar?

A

Conjugation (i.e. π-electron delocalization) between the carbonyl group and the hydroxyl group sets the entire carboxylic acid domain in the same plane.

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2
Q

Structure of Carboxylic Acid Groups

A

Planar

The carbonyl group and the hydroxyl group are in the same plane due to π-electron delocalization across the two functional groups.

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3
Q

Reagent Reactions with Carboxylic Acids

A
  • Nucleophile: Addition to Carbonyl Carbon
  • Base: Deprotonation of Hydroxyl Hydrogen
  • Acid: Protonation of Carbonyl Oxygen

The acidic protonation of the carbonyl oxygen is more favored than protonation of the hydroxyl oxygen. (The carbonyl oxygen will always be protonated before the hydroxyl oxygen.)

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4
Q

What determines the acidity of a carboxylic acid?

A

Stability of the (Carboxylic Acid’s) Conjugate Base

The acidity of a carboxylic acid increases as the stability of its conjugate base increases.

(Carboxylic acids with conjugate bases possessing a lower negative charge density are MORE STABLE than carboxylic acids with conjugate bases possessing a higher negative charge density.)

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5
Q

Carboxylate Anion

A

Deprotonated Form of Carboxylic Acid

—COO–

The carboxylate anion is the conjugate base of the carboxylic acid.

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6
Q

Carboxylic Acid Acidity: Electron-Withdrawing Group

Electron-Withdrawing Group = EWG

A

Increases Acidity

The EWG stabilizes/delocalizes the negative charge of the carboxylate anion (through inductive effects), so the carboxylic acid is more prone to donating the H+ ion.

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7
Q

Carboxylic Acid Acidity: Electron-Donating Group

Electron-Donating Group = EDG

A

Decreases Acidity

The EDG destabilizes/increases the negative charge of the carboxylate anion (through inductive effects), so the carboxylic acid is less prone to donating the H+ ion.

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8
Q

Carboxylic Acid Acidity: Number of EWGs

Electron-Withdrawing Group = EWG

A

As the number of EWGs increases, the acidity of the carboxylic acid increases.

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9
Q

Carboxylic Acid Acidity: Number of EDGs

Electron-Donating Group = EDG

A

As the number of EDGs increases, the acidity of the carboxylic acid decreases.

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10
Q

Carboxylic Acid Acidity: Distance from EWG

Electron-Withdrawing Group = EWG

A

As the distance to the EWG(s) decreases, the acidity of the carboxylic acid increases.

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11
Q

Carboxylic Acid Acidity: Distance from EDG

Electron-Donating Group = EDG

A

As the distance to the EDG(s) decreases, the acidity of the carboxylic acid decreases.

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12
Q

Why is protonation of the carbonyl Oxygen more favorable than protonation of the hydroxyl Oxygen?

A

Protonation of the carbonyl Oxygen results in multiple cationic resonance structures (i.e. a greater delocalization of positive charge).

Protonation of the carbonyl Oxygen results in a single cationic resonance structure (i.e. no delocalization of positive charge).

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13
Q

Methods to Synthesize Carboxylic Acids

A
  • Oxidation of 1° Alcohols OR Aldehydes
  • Organometallic Addition to CO2
  • Hydrolysis of Nitriles
  • Synthesis of 2-Hydroxyl Carboxylic Acids
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14
Q

Electron-Donating Groups (EDGs)

A
  • —R (Akyl)
  • —OR (Ether)
  • —OCOR (Acyloxyl)
  • —OH (Hydroxyl)
  • —NHCOR (Amide)
  • —NR2 (Amine)
  • —NHR (Amine)
  • —NH2 (Amine)

EDGs decrease the acidity of carboxylic acids.

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15
Q

Electron-Withdrawing Groups (EWGs)

A
  • —X (Halide)
  • —COOH (Carboxylic Acid)
  • —COOR (Ester)
  • —COR (Ketone)
  • —CF3 (Trialkylfluoride)
  • —CN (Nitrile)
  • —SO3+H (Sulfonic Acid)
  • —NO2 (Nitro)
  • —NR3+ (Trialkylammonium)

EWGs increase the acidity of carboxylic acids.

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16
Q

1° Alcohol ⟶ Carboxylic Acid

A

Jones Oxidation

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17
Q

Aldehyde ⟶ Carboxylic Acid

No Intermediate

A

Jones Oxidation

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18
Q

Reagents: Jones Oxidation

A

Na2Cr2O7, H2SO4

  • CrO3, H2SO4
  • HNO3
  • KMnO4
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19
Q

Organometallic ⟶ Carboxylic Acid

Organometallic = Grignard or Organolithium

A

Organometallic Addition to CO2

The addition of an organometallic to CO2 results in a carboxylic acid compound with one more carbon than the organometallic reagent.

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20
Q

CO2 ⟶ Carboxylic Acid

A

Organometallic Addition to CO2

The addition of an organometallic to CO2 results in a carboxylic acid compound with one more carbon than the organometallic reagent.

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21
Q

Reagents: Organometallic Addition to CO2

Starting Material: Organometallic Compound

A
  1. CO2
  2. H3O+
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22
Q

Alkyl Halide ⟶ Carboxylic Acid

Grignard Intermediate

A
  1. Grignard Synthesis
  2. Organometallic Addition to CO2

This Grignard-intermediated synthesis reaction can occur with any alkyl halide compound.

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23
Q

Alkyl Halide ⟶ Carboxylic Acid

Nitrile Intermediate

A
  1. Nitrile Synthesis
  2. Nitrile Hydrolysis

This nitrile-intermediated synthesis reaction can only occur with 2°/1°/0° alkyl halides.

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24
Q

Alkyl Halide ⟶ Carboxylic Acid

Alcohol Intermediate

A
  1. OH– Addition
  2. Jones Oxidation

This alcohol-intermediated synthesis reaction can ONLY occur with 1°/0° alkyl halides.

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25
Q

Nitrile ⟶ Carboxylic Acid

Nitrile = —CN

A

Nitrile Hydrolysis

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26
Q

Alkyl Halide ⟶ Nitrile

Nitrile = —CN

A

SN2 Addition of CN– to Alkyl Halide

NaCN = CN–

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27
Q

Reagents: Nitrile Hydrolysis

A
  1. NaOH, Δ
  2. H3O+

Alternative: H2SO4, H2O, Δ

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28
Q

Limitation of SN2 Nitrile Synthesis

A

SN2-mediated nitrile synthesis CANNOT occur with 3° alkyl halides, phenyl halides, or alkenyl halides.

SN2-mediated nitrile synthesis can ONLY occur with 2°/1°/0° alkyl halides.

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29
Q

Aldehyde ⟶ Carboxylic Acid

Cyanohydrin Intermediate

A

2-Hydroxyl Carboxylic Acid Synthesis

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30
Q

Cyanohydrin

A

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

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31
Q

Reagents: 2-Hydroxyl Carboxylic Acid Synthesis

A
  1. NaCN, H2SO4
  2. H2SO4, H2O, Δ
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32
Q

Mechanisms: Synthesis of Carboxylic Acid from Alkyl Halide

A
  • Jones Oxidation (Alcohol Intermediate)
  • Nitrile Synthesis-Hydrolysis (Nitrile Intermediate)
  • Organometallic Addition (Carboxylate Intermediate)

  • 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.
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33
Q

Examples: Carboxylic Acid Derivatives

A
  • Acyl Halide
  • Anhydride
  • Ester
  • Amide
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34
Q

Anhydride

A
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35
Q

Acyl Halide

A
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36
Q

Amide

A
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37
Q

Ester

A
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38
Q

Carboxylic Acid ⟶ Ester

A

Fischer Esterification

Reversible

  • A catalytic acid (i.e. H2SO4, HCl) must be present for Fischer Esterification to occur.
  • The esterification process yields one molecule of byproduct H2O.
39
Q

Reagents: Fischer Esterification

Starting Material = Carboxylic Acid

A

R—OH (Large Excess), H2SO4, Δ

40
Q

Ester ⟶ Carboxylic Acid

A

Acid-Catalyzed Ester Hydrolysis

Reversible

41
Q

Reagents: Acid-Catalyzed Ester Hydrolysis

Starting Material = Ether

A

H2O, H2SO4, Δ

42
Q

Why must an acid catalyst be present for Fischer Esterification to occur?

A

The carbonyl Oxygen (of the carboxylic acid) must be protonated (by the acid catalyst) to increase the electrophilicity of the carboxylic acid compound.

The unprotonated carboxylic acid compound is NOT sufficiently electrophilic to be attacked by the alcohol nucleophile.

43
Q

Mechanism: Fischer Esterification

A
  1. Protonation of Carbonyl Oxygen
  2. Attack of Alcohol at Carbonyl Carbonyl
  3. Elimination of Water

The nucleophilic attack of the alcohol at the carbonyl Carbon results in an sp3-hybridized tetrahedral intermediate.

44
Q

Hydroxycarbonic Acid

A

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

45
Q

Hydroxycarbonic Acid ⟶ Lactone

A

Intramolecular Esterification

Reversible

46
Q

Lactone

A

Cyclic Ester

Lactone are formed via the intramolecular esterification reaction.

47
Q

Why does the intramolecular esterification reaction favor the lactone product?

A

Entropic Effects

The hydroxycarbonic acid reagent is converted to a lactone compound and a water molecule.

48
Q

Reagents: Intramolecular Esterification

Starting Material = Hydroxycarbonic Acid

49
Q

Reagents: Lactone Hydrolysis

A

H2O, H2SO4

50
Q

Lactone ⟶ Hydroxycarbonic Acid

A

Lactone Hydrolysis

Reversible

51
Q

Carboxylic Acid ⟶ Amide

A

High-Temperature Amine Addition

Reversible

The high-temperature amine addition reaction is an addition-elimination mechanism (that occurs slowly).

52
Q

Carboxylic Acid ⟶ Ammonium-Salt

A

Low-Temperature Amine Addition

Reversible

The low-temperature amine addition reaction is an acid-base mechanism (that occurs rapidly).

53
Q

Ammonium-Salt Synthesis vs. Amide Synthesis

Carboxylic Acid Addition to Amines

A
  • Ammonium-Salt Synthesis: Rapid Acid-Base Mechanism
  • Amide Synthesis: Slow Addition-Elimination Mechanism

  • 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.
54
Q

Conditions: Ammonium-Salt Synthesis

Carboxylic Acid Addition to Amines

A

Amine at 0°C–100°C

Low Temperature

55
Q

Conditions: Amide Synthesis

Carboxylic Acid Addition to Amines

A

Amine at >100°C

High Temperature

56
Q

Why is amine addition an ineffective way to synthesize amide compounds?

Carboxylic Acid Addition to Amines

A
  • High reaction temperatures create dangerous laboratory conditions.
  • Presence of competing reactions to form ammonium carboxylate salt.
57
Q

Imide

58
Q

Why is Imide Synthesis only possible with 0°/1° amines?

A

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

59
Q

Dicarboxylic Acid ⟶ Imide

A

Imide Synthesis

  • 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.)
60
Q

Reagents: Imide Synthesis

A

2 NH3, Δ

Alternative: 2 NRH2, Δ

61
Q

Lactam

A

Cyclic Amide

62
Q

Amino Acid ⟶ Lactam

A

Lactam Synthesis

  • The lactam synthesis reaction involves the cyclization of an amino acid.
  • Heat is required for the cyclization reaction to occur.
63
Q

Reagents: Lactam Synthesis

A
  1. Low Temperature
  2. Δ
64
Q

Lactone Classifications

A
  • 3-Membered Ring: α-Lactone
  • 4-Membered Ring: β-Lactone
  • 5-Membered Ring: γ-Lactone
  • 6-Membered Ring: δ-Lactone
65
Q

Carboxylic Acid ⟶ Acyl Chloride

A

SOCl2-Faciliated Chloride Substitution

The hydroxyl group (of the carboxylic acid) is substituted for a chloride to yield an acyl chloride.

66
Q

Carboxylic Acid ⟶ Acyl Bromide

A

PBr3-Faciliated Bromide Substitution

The hydroxyl group (of the carboxylic acid) is substituted for a bromide to yield an acyl bromide.

67
Q

Mechanism: SOCl2-Faciliated Chloride Substitution

Starting Material = Carboxylic Acid

A
  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–
68
Q

Mechanism: PBr3-Faciliated Bromide Substitution

Starting Material = Carboxylic Acid

A
  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
69
Q

Reagents: SOCl2 Substitution vs. PBr3 Substitution

Starting Material = Carboxylic Acid

A
  • SOCl2 Substitution: SOCl2, Δ
  • PBr3 Substitution: PBr3
70
Q

Elimination Step: SOCl2 Substitution vs. PBr3 Substitution

Carboxylic Acid Substitution

A
  • 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.
71
Q

Why should acid catalysts NOT be used in the amine-nucleophile addition to carboxylic acids?

A
  • The acid catalyst could potentially protonate the amine nucleopile, which would eliminate the amine’s nucleophilic character.
72
Q

Carboylic Acid ⟶ 1° Alcohol

A

LiAlH4 Reduction

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.)

73
Q

Reagents: LiAlH4 Reduction

A
  1. LiAlH4
  2. H3O+
74
Q

What factors determine the reactivity/electrophilicy of carboxylic acid derivates?

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

LG = Leaving Group

75
Q

Reactivity: Partial Positive Charge on Carbonyl Carbon

Carboxylic Acid Derivates

A

As the carbonyl carbon becomes more partially positive, the carboxylic acid derivative becomes more reactive.

A greater partial positive charge on the carbonyl carbon increases the derivative’s susceptibility to nucleophilic attack.

76
Q

Reactivity: Stability of Leaving Group

Carboxylic Acid Derivates

A

As the stability of the leaving group increases, the carboxylic acid derivative becomes more reactive.

A more stable leaving group denotes a weaker (i.e. more easily broken) C—LG bond.

77
Q

What detemines the strength of the Carbon—LG bond?

Nucleophilic Attack of Carboxylic Acid Derivatives

A

The extent of conjugation between the carbonyl group and the adjacent heteroatom.

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).

78
Q

Strength of CCarbonyl—X Bond

A

The CCarbonyl—X bond is weaker due to the halogen being a weak π-electron donor.

The weak conjugation between the carbonyl group and the halogen atom increases reactivity of the acyl halide.

79
Q

Strength of CCarbonyl—N Bond

A

The CCarbonyl—N bond is stronger due to the nitrogen being a strong π-electron donor.

The strong conjugation between the carbonyl group and the nitrogen atom decreases reactivity of the amide.

80
Q

Reactivity of Acyl Halides

Carboxylic Acid Derivates

A

Acyl halides are highly reactive due to the (1) the halide’s electron-withdrawing character and (2) the weak CCarbonyl—X bond.

81
Q

Reactivity of Amides

Carboxylic Acid Derivates

A

Amides are relatively unreactive due to the (1) the nitrogen’s electron-donating character and (2) the strong CCarbonyl—N bond.

82
Q

Why is the CCarbonyl—N bond shorter than typical C—N bonds?

A

Conjugation between the carbonyl group and the nitrogen atom increases the strength of the CCarbonyl—N bond.

83
Q

Why is rotation of the CCarbonyl—N bond slow?

A

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

84
Q

What determines the basicity of carboxylic acid derivatives?

Basicity of Carbonyl Oxygen

A

Stability of the (Derivative’s) Conjugate Acid

85
Q

What determines the acidity of carboxylic acid derivatives?

Acidity of α-Hydrogen

A

Stability of the (Derivative’s) Conjugate Base

86
Q

What factors dictate the basicity of carboxylic acid derivatives?

Basicity of Carbonyl Oxygen

A
  • Positive-Charge Density of Conjugate Acid
  • Positive-Charge Compatibility in Conjugate Acid

  • 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.
87
Q

What factor dictates the acidity of carboxylic acid derivatives?

Acidity of α-Hydrogen

A

Negative-Charge Density of Base

If there is a smaller negative charge on the conjugate base’s α-Carbon, the derivative is more acidic.

88
Q

EWGs: Acidity of Carboxylic Acid Derivatives

A

Increased Acidity

EWGs delocalize the negative charge of the enolate conjugate base, which results in a more stable anionic compound.

89
Q

EWGs: Basicity of Carboxylic Acid Derivatives

A

Decreased Basicity

EWGs concentrate the positive charge on the conjugate acid’s hydroxyl oxygen, which results in a less stable cationic compound.

90
Q

EDGs: Acidity of Carboxylic Acid Derivatives

A

Decreased Acidity

EDGs concentrates the negative charge of the enolate conjugate base, which results in a less stable anionic compound.

91
Q

EDGs: Basicity of Carboxylic Acid Derivatives

A

Increased Acidity

EDGs delocalize the positive charge on the conjugate acid’s hydroxyl oxygen, which results in a more stable cationic compound.

92
Q

Alkyl Halide ⟶ Carboxylic Acid

A
  • Same # of Carbons: Jones Oxidation
  • One Additional Carbon: [Grigard + CO2] OR [Nitrile Hydrolysis]
93
Q

Why is Imide Synthesis only possible with 0°/1° amines?

94
Q

Four Differences: Carboxylic Acid Esterification vs. Carboxylic Acid Amidification

A
  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

  • 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).

Organic Chemistry 2 (12 decks)

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