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Organic Chemistry 2 > Chapter 21 (Amines) > Flashcards

Chapter 21 (Amines) Flashcards

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1
Q

Amine

A

A Nitrogen-based compound possessing one/two/three alkyl or aryl groups (bonded to the Nitrogen).

The reactivity of Amines differs greatly from other Nitrogen-containing compounds (i.e. Enamines, Amides, Imines, Iminiums, Ammoniums).

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2
Q

Enamine

A

A compound possessing an amino group adjacent to an alkene group.

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3
Q

Amide

A

A compound possessing an amino group adjacent to a carbonyl group.

The Nitrogen lone-pair electrons are in conjugation with the π electrons of the carbonyl group.

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4
Q

Imine

A

A compound possessing a Carbon-Nitrogen double bond.

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5
Q

Iminium Ion

A

A cationic compound possessing a Carbon-Nitrogen double bond and a quadruple-substituted Nitrogen.

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6
Q

Ammonium

A

A cationic Nitrogen compound with four alkyl/aryl substituents (bonded to the Nitrogen).

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7
Q

Amino Group

A

—NR2

R = Alkyl/Aryl/Hydrogen

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8
Q

Geometry: Simple Amines

A

Tetrahedral Geometry (sp3-Hybridized Nitrogen)

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9
Q

Geometry: Aryl Amines

A

Tetrahedral Geometry (sp3-Hybridized Nitrogen)

The aryl amine displays a tetrahedral-like geometry despite the weak conjugation between the Nitrogen lone pair and the aromatic π electrons. (This conjugation is significantly weaker than the conjugation present in amides, so the aryl amine is tetrahedral-like overall.)

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10
Q

Geometry: Amides

A

Planar Geometry (sp2-Hybridized Nitrogen)

The planar geometry of amides is caused by the strong conjugation between the Nitrogen lone pair and the carbonyl π electrons.

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11
Q

Why are Alkyl Amines more nucleophilic than Aryl Amines?

A

The Nitrogen lone-pair electrons of alkyl amines are better able to undergo nucleophilic attack due to the absence of conjugation to delocalize the electrons.

The Nitrogen lone-pair electrons of aryl amines are in conjugation with the aromatic π electrons, so they are less nucleophilic/reactive.

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12
Q

Reactivity: Enolate

A

β-Carbon Serves as Nucleophile

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13
Q

Reactivity: Amide

A

Carbonyl Carbon Serves as Electrophile

The Nitrogen lone pair cannot serve as the nucleophile.

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14
Q

Reactivity: Imine

A

Imine Carbon Serves as Electrophile

Imine Carbon = C=N

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15
Q

Reactivity: Ammonium

A

Hydrogen Serves as Acid

Acid-Base Reactions

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16
Q

Reactivity: Iminium

A

Iminium Carbon Serves as Electrophile

Imine Carbon = C=N+

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17
Q

Chirality of Amines

A

An amine is chiral if it possess three unique substituents (bonded to the Nitrogen atom).

Chiral amines are not optically active since the two enantiomers cannot be separated/isolated. (The enantiomers undergo rapid transversion through a trigonal planar transition state.)

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18
Q

Why are chiral amines not optically active?

A

The two enantiomers of chiral amines undergo rapid interconversion (through a trigonal planar intermediate state), so each individual enantiomer cannot be isolated.

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19
Q

pKa: Amines

A

pKa ≈ 35

Amines are weak acids and moderate bases.

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20
Q

pKa: Ammonium

A

pKa ≈ 10

Ammoniums are moderately acidic (i.e. more acidic than water/alcohol and less acidic than carboxylic acids).

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21
Q

Acidity of Amines

A

Weakly Acidic

The conjugate bases of amines (e.g. LDA, NaNH2) are strongly basic (due to the N—H bond being relatively strong/stable).

22
Q

Basicity of Amines

A

Moderately Basic

The conjugate acids of amines (i.e. Ammoniums) are moderately acidic (due to the instability of a quadruple-substituted cationic Nitrogen compound).

23
Q

Factors Determining Basicity of Amines

3 Factors

A
  • Conjugation
  • Hybridization
  • Aromaticity

  • The Nitrogen lone pair is less basic if it is in conjugation with a π system.
  • The Nitrogen lone pair is less basic if it is possesses a lower hybridization.
  • The Nitrogen lone pair is less basic if it is within an aromatic system.
24
Q

Basicity of Amines: Conjugation

A
  • The Nitrogen lone pair is more basic if no conjugation is present (since the lone-pair electrons are more capable of attacking/reacting).
  • The Nitrogen lone pair is less basic if it is in conjugation with a π system (since the lone-pair electrons are less reactive/nucleophilic).
25
Q

Basicity of Amines: Hybridization

A
  • The Amine is more basic if it is sp3-hybridized (since the lone-pair electrons not stabilized by the less electronegative Nitrogen).
  • The Amine is less basic if it is sp-hybridized (since the lone-pair electrons are stabilized by the more electronegative Nitrogen).
26
Q

Basicity of Amines: Aromaticity

A
  • The Amine is more basic if it is outside of an aromatic system (since the lone-pair electrons are more concentrated/reactive).
  • The Amine is less basic if it is within an aromatic system (since the lone-pair electrons are highly delocalized throughout the aromatic ring).
27
Q

Amine ⟶ Alkyl Amine

A

SN2 Alkyl Halide Alkylation

The SN2 Alkyl Halide Alkylation reaction will produce a mixture of 1° amines, 2° amines, and 3° amines.

28
Q

Reagents: SN2 Alkyl Halide Alkylation

Starting Material = Amine

A

0°/1° Alkyl Halide

The Nitrogen lone-pair (of the amine) undergoes SN2 attack at the alkyl halide Carbon to yield an Alkyl Amine (and a Halogen anion leaving group).

29
Q

Why is the SN2 Alkyl Halide Alkylation reaction not useful/effective for creating Alkyl Amines?

A

The initial 1° Amine product will undergo further alkylation reactions to yield a mixture of 1° Amines, 2° Amines, and 3° Amines.

30
Q

Nitrile ⟶ 1° Amine

R—CN ⟶ R—NH2

A

LiAlH4 Reduction

31
Q

Alkyl Azide ⟶ 1° Amine

R—N3 ⟶ R—NH2

A

LiAlH4 Reduction

32
Q

Reagents: LiAlH4 Reduction

A
  1. LiAlH4
  2. H2SO4, H2O
33
Q

Alkyl Halide ⟶ 1° Amine

R—X ⟶ R—NH2

A
  1. SN2 Nitrile/Azide Synthesis
  2. LiAlH4 Reduction

  • Nitrile Intermediate: The final reduced product has one more Carbon than the reagent Alkyl Halide.
  • Azide Intermediate: The final reduced product has the same number of Carbons as the reagent Alkyl Halide.
34
Q

Alkyl Halide ⟶ Alkyl Azide

R—X ⟶ R—N3

A

SN2 Azide Synthesis

35
Q

Alkyl Halide ⟶ Nitrile

R—X ⟶ R—CN

A

SN2 Nitrile Synthesis

36
Q

Reagents: SN2 Azide Synthesis

Starting Material = Alkyl Halide

A

NaN3

37
Q

Reagents: SN2 Nitrile Synthesis

Starting Material = Alkyl Halide

A

NaCN

38
Q

Amide ⟶ Amine

A

LiAlH4 Reduction

The order/substitution of the Amine product corresponds to the order/substitution of the Amide reagent.

39
Q

Aldehyde/Ketone ⟶ Alkyl Amine

A

Reductive Amination

The order/substitution of the Alkyl Amine product is one greater than that of the Amine reagent.

40
Q

Reagents: Reductive Amination

Starting Material = Aldehyde/Ketone

A
  • Amine, NaBH3CN
  • Amine, H2, Ni(s)

  • The amine reagent can be a 0° Amine, 1° Amine, or 2° Amine.
  • All reagents can be added together at one time.
41
Q

Mechanism: Reductive Amination

A
  1. Nucleophilic addition of the Amine to the carbonyl Carbon (of the aldehyde/ketone) to yield an Imine/Iminium.
  2. Reduction of the imine/iminium Carbon-Nitrogen double bond (C=N) to yield an Amine.

  • Step 1: An imine will form if the reagent amine is a 0° Amine or 1° Amine. An iminium ion will form if the reagent amine is a 2° Amine.
  • Step 2: Reduction of the imine/iminium compound involves the addition of two Hydrogens across the C=N double bond.
42
Q

Stability/Reactivity: NaBH3CN vs. NaBH4

A
  • The NaBH3CN reductant is more stable under weakly acidic conditions.
  • The NaBH3CN reductant is less reactive due to the electron-withdrawing Nitrile group.
43
Q

NaBH3CN

A

Sodium Cyanoborohydride

44
Q

Reductive Amination: Reduction Selectivity

A

The reductive agents used in Reductive Amination (i.e. NaBH3CN or H2/Nickel) react faster with the imine/iminium C=N bond that with the aldehyde/ketone C=O bond.

Since the aldehyde/ketone C=O bond will not react with the reductive agents (i.e. the reductive agents will always preferentially react with the imine/iminium C=N bond), all three reagents can be added together to the reaction mixture to yield the desired alkyl amine product.

45
Q

Ketone/Aldehyde ⟶ β-Aminocarbonyl Compound

β-Aminocarbonyl = β-Aminoketone or β-Aminoaldehyde

A

Mannich Reaction

The Mannich Reaction requires acidic conditions to occur.

46
Q

1°/2° Amine ⟶ β-Aminocarbonyl Compound

β-Aminocarbonyl = β-Aminoketone or β-Aminoaldehyde

A

Mannich Reaction

The Mannich Reaction requires acidic conditions to occur.

47
Q

Reagents: Ketone Mannich Reaction

β-Aminoketone Product

A
  1. Ketone, Aldehyde, Amine, H2SO4, Δ
  2. NaOH, H2O

The amine reagent must be a 1° Amine or 2° Amine.

48
Q

Reagents: Aldehyde Mannich Reaction

β-Aminoaldehyde Product

A
  1. Aldehyde, Aldehyde, Amine, H2SO4, Δ
  2. NaOH, H2O

The amine reagent must be a 1° Amine or 2° Amine.

49
Q

Mechanism: Ketone Mannich Reaction

β-Aminoketone Product

A
  1. Nucleophilic addition of the Amine to the aldehyde’s carbonyl Carbon to form an Iminium cation intermediate.
  2. Acid-catalyzed enolization of the ketone via protonation of the ketone’s carbonyl Oxygen.
  3. Nucleophilic attack of the enol’s α-Carbon (via π-electron rearragement) to the iminium’s C=N Carbon to form a β-Aminooxocarbenium intermediate.
  4. Intramolecular proton transfer to deprotonate the Oxocarbenium and protonate the Nitrogen.
  5. Base-mediated workup to deprotonate the ammonium group to form a β-Aminoketone product.
50
Q

Mechanism: Aldehyde Mannich Reaction

β-Aminoaldehyde Product

A
  1. Nucleophilic addition of the Amine to the reactive aldehyde’s carbonyl Carbon to form an Iminium cation intermediate.
  2. Acid-catalyzed enolization of the non-reactive aldehyde via protonation of that aldehyde’s carbonyl Oxygen.
  3. Nucleophilic attack of the enol’s α-Carbon (via π-electron rearragement) to the iminium’s C=N Carbon to form a β-Aminooxocarbenium intermediate.
  4. Intramolecular proton transfer to deprotonate the Oxocarbenium and protonate the Nitrogen.
  5. Base-mediated workup to deprotonate the ammonium group to form a β-Aminoaldehyde product.

Organic Chemistry 2 (12 decks)

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