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Chamras Chemistry 106 Lecture Notes

Examination 3 Materials

Chapter 18: Aldehydes & Ketones General Discussion: Aldehydes & ketones are examples of carbonyl compounds: Carbon of the carbonyl group is considered a good electrophile. General Formulas: Which one of these two functional groups is more reactive towards nucleophiles? Why?

C

O

Carbonyl group

C

O

R

C

H

O

R

C

R'

O

Aldehyde Ketone

2

Nomenclature: IUPAC Method

a) Aldehydes:

b) Ketones:

Common naming method for aldehydes: Common names for structural fragments:

O O

OH

O

O

O

O O

H

O

CH3

O

C2H5

O

C3H7

O

formic acetic propionic butyric

3

Examples:

Common naming method for ketones: “Alkylalkyl ketone”

Examples:

Physical Properties of Aldehydes & Ketones: H-Bond Donors: Water Solubility: Spectroscopic Remarks:

a) Aldehydes:

IR: C=O Stretch: Around 1710. cm–1

C(carbonyl)–H Stretch: Around 2750 cm–1 1H–NMR: Aldehyde H around 9.5 ppm 13C–NMR: Carbonyl C around 200 ppm

H H

O

H CH3

O

H C2H5

O

H C3H7

O

OO O

4

b) Ketones: IR:

C=O Stretch: Around 1710. cm–1 C(carbonyl)–H Stretch: Around 2750 cm–1 ***Some structural points on the C=O stretches of Aldehydes & Ketones: 1H–NMR: 13C–NMR: Carbonyl C around 200 ppm

O

O

O

O

1685 cm–11690 cm–1 1745 cm–1

1815 cm–1

5

Syntheses of Aldehydes & Ketones:

1. Oxidation of Alcohols: (Covered in Chp. 11)

Common Oxidizing Agents: Mild: PCC Strong: Na2Cr2O7, H2SO4

2. Ozonolysis of Alkenes: (Covered in Chp. 8)

R'R

OH

[O]

R'R

O

A secondary Alcohol Ketone

R OH

[O]

R O

A primary Alcohol Aldehyde

[O]

R O

OH

Carboxylic Acid

Overoxidation

R"

R'" R

R'

1. O3

2. (CH3)2S

R"

R'" R

R'

OO +

6

3. F.C. Acylation: (Covered in Chp. 17) ***A great method for the synthesis of diaryl ketones or alkyl aryl ketones. Disadvantage: Does not work with strongly deactivated aromatic systems.

4. Hydration of Alkynes: (Covered in Chp. 9)

5. Hydroboration–Oxidation of Alkynes: (Covered in Chp. 9)

R

O

Cl

Y

+Y

O

R

+

Y

O

R

1. AlCl3

2. H2O

R H

Hg2+, H2SO4

H2OH

HR

HO

enol

H+

H

HR

O

R H

1. Sia2BH

2. H2O2, OH–

OH

HR

H

enol

O

HR

H

7

6. Substitution Reactions of 1,3-Dithianes: General Equation: Example:

7. From Carboxylic Acids: (Only ketones could be synthesized) General Equation:

S S

1. Strong Base

2. Alkylating Agent

3. HgCl2, H3O+R R'

O

S S

NaH+

Br

HgCl2, H3O+

H

O

1. NaH

2.Br

HgCl2, H3O+

R OH

O1. LiOH

2. R'–Li

3. H3O+ R R'

O1. 2 R'–Li

2. H3O+OR

8

Example: Mechanism:

O

OH

Li

2

H3O+

9

8. From the Reaction of Nitriles with Grignard Reagents: Example:

N

MgBr

+

9. From Acid Chlorides:

A) Aldehydes:

Reactivity of Carboxylic Acids: Synthetically speaking… If Carb. Acids are simply reduced:

R C N R' MgBr+

R'R

N

BrMg

H3O+

R'R

N

H

R'R

O

OH

O

LiAlH4

(Reduction)H

O

SLOW

LiAlH4

(Reduction)

FAST

O

10

Synthetic Alternative from Carb. Acids: Carb. Acids to Acid Chlorides, then into Aldehydes Example:

OH

O

Cl

O

Cl

S

Cl

O

+ + HClSO2

Li+AlH(O-t-Bu)3

H

O

11

B) Ketones: Synthetic Alternative from Carb. Acids:

Carb. Acids to Acid Chlorides, then into Ketones

Example: Gilman Reagent:

OH

O

Cl

OCl

S

Cl

O

+ + HClSO2

O

MgBr

MgBr

O

FAST

FAST

OH

O

Cl

O

Cl

S

Cl

O

+ + HClSO2

O

CuLi2

12

Reactions of Aldehydes & Ketones: Real Structure: Nucleophilic Additions: Previously Covered examples:

a) Grignard Addition to Aldehydes & Ketones:

O

O

!+

!–

13

b) Hydride (NaBH4) Reductions: Sometimes, to make the carbonyl carbon more activated (more positive) towards nucleophiles, acidic condition is suggested. The existing acid activates the carbonyl carbon in the following way: This is usually a general measure for activating the less active ketones.

The Wittig Reaction Triphenylphosphonium Ylide Triphenylphosphene Oxide *Ylide: Neutral molecules with two oppositely charged adjacent atoms. *Intermediate: Oxaphosphetane *Alkene Isomerism: Cis-product preferred.

R R'

O

C

B(C6H5)3HP

A

+

–

R R'

A B

O(C6H5)3HP+ –

++

14

Example: Mechanism: Ideal Triphenylphosphonium ylide:

O

+ Ph3P CH2

15

Hydration General Equation: Example: Reaction Conditions: a) Acidic OR b) Basic Mechanism: a) Hydration Under Acidic Conditions:

R R'

O

+ H2O

R R'

HO OH

O

OH

H

H

+

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b) Hydration Under Basic Conditions:

Cyanohydrin Formation Cyanohydrin (General Formula): Example: Mechanism: Ideal Aldehyde or Ketone:

O

+ OH–

R R

NC OH

O

HCN, NaCN

17

The Fate of A Cyanohydrin Under Acidic Conditions:

Imine Formation Imine (General Formula): *With Primary Amines. *Intermediate: Carbinolamine *Product: An Imine Mechanism:

H3O+

N

R

O

N

H

H

+

H3O+

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Condensation with Hydroxylamine Hydroxylamine (Formula): Example: Mechanism: Same as “Imine Formation” mechanism. Product: An Oxime

Condensation with Hydrazines Hydrazines (General Formula): Example: Mechanism: Same as “Imine Formation” mechanism. Product: A Hydrazone For a more detailed account on different functional group possibilities, see summary table on p. 844 of Wade.

N

OHH

H

N

OHH

HO

+H3O

+

N N

R

RR

R

O

+H3O

+

N N

H

HH

H

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Acetal & Ketal Formation (Protection Group Chemistry)

General Equation: Example: Mechanism: (Shown for Acetal Formation): *Unhindered Aldehydes & Ketones are ideal for this reaction. **For more sterically hindered ones, use excess alcohol, to assure the progress of the equilibrium towards the acetal side.

R H

O

R R

O

+

+

H+

H+

R'OH

R'OH

Hemiacetal

Hemiketal

R H

HO OR'

R R

HO OR'

H+

H+

Acetal

Ketal

R H

R'O OR'

R R

R'O OR'

H

O

O

H

+

H3O+

2

20

Use of a diol instead of 2 equivalents of alcohol: Example: Reversibility of Acetal & Ketal Formation: Measures to reverse: Protecting Group Chemistry Example: Synthetic Goal: Problem:

H

O

+

H3O+

HO

HO

O

O Selective

Reduction

OH

O

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Alternative (Protecting Group Chemistry) Approach:

Oxidation of Aldehydes General Equation: Oxidizing Agents:

a) NaCr2O7, H3O+

b) Ag2O, THF/H2O Ketones???

R H

O

[O]

R OH

O

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Reduction of Aldehydes & Ketones

Agents for the process “A”:

1. NaBH4, ROH 2. NaBH4, H2O 3. a) LiAlH4 , b) H2O 4. Ni-H2 (AKA: Raney nickel) *Also reduces C=C to C–C

Agents for the process “B”:

1. Wolff-Kishner (basic hydrazine, water) 2. Clemmensen (mercurial zinc, hydrochloric acid)

*** Please Read on 2,4-DNP and Tollens tests. These characterization tests will be covered in detail in the laboratory in the context of the Qualitative Analysis project. Suggested Problems: 39, 41, 43, 46, 49 (part 2), 50, 51, 53, 58, 61, 66, 70, 75.

R R

O

R H

OH

R

A B

R H

H

R

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Chapter 19: Amines Functional Group: R, R’, R”= hydrogen, alkyl, or aryl Types: Nomenclature:

a) Common Method: Is based on the “alkylalkylamine” template. Example:

R''

N

R'

R

R''

N

R'

R

1. Ammonia: 2. Primary:

3. Secondary: 4. Tertiary:

*Quaternary Ammonium Salts (or Ions):

H

N

R'

R

H

N

H

R

H

N

H

R

R'' N

R'

R

R"'

N

H

N

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b) IUPAC method: Based on the “alkanamine” template.

Example:

*Common Names for Some Cyclic Amines: (The nitrogen is assigned the position #1) Structure & Physical Properties: Polarity: Primary & Secondary amines are polar and H-bond donors & acceptors. Tertiary amines are only H-bond donors

N

H

N

N

H

N

H

N

H

N

H

N

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Chirality: The following amines are chiral:

a) Amines possessing chiral carbons:

Example:

b) Quaternary Ammonium salts with asymmetric nitrogen atoms:

Example:

c) Small cyclic amines with an asymmetric nitrogen as a member of the ring:

Example:

What about other amines with asymmetric nitrogens? Nitrogen Inversion in Amines: (AKA: Umbrella Motion)

N

N H

N

N

N N

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Solubility in Water:

Basicity:

Ammonia Primary Secondary Tertiary Amines Amines Amines

Remember: Acidity / Basicity is about the extent of acidic /basic dissociation equilibrium:

N

C

H

H

H

N

HH

H

H

O

H+ pKb =

N

CH3H

H

H

O

H+ pKb =

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Amine pKa pKb ammonia 9.3 methylamine 10.64 dimethylamine 10.72 trimethylamine 9.7 aniline 4.6 p-nitroaniline 1.0 p-chloroaniline 4.0 pyridine 5.25 *pyrrole –1.0 piperidine 11.12

The Effect of Resonance on Basicity: Aniline Vs. Protonated aniline Pyrrole Vs. Protonated pyrrole

28

The Effect of Hybridization on Basicity: Aniline Vs. Piperidine Phase Transfer Catalysts: Spectroscopic Remarks:

1. IR: N–H Stretch: 3200-3500 cm–1 1 peak for 2o and 2 peaks for 1o amines.

2. 1H–NMR: N–H proton: Usually singlets @2-3 ppm.

3. 13C–NMR: Carbon alpha to N @ 30-50 ppm.

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Synthesis of Amines:

1. Reductive Amination:

a) For Primary Amines:

b) For Secondary Amines:

c) For Tertiary Amines:

H

N

H

OH

+

R'

O

R

H+

R'

N

R

OH

[R]

R'

N

R

HH

Reducing Agent:H2–Ni, LiAlH4, or Zn– HCl

H

N

R"

H

+

R'

O

R

H+

R'

N

R

R"

[R]

R'

N

R

R"H

A Schiff Base

H

N

R"

R"'

+

R'

O

R

H+

R'

N

R

R"

[R]

R'

N

R

R"R'"

Iminium Salt

R'"

R = sodium triacetoxyborohydride, acetic acid

30

2. Acylation–Reduction: General Scheme: Example:

3. Syntheses of 1o Amines:

a) Direct Alkylation: General Scheme: Example: Why Excess NH3?

Amine(Ammonia, 1o, or 2o)

+ Acid ChlorideOH–, pyridine

Amide

ReductionAcylation

1. LiAlH42. H2O

Higher Amine

N

H

Cl O

OH–, pyridine

N O

1. LiAlH42. H2O

N

+

Ammonia (Large excess)

Alkyl Halide or Alkyl Tosylate+ 1o Amine

SN2

N

HH

H

+

Cl

N

H

H

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b) Gabriel Synthesis: This method uses a similar approach to protecting-group chemistry:

General Scheme: RX= tosylate or halide (1o) Example: Mechanism:

N

RH

H

N

O

O

H

1. OH–(aq)

2. RX

3. NH2NH2, HeatN

N

O

O

H

H

+

Phthalimide Phthalimide Hydrazide Primary Amine

N

H

H

N

O

O

H

1. OH–(aq)

2. CH3CH2Br

3. NH2NH2, HeatN

N

O

O

H

H

+

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c) Reduction of Alkyl Azides: Similar to Gabriel synthesis, but using azide ion as the nucleophile (an SN

2 mechanism for alkyl Azide formation). General Scheme: RX= tosylate or halide Example:

d) Reduction of Alkyl Nitriles: Similar to Gabriel synthesis, but using cyanide ion as the nucleophile (an SN

2 mechanism for alkyl cyanide formation). General Scheme: ***Note: The alkyl group on the amine product is subjected to chain lengthening due to the carbon of the cyanide ion. Example:

N

RH

H

1. RX

2. a) LiAlH4, b) H2O or H2, Pd

N N N +

1. LiAlH4,

2. H2ON N N +

Br

N

N

N

N

H

H

N

H

H

1. RX

2. a) LiAlH4, b) H2O or H2, Pd

N C+

R

1. LiAlH4,

2. H2O+

BrC

N C

N

N

H H

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e) Reduction of Nitro Compounds: Example:

f) Hofmann Rearrangement of Amides:

NO2 NH2 H2, catalyst

or

Active Metal, H+

Choice of Catalyst: Ni, Pd, or PtChoice of Active Metal: Fe, Zn, or Sn

R NH2

O

X2, 4NaOH+ 2NaX + Na2CO3 + 2H2O

R

N

H

H

Primary Amide

Primary Amine

X = Cl or Br

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Mechanism:

R N

O

Primary Amide

H

HOH

Br Br

Deprotonated Amide

N-bromo amide

OH

Deprotonateed N-bromo amide

IsocyanateR

N C O

OH

H

O

H

Carbamic Acid

OH

Deprotonated Carbamic AcidDeprotonated Amine

R

N

H

H

O

H

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Reactions of Amines:

a) Reactions with Aldehydes & Ketones (Review from Chp. 18): General Scheme:

b) Acylation: General Scheme: Amine Acid Chloride Amide Usually, pyridine is used as an acid scavenger. Mechanism:

R R'

O

Y

N

H

H

+

H+

R R'

N

Y

If Y = H or alkyl Imine (Schiff Base)

If Y = OH Oxime

If Y = NHR Hydrazone

R' Cl

O

+

R

N

H

H

R' N

O

H

R

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c) Alkylation:

d) Formation of Sulfonamides: General Scheme: 1o or 2o Amine Sulfonyl Chloride Sulfonamide

e) Hofmann Elimination (Amine as a Leaving Group): General Scheme: Example: Mechanism:

+

R

N

H

H

S ClR'

O

O

NaOH

Quaternary Ammonium Salt Alkene + AmineHeat

(E2)

N

H

H

Heat, OH–

C C

H

HH

H

H

O

H N++

37

***Product Multiplicity (Hofmann Vs. Saytzeff Products): Why is there a preference for Hofmann product? ***When performed with a cyclic ammonium salt, an acyclic alkenamine results.

N

38

f) Oxidation of Amines: General Scheme:

R

N

H

H

R

N

H

R

R

N

R

R

[O]

[O]

[O]

R

N

OH

H

[O]R

N

O[O]

R

N

O

O1oAmine

2oAmine

3oAmine

Hydroxylamine Nitroso Nitro

R

N

OH

R

Hydroxylamine

N O

R

R

R

3oAmine Oxide Commonly Used Oxidizing Agents: H2O2 or ArCO3H

g) Cope Elimination: (Hofmann product preference)

General Scheme: Example: Mechanism:

3o Amine Oxide Alkene + 2oAmine Oxide

N

O

N

HO

+

H H

HH

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h) Reaction with Nitrosonium Ion (Nitrous Acid): General Scheme: Generation of Nitrosonium Ion: Mechanism:

N

H

R

H

N

R

R

H

1o Amine

2o Amine

NO+

NO+

R N N

Alkyldiazonium Ion

R

N

R

N

O

2o N-Nitrosoamine

R

N

R

N

O

1o N-Nitrosoamine

NaNO2 + HCl HNO2 + NaCl

HNO2 + H+ H2NO2+

H2O + NO+

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i) Reactions of Arenediazonium Salts:

NN

OHH3O+

CuCl or CuBrCl Bror

CuCNC N

HBF4 or KIF Ior

H3PO2

Ar'H

N

N

Diazo Coupling

Deamination

Sandmeyer Reaction

Hydrolysis