Chemistry E-2b: Lecture 3

February 11, 2010

While Youre Waiting for Lecture to Start

Trinitrotoluene (TNT) is prepared by starting with toluene and nitrating the aromatic ring three times. Explain why the primary product of this nitration is (2,4,6)-trinitrotoluene.
O2N NO2

exhaustive nitration

primary product (2,4,6)trinitrotoluene

NO2

A small amount of other isomers of TNT are also produced. These isomers are separated from the TNT using a clever trick: The mixture is reacted with Na2SO3 (the sulfite ion, SO32 is a good nucleophile). The desired isomer does not react, while any other isomers undergo nucleophilic aromatic substitution. Explain why the desired isomer does not react, and provide a curved-arrow mechanism for the reaction of the isomer shown here:
NO2

O2N

Na2SO3

no reaction

NO2

O2N

O2N

Na2SO3
NO2 NO2 NO2 SO3

Na

+ NO2

How can this reaction help to separate the unwanted isomers from the desired product?

Chemistry E-2b: Lecture 3

February 11, 2010

Aldehydes and Ketones

Draw some examples of aldehydes and ketones. What do these compounds have in common? How are these compounds different from one another?

List all the ways you have learned to synthesize aldehydes and/or ketones.

Reading: Sections 19.1 and 19.4

Chemistry E-2b: Lecture 3

February 11, 2010

Molecular Orbitals of Aldehydes and Ketones

Draw the molecular orbitals of the following molecules. Identify the HOMO and LUMO of each species. In what ways are these species similar? In what ways are they different?
H H O H H

Reading: Section 19.5

Chemistry E-2b: Lecture 3

February 11, 2010

Reactions of Aldehydes and Ketones with Grignard and Organolithium Reagents

Provide a curved-arrow mechanism and predict the product of each of the following reactions:
MgBr O

H+ workup

MgBr

+
H H

H+ workup

Li

H+ workup

Reading: Section 19.9

Chemistry E-2b: Lecture 3

February 11, 2010

Synthesis of Alcohols
Propose a synthesis of the following alcohol starting with benzene and any compounds containing three or fewer carbons. Do you have any control over the stereochemistry of the final product?

OH

Reading: Section 19.9 5

Chemistry E-2b: Lecture 3

February 11, 2010

Reduction of Aldehydes and Ketones with NaBH4 and LiAlH4

Provide a complete curved-arrow mechanism for each of the following reactions. Why is acid workup required for reduction with LiAlH4 but not for reduction with NaBH4?
O

LiAlH4 Et2O

H+ workup

O H

NaBH4 CH3OH

Reading: Section 19.8

Chemistry E-2b: Lecture 3

February 11, 2010

Nucleophilic Addition to Aldehydes and Ketones: Acidic Conditions

Provide a complete curved-arrow mechanism for each of the following reactions:
OH O

H2O H+

OH

a vicinal diol

O H

HO

OH H

H2O H+

a geminal diol or hydrate

Why is the hydration of an aldehyde reversible? Reading: Section 19.7

Chemistry E-2b: Lecture 3

February 11, 2010

Equilibria for Hydration of Carbonyls: Relative Reactivity of Carbonyl Compounds

Explain the observed ranking of equilibrium constants for carbonyl hydration in the following substrates:
O R R'

H2O

HO R

OH R'

K=

[hydrate] [carbonyl]

Carbonyl Compound
O

K 1 x 106

F3C O

CF3

3 x 104
F3C O H

2 x 103
H O H

1
H3C O H3C O CH3 CH3 H

1 x 103

9 x 106

The following compound has 2 carbonyl groups. Which one will become hydrated under aqueous conditons? Explain why the hydration equilibrium ratio K is equal to 0.8, that is, significantly larger than the ratio for most unsubstituted ketones such as acetone (above).
O O

H2O
CH3

H3C O

Reading: Section 19.7 8

Chemistry E-2b: Lecture 3

February 11, 2010

Nucleophilic Addition to Aldehydes and Ketones: Basic Conditions

Provide a complete curved-arrow mechanism for each of the following reactions:
OH O

OH H2O

OH

a vicinal diol

O H

HO

OH H

OH H2O

a geminal diol or hydrate

N O H HO C H

NaCN HCN

a cyanohydrin

Reading: Section 19.7 9

Chemistry E-2b: Lecture 3

February 11, 2010

Addition of Alcohols: Formation of Hemiacetals under Basic Conditions

Provide a complete curved-arrow mechanism for each of the following reactions:
O H HO OMe H

NaOMe MeOH

a hemiacetal

O HO H

OH (cat.)

OH

a cyclic hemiacetal

Monosaccharides (glucose, fructose, etc.) all exist naturally as hemiacetals; well discuss later... Reading: Section 19.10

10

Chemistry E-2b: Lecture 3

February 11, 2010

Addition-Elimination of Alcohols: Formation of Acetals under Acidic Conditions

Provide a complete curved-arrow mechanism for each of the following reactions:
O H MeO OMe H

MeOH H+ (cat.)

an acetal

O OH H HO

O H

an acetal

H+

(cat.)

Reading: Section 19.10

11

Chemistry E-2b: Lecture 3

February 11, 2010

Using Acetals as Protecting Groups for Carbonyls

How would you carry out the following synthetic transformations?
HO

O H

O H

Br

OH

Reading: Section 19.10 12

Chemistry E-2b: Lecture 3

February 11, 2010

Addition-Elimination of Amines: Formation of Imines and Enamines

Provide a complete curved-arrow mechanism for each of the following reactions:
Me O H Me NH2 N H

pH ~ 5

reaction with a primary amine gives an imine

H N

pH ~ 5

reaction with a secondary amine gives an enamine

Reading: Section 19.11 13

Chemistry E-2b: Lecture 3

February 11, 2010

Hydrolysis of Acetals and Imines

The hydrolysis of acetals and imines is simply the reverse of their formation! Provide a complete curved-arrow mechanism for each of the following reactions:
O O H O

H3O+
H

Me N O

H3O+
H H

Reading: Sections 19.10 and 19.11

14

Chemistry E-2b: Lecture 3

February 11, 2010

The Wittig Alkene Synthesis

The Wittig reaction is a remarkably useful synthesis of alkenes. First, an alkyl halide is used to form a phosphonium ylide. Provide a curved-arrow mechanism:
Br

Ph3P

n-BuLi

PPh3

phosphonium ylide

Then, the phosphonium ylide is added to an aldehyde or ketone to yield a new carboncarbon double bond! Provide a curved-arrow mechanism:
H O O H PPh3 H

Ph3P

The Wittig reaction tends to give cis-alkenes when there is a choice.

Reading: Section 19.13

15

Chemistry E-2b: Lecture 3

February 11, 2010

Using the Wittig Reaction in Synthesis

How would you carry out the following synthetic transformation?

Cl2C

Reading: Section 19.13

16

Chemistry E-2b: Lecture 3

February 11, 2010

Removing the Carbonyl Group from Aldehydes and Ketones

What reagents can you use to carry out the following transformations?
O

Note: These reactions do not work with esters or amides!

Reading: Section 19.12

17