Download organic chemistry ii

ORGANIC CHEMISTRY II
EXAM 3 MATERIAL REVIEW
Spring Semester Week 15, 2013
I.
Chapter 21: Aldehydes and Ketones –Nucleophilic Addition
The carbonyl group is polarized in such a way that the -electron density is concentrated around
the oxygen atom thus making the carbon atom electron deficient. This can be visualized using
resonance theory:
C O
C O
In terms of reactivity, this means that the carbonyl carbon is susceptible to nucleophilic attack. In
most cases nucleophilic addition to aldehydes of ketones follows the general mechanism outlined.
Nu
C O
Nu
O
C
Or
Nu
C O
H
Nu
O
C
H
if acid catalyzed…
There are a large range of nucleophiles which can react with aldehydes of ketones. These can be
classified as
1. Carbon nucleophiles
2. Oxygen nucleophiles
3. Nitrogen nucleophiles (classified as “reactions which go beyond the nucleophile
addition step”)
1. Carbon Nucleophiles
(i)
Carbanionic species
i.e. cyanide, acetylides
(ii)
Organometallic species
i.e. organolithium compounds, organomagnesium compounds (Grignard
reagents)
(iii)
“Assisted” Carbanionic species (by third-row elements such as phosphorus and
sulfur)
i.e. phosphorus ylides
(classified as “reactions which go beyond the nucleophile addition step”)
The following are examples of the products obtained when benzaldehyde undergoes reactions of
the types mentioned above:
1(i)
nucleophile
reaction products
OH
CN
CN
OH
C C R
R
Note that the alkyne can be converted into a number of functional groups
1(ii)
nucleophile
reaction products
OH
CH 3 CH 2MgBr
review reactions of epoxides with Grignard reagents as well
1(iii)
nucleophile
reaction products
CH3 CHP(C 6H5)3
Page 2
2. Oxygen Nucleophiles
An aldehyde or a ketone undergoing a reaction with two equivalents of alcohol gives an acetal or
ketal. A diol is considered a “two equivalent alcohol” and gives a cyclic acetal or ketal. Most
ketals can only be prepared from diols (acyclic ketals are less stable)
Acetals/ketals can be hydrolyzed back to the parent aldehyde/ketone under acidic conditions.
Given below is an example of a cyclic hemiacetal, acetal, and a ketal
OH
O
OR
O
O
O
Acetals are commonly used as protecting groups.
3. Nitrogen Nucleophiles
Aldehyde/Ketones + primary amine
imine
Aldehyde/Ketones + primary amine
enamine
Note that imines are very basic (Schiff bases) and they can be hydrolyzed back into
aldehydes/ketones under acidic conditions.
II.
Chapter 27: Carbohydrates
 classification: (i) number of carbons; (ii) aldehyde or ketone; (iii) D or L; (iv) ring size;
(v)  or 
 Stereochemistry: Fischer structures
 Conversion from straight chain to ring structures (and from ring to chain); mutarotation
(omit Sect. 27.4)





Reactions of Monosaccharides:
reduction (into alditols)
oxidation (into aldaric acids)
loss of optical activity (with certain monosaccharides), introduction of a plane of
symmetry into the molecule
(omit oxidation into aldonic acid)
ring extension, Kiliani-Fischer reaction
(omit Sect. 27.10A)
exhaustive methylation: strategy to determine ring size
glycoside formation
Page 3
Disaccharides
1,1- and 1,4-linkages
(omit Sect. 27.13, 27.14A)
N-Glycosides (Sect. 27.14B)
nucleosides; nucleotides
III.
Chapter 22: Carboxylic Acids and their Derivatives –Nucleophilic Acyl Substitution
The common features of these classes of compounds is that they can all be hydrolyzed into
carboxylic acids
Syntheses of Carboxylic Acids:
(i)
Oxidation of aldehydes and 1o alcohols (remember 1o alcohols will only oxidize
to aldehydes if the reaction is carried out in non-aqueous conditions).
(ii)
Hydrolysis of nitriles (in acid catalyzed conditions)
O
NaCN
?
H3 O
?
CN
C 6 H 8O
C7H10O3
(also an example for conjugate addition)
(iii)
Carbonylation of Grignard reagents
MgBr
CO2
H3O
?
Types of CA derivatives (in order of reactivity)
Acid halides (chlorides) > Acid anhydrides > Esters > Amides
(and nitriles)
Synthetic Strategy
A CA derivative can be prepared starting from the more reactive derivative going to less reactive,
i.e. esters and/or amides from acid chlorides or anhydrides; amides from esters, etc.
Mechanism of Nucleophilic Acyl Substitution
When a nucleophile attacks a CA derivative, a tetrahedral intermediate (unstable) forms, which
subsequently dissociates into a new CA derivative (or into a carboxylate)
Reactions of Nitriles
Nitriles are extremely versatile as precursors; they can be converted into
(i) carboxylic acids, (ii) imines, (iii) amines, (iv) aldehydes (v) ketones (upon reaction with
Grignard or organolithium reagents)
Page 4
Other Reactions
Fischer Esterification: an acid catalyzed reaction between a carboxylic acid and an
alcohol
O
R
O
O
H
H
HO R
R
OR
Note that the carboxylic acid hydroxyl oxygen is protonated and subsequently dehydrated
(not the alcohol hydroxyl)
An intramolecular esterification of a - (or -) hydroxycarboxylic acid would give a cyclic ester,
which is referred to as a “lactone”
O

OH
HO
O
O
 -lactone
O
HO
O
OH

O
 -lactone
Dicarboxylic Acids:
Note that -carbonyl carboxylic acids undergo thermal decarboxylation
IV.
Chapter 23: -Substitution Reactions
Aldehydes and ketones which possess -hydrogens can undergo enolization. Most enols are
unstable and reactive and instantly equilibrate to the “keto” form. Certain enols, such as
-dicarbonyl compounds, among others, are exceptionally stable. Under basic conditions
aldehydes and ketones form enolates, which can function as nucleophiles.
-Halogenation
Enolizable aldehydes and ketones can be halogenated at the -carbon (see iodoform reaction,
Sect. 23.7B)
-Alkylation
Enolizable aldehydes and ketones can be alkylated at the -carbon upon reaction with an alkyl
halide.
Page 5
In cases where enolate formation can take place at non-equivalent carbons the reaction can take
place under (i) thermodynamic or (ii) kinetic conditions
(i) a thermodynamic enolate is the more stable (more substituted) enolate which can be
formed upon reaction with only a mildly strong base such as an alkoxide
(ii) a kinetic enolate is the less stable (less substituted) enolate which can be
formed upon reaction with a very strong base such as LDA.
Although the more stable enolate is also formed under these conditions, the less
stable enolate will undergo alkylation more rapidly.
Acetoacetic Ester (or Malonic Ester) Synthesis:
Acetoacetic ester (ethyl acetoacetate) is a -keto ester. It will form an enolate under milder
conditions.
O
O
H
H
O
OCH2CH3
O
O
O
H
The product of AAE synthesis is usually a substituted acetone at the end of the following four
steps: (i) enolate formation; (ii) alkylation; (iii) ester hydrolysis; (iv) decarboxylation.
The product of an analogous (four-step) reaction with malonic ester is a substituted acetic acid.
V.
Chapter 24: Enols and Enolates
An enolate which is in equilibrium with its keto (non-enolate) form, can undergo a reaction with
“itself”, the Aldol Reaction.
O
C
C
H
H
H
C
O
C
H
OH
H
C
H
O
C
H
H
+
H
H
H2O
Aldol Reactions: Two steps –addition and condensation
Addition products: -hydroxy aldehydes (or ketones)
Condensation:
,-unsaturated aldehydes (or ketones)
Mixed Aldol Reactions: yields are higher if only one of the aldehydes (or ketones) is
enolizable (i.e. if the other aldehyde/ketone does not have any -hydrogens) –remember
Page 6
the Aldol reaction you carried out in the lab (between acetone and benzaldehyde –
anisaldehyde)
Intramolecular Aldol Reactions: the staring material contains two carbonyl
functionalities, and the product is usually a five- or six-membered ring.
HO
O
O
O
O
C16H24O2
C16H24O2
Ester Enolates
Esters which possess -hydrogens can undergo enolization in an analogous fashion to aldehydes
and ketones. Similarly ester enolates can function as nucleophiles. Since the ester enolate is in
equilibrium with its non-enolate form, it can undergo a reaction with itself. This type of a reaction
is referred to as Claisen Condensation.
Claisen Condensation:
Step 1: formation of the ester enolate (the base used is the same alkoxide as the one in the ester)
Step 2: formation of a bond between the -carbon of one ester and the carbonyl carbon of the
other (the structure formed is referred to as tetrahedral-intermediate and is relatively unstable)
Step 3: dissociation of the tetrahedral intermediate
Step 4: formation of a -keto ester and a new enolate
Step 5: acid work-up and isolation of the 1,3-dicarbonyl (-dicarbonyl) compound
Dieckman Condensation:
An intramolecular Claisen Condensation at the end of which a cyclic ester (a lactone) is formed.
Reactions of ,-unsaturated aldehydes (or ketones):

O
two possible electrophilic sites
More reactive nucleophiles add to the carbonyl carbon; whereas the less reactive ones
(where there is possibility for reversibility) add to the -position.
Page 7
Michael Addition Reactions: the nucleophile is an enolate which adds to the -carbon of an
,-unsaturated aldehydes or ketone (the electrophile). The product of a Michael reaction is a
1,5-dicarbonyl compound.
O
+
O
O
O
C16H24O2
C5 H8 O
Enolates which take part in Michael additions are usually stable enolates (from -dicarbonyl
compounds)
Robinson Annulation Reaction: a Michael addition followed by an intramolecular Aldol
reaction (see above)
Page 8