Chemistry 211
2009
Equilibrium Controlled Reactions:
Carbonyl Reactions - 5
A. Original Reactions:
In the Carbonyl Reactions-2 through -4, we explored fifteen examples of three general types of reaction of carbonyl containing compounds. The
fifteen example reactions are reproduced below. The mechanistic analyses of these reactions can be found in the summaries of class discussion
files for Carbonyl Reactions-2, -3 & -4.
1. Carbonyl Addition Reactions.
2. Carbonyl Addition-Elimination Reactions.
Acid-Catalyzed
Uncatalyzed
O
a.
C
CH3
+
H 3O
H2O
CH3
+
H
O
O
C
CH3
H
c.
CH3
Base-Catalyzed
C
+
H
H
C
H
H2O
CH2
NH3OH
CH3
N
C
C
N
j.
CH3
CH2
HN
NH2
CH3
H2O
C
H
OH
H
H 2O
CH3
O
HN
H
C
H2O +
+
C
O
H
C
CH2
CH
CH2
Uncatalyzed
Cl
+
H
H
O O
O
O ..
S O
C
Cl
S
O
+ H2O
N
N
H
H
NH3
O
m.
C
H
CH3
CH2
CH2
C
H
CH3
CH2
CH2
+ H
O
H
O
+
O
C
H
H2O

CH3
C
CH2
C
C
CH2
CH3 CH2
H
+ H2O
O
n.
O
O
+
C
O + H2O
OH

H
H O
Base-Catalyzed
l.
CH3
Base-Catalyzed
H
O
C
H
CH2
CH3 CH2
k.
C
CH2
O
Base-Catalyzed
O
CH3
H2O
CH3
O
Base-Catalyzed
CH2
C
CH2
O
H
d. 2
CH3
.
+ NH2OH
N
Uncatalyzed
O
b.
O
Uncatalyzed
H2O
C
N
N
C
O
O
H
o.
C
+ NH2OH
CH3
H2O
NH3OH
N
C
CH3
O
H
+ H2O
2
Carbonyl Reactions - 5
3. Acyl Substitution Reactions.
Acid-Catalyzed
Base-Catalyzed
O
f.
O
C NH +
2
C
H3O
O
+
O
H + NH4
C
2
h.
O
OCH3
CH3
O
O
C
C
O
CH3
+ HOCH3
Acid-Catalyzed
Uncatalyzed
O
O
p.
O
+ H2O
O
H3O
H +
OH
O
r.
CH3 C
CH3 C
O
O
H
O + CH3OH
C
+
O CH3
H
C
O H
O
Uncatalyzed
O
O
i. CH3
C
Cl
+
2 CH3CH2OH
CH3
C
O
CH2
+
Cl
CH3
+ CH3CH3OH2
So far we have been working with reactions that provide structures of products as well as structures reactants and the reaction conditions. Now that
we have an understanding of how the energies of HEE in the reactions control possible steps in the reaction mechanism of carbonyl reactions, we are
prepared to use our understanding of mechanistic possibilities to determine likely products for reactions such as the one below that provide only
reactant structures and reaction conditions.
O
O +
NH2
?
O
Since we don’t have product structures to guide us, we need to use energies of HEE and our experiences with the reactions on pp. 1 & 2 to help us
determine the likely course of the mechanism. To assist us in using our experience, the types of mechanisms are indicated above each reaction on pp. 1 & 2
and formalized general representations of the types of mechanisms are provided on pp. 3-5. The questions on p. 6 should help in exploring the general
mechanisms to develop approaches for analyzing mechanisms and predicting products for reaction like the example above.
Carbonyl Reactions - 5
General Mechanisms for Reactions of Carbonyl Compounds
3
= H or group with carbon attached to C=O carbon
Nu: = Nucleophile
= group with O, N, Cl, Br attached to C=O carbon
H-A & H-B = potential acid catalysts B:- &A:- = potential base catalysts
Base Catalyzed Addition
H
Nu
B
H
1
O
O
Nu
+
H B
C
C
2
O
C
3
+
B
+
B
Nu
Nu
Base Catalyzed Acyl Substitution
Nu
B
H
1
Nu
+
O
O
O
C
C
2
C
3
Nu
+
Nu
Base Catalyzed Addition-Elimination
H
Nu
H
H
B
1
H B
Nu
H
+
O
O
H B
C
C
2
O
C
3
Nu H
Nu H
4
H O
H
+ H A
C
Nu
O
C
5
Nu
+ H B
4
Carbonyl Reactions - 5
Uncatalyzed addition
H
Nu
+
O
O
O
H A
C
C
1
C
2
+
A
+
A
Nu
Nu
Uncatalyzed Acyl Substitution
Nu
+
O
O
O
C
C
1
C
2
Nu
+
Nu
Uncatalyzed Addition-Elimination
H
O
Nu
H
+
O
O
H A
C
C
1
C
2
Nu H
Nu H
3
H O
H
+ H A
C
Nu
4
O
C
Nu
+ H A
Carbonyl Reactions - 5
5
Acid Catalyzed Addition
..O ..
C
+
+
H
H
+
A
Nu:
1
O
C
H
O
+
Nu :
H
A:
+
2
:A
+
Nu
3
.. O
Nu :
2
..
H
+
.. H
+ .O
.
H 3
C
+ Nu
+
H
+
A
Nu
H
Acid Catalyzed Acyl Substitution
H
.. O
+
H
C
..
.+ H
+ H .O
H 1
H Nu:
.. + H
O
C
O
C
+
..O ..
C
H
H
H
. .+
+ H O
H
C
Nu ..
H
4
+
.. O
.. ..
O
C
+
H
Nu ..
H-A & H-B = potential acid catalysts B:- &A:- = potential base catalysts
C
5
H
+
Nu ..
Nu: = Nucleophile
Exploration:
1. Compare each of the reactions on p.1 with its formalized general mechanism on pp. 3-5 and assign the symbols in the general mechanism to
the corresponding component of the reaction.
e.g. For reaction b. – base catalyzed addition (p. 1) – compare with Base Catalyzed
Addition Mechanism on p. 3.
O
C
H
+
H
H-Nu
C
N
H2O B:
H
O
C
C
H
N
6
Carbonyl Reactions - 5
2. Examine the first step of all of the base-catalyzed reactions:
 Where are the HEE in each?
The HEEs are on the base catalyst :B What is accomplished in the first step?
The nucleophile gives up a proton to a case and becomes negatively charged. (Deprotonation of a nucleophile)
3. Examine the first step of all of the uncatalyzed reactions:
 Where are the HEE in each?
The HEEs are on the negative nucleophile.

What is accomplished in the first step?
The arrows are drawn towards the carbonyl carbon. The carbonyl oxygen becomes negatively charged and the nucleophile forms a bond
with the carbonyl carbon.

Where does this first reaction occur in the base-catalyzed mechanism?
On the second step in the base-catalyzed mechanism.
4. Examine the first step of all of the acid-catalyzed reactions:
 Where are the HEE in each?
The HEEs are on the carbonyl oxygen atom.

What is accomplished in the first step?
The carbonyl oxygen receives a proton from a positively charged acid. The oxygen becomes positively charged and the acid becomes
neutral. (Protonates the carbonyl oxygen)

Where does this first reaction occur in the base-catalyzed mechanism?
The third step in the base-catalyzed mechanism for addition and addition-elimination, but nowhere in the acyl substitution.

Where does this first reaction occur in the uncatalyzed mechanism?
The second step in the uncatalyzed mechanism for addition and addition-elimination, but nowhere in the acyl substitution.
Carbonyl Reactions - 5
7
5. Considering your experience with questions 2-4, classify the example reaction from p. 2 (reproduced below) as most likely to be base
catalyzed, acid catalyzed or uncatalyzed, then propose the most likely first step in the reaction. Draw the arrows on the structures and then
draw the structures of the first intermediate products after the equilibrium arrows.
O
O +
NH2
O
6. Again examine the three base catalyzed general mechanisms for carbonyl reactions on p. 3.
 Identify the step where each of the three mechanisms first begins to differ from the others.
The third step in the three mechanisms.

Which mechanism changes path first? What is happening in that step? What structural difference appears to allow this mechanism to
follow a different reaction path from the other two? Explain why the step is reasonable for this reaction and not for the others.
The substitution mechanism changes path first. The heteroatom breaks off on the third step.
The presence/absence of protons (on catalyst) makes the other two reactions different from the substitution reaction.

When do the other two mechanisms begin to change? What is happening in that step? What structural difference appears to be responsible
for this change in mechanism? Explain why the different paths are reasonable for each reaction.
.The fourth step in the three mechanisms.
Negatively charged base is reused in the base catalyzed addition-elimination mechanism.
Nucleophile is being deprotonated/double bond forms between the nucleophile and carbonyl carbon; O-H group breaks off.
Difference: the presence of a hydrogen on a nucleophile in the addition-elimination mechanism.
The NRG difference is acceptable!
7. Now examine the three uncatalyzed general mechanisms for carbonyl reactions on p. 4.
 Identify the step where each of the three mechanisms first begins to differ from the others.
Step two

Which mechanism changes path first? What is happening in that step? What structural difference appears to allow this mechanism to
follow a different reaction path from the other two? Explain why the step is reasonable for this reaction and not for the others.
Uncatalyzed Acyl substitution changes path first.
Green ball breaks off and pi bond is formed between carbonyl carbon and oxygen.
8
Carbonyl Reactions - 5
Structural differences: The presence of heteroatom attached to carbonyl group
The presence of the acidic catalyst.

When do the other two mechanisms begin to change? What is happening in that step? What structural difference appears to be responsible
for this change in mechanism? Explain why the different paths are reasonable for each reaction.
Step 3
Nucleophile protonates the acid; OH breaks off.
Negative A deprotonates the nucleophile.
8. Finally examine the two acid catalyzed general mechanisms for carbonyl reactions on p. 5.
 Identify the step where the two mechanisms first begin to differ. What is happening in that step? What structural difference appears to be
responsible for this change in mechanism? Explain why the different paths are reasonable for each reaction.
Step 4
Carbonyl oxygen forms a double bond while heteroatom group breaks off. (substitution mechanism).
In acid catalyzed mechanism, there is no fourth step present.
9. Review your responses to questions 6-8.
 Is there any pattern in the identity of the reaction that varies first (Addition, Addition-Elimination or Acyl Substitution)? Explain?
Acyl substitution mechanism vary first. That’s the only one that has heteroatom.

Is there any pattern in the aspect of reactant structure that seems to be responsible for this change in path? Explain.
There’s always heteroatom group present (green ball); usually the one that’s attached to carbonyl group. The nucleophile gets substituted
with an heteroatom.

Is there any pattern in the point of variation between the remaining mechanisms? Explain.
It occurs at the point when the HEEs on the carbonyl oxygen are being manipulated: They (HEE) form a bond.

Is there any pattern in the aspect of reactant structure that seems to be responsible for this change in path? Explain.
The absence of protons.
Carbonyl Reactions - 5
9
10. Considering your experience with questions 6-9, continue developing the mechanism of the example reaction (Reproduced below) to
determine the structures of the most likely products. Classify the reaction as an Addition, Addition-Elimination or Acyl Substitution and
identify the step in your mechanism where the type of reaction (the nature of the final product) was determined.
O
O +
O
NH2
10
Carbonyl Reactions - 5
11. Apply your experience in this activity to develop mechanisms for the following reactions, classify the reaction type and identify the step in
your mechanism where the type of reaction (the nature of the final product) was determined.
a.
O
CH3
+
CH3
H
C
H2O
N
CH3
b.
O +
N
H
H
H
O
H
H
N H
H
Carbonyl Reactions - 5
11
Carbonyl Reactions - 5
Out of Class Applications
A. Additional Nucleophiles for Carbonyl Reactions:
1. Organometallic Reagents (See Also CGWW pp. 142-142, 211-212 & 220-224)
Compounds with carbon-metal bonds. Most generally useful reagent includes Mg as the metal.
a. Availability of Reagents:
These compounds can be synthesized by treating organic halides with the free metal:
Organomagnesium Compounds -- Grignard Reagents
CH3
CH
CH3 CH
Cl
+ Mgo
CH3
3
CH3 CH
Mg
CH3
Br
Cl
+ Mgo
Mg
Grignard Reagents
Br
b. Reactivity: In organometallic reagents the highest energy e-'s are those in the partially covalent carbon-metal bond. These e-'s have lower
energy than a free localized carbanion, but have considerably higher energy than a carbanion  to a carbonyl group.
CH3
CH2
Mg
CH3
Br
-
CH2 :
+2
Mg
Br
-
Potential reactions:
(1.) Forming a bond to a proton -- Strong Base – Not very useful
(2.) Addition to a carbonyl carbon atom -- Reactive nucleophile
– very useful!!
O
+
H
Br
Mg
1.
Dry
Ether
2.
-O
2+
Mg Br
Dilute
H2SO4 H2O
O
H
+
2+
Mg +
Br
-
12
Carbonyl Reactions - 5
2. Metal Hydrides: CGWW pp. 139-142, 355-356.
a. Reagents and Reaction Conditions:
(1.) NaBH4 + H2O
(2.)
LiAlH4 + (1. Ether
2. H3O+/ H2O)
b. Reactivity: Both react as H: - nucleophiles or bases. In both types of hydride reagents the highest energy e-'s are those in the partially
covalent hydrogen-metal bond. As with Grignard reagents, these e-'s have lower energy than a free localized hydride ion, H: - , but have
considerably higher energy than electrons on negatively charged nitrogen or oxygen atoms.
Compared to the larger aluminum atom, the smaller boron atom provides more e--nuclear attraction to lower the energies of the e-'s in the
B-H bond so:
(1.) NaBH4 The B-H bonding e-'s have low enough energy that NaBH4 can be used in the presence of H2O or ROH. The acid-base
reaction between NaBH4 and H2O or ROH is slow enough that it doesn't out compete with the NaBH4 reactions with carbonyl
compounds. H2O or ROH can then act as proton sources for the alkoxide ion formed in the addition reaction.
Example: See Class Group Activity # 15, reaction l.
(2.) The Al-H bonding e-'s have high enough energy that LiAlH4 reacts very rapidly with acidic protons of water, alcohols or amines. So
LiAlH4 addition reactions must be done in the absence of acidic protons (H2O, ROH, RNH2 or RCOOH). The proton for the alkoxide
ion formed in the reaction is supplied by acid added in the second step.
H
O
C
+
H
H Al H + LiH
H
1.
Dry
Ether
O
Li
C
+
H
H
2.
H
Al H Dilute
H2SO4 H2O
H
O H
C
H H
H
+
H Al OH
H
a. Wittig Reagents -- Phosphorus Ylides (See CGWW pp. 357-358 & 814-815)
b. Structure
These compounds contain a polarized carbon-phosphorus double bond with the phosphorus having an expanded octet. Such compounds
with positive phosphorous or sulfur atoms bonded to negative carbon atoms are known as ylides.
P
C
CH2 CH3
H
P
+
CH2 CH3
CH
P
C
CH2 CH3
P
+
CH2 CH3
C -
Carbonyl Reactions - 5
13
c. Reactivity: The highest energy e-'s are those in the C-P bond, which is polarized toward the carbon atom. Consequently Wittig reagents are
carbon nucleophiles and phosphorus electrophiles.
NOTE: Since P is in the Third Row of the Periodic Table, it has low energy d-orbitals that allow it to expand its octet and form 4membered ring transition-state and intermediate structures.
O
O
P
P
+
P
O
+
B. Applications:
Applications of carbonyl compound reaction mechanisms for predicting products from reactant structures and reaction conditions.
Use the approach you developed in Carbonyl Reactions-5 to develop reaction mechanisms and predict final products for the following reactions.
O
-O
(1.)
CH 2

O
(2.)
CH 3
O
+
Mg
O
1. Dry Ether
Cl
2. H3O+ H2O
O
(3.)
(4.)
Cl +
O
NaBH4
+
H2O
excess
Mg
+
O
excess
1. Dry Ether
Br
2. H 3O+ H 2O
H
(5.)
14
N
+
O
(6.)
O
Carbonyl Reactions - 5
H3O+
O
H2O
-
OH
H2 O
Text Applications of Carbonyl Reactions:
 References:
CGWW Chapters:
6, 10, 12, 13, 14, 27, 28 & 29
 Appropriate Questions:
Chapter 6: Problems 6-8 & 10, Chapter 10:
Problems
4 & 5, Chapter 12: Problems
2-7 & 9-11
Chapter 14: Problems 1-3, 5-7, 10-12, Chapter 27: Problems
1, 2 & 14, Chapter 29:
Problems
5, 6, 8 & 12
B. Nomenclature of Amides
References:
1. CGWW: pp. 37-44
2. Tutorials:
a.
http://chemistry.boisestate.edu/people/richardbanks/organic/nomenclature/organicnomenclature1.htm
Section
Amides
Developed by Richard C. Banks, Professor of Chemistry, Boise State University
Provides questions with answers
b. http://www.molecularmodels.ca/nomenclature/index-2.htm
Developed by Professor Dave Woodcock,
Okanagan University College, British Columbia, Canada
(Contains many examples.)
Sections:
5. Functional Groups with Suffix and Prefix
VI. Alkanamides (Amides)
c. http://www.acdlabs.com/iupac/nomenclature
Developed by Advanced Chemistry Development Laboratories
(Gives detailed rules for nomenclature.)
Recommendations 1993
Carbonyl Reactions - 5
R-5 Applications to Specific Classes of Compounds
R-5.7 Acids and Related Characteristic Groups
R-5.7.8 Amides, imides, and hydrazides
R-5.7.8.1 Monoacyl derivatives of ammonia (primary amides
3. Applications
a. Name the following:
H
O
N
O
H2N
H
O
N
N
O
b. Draw structural formulas for the following compounds:
N-(2-butyl)-2-methylpentanamide
N-ethyl-2-hydroxy-3-methylbutanmide
N-propylbenzamide
2-chloro-4-ethylhexanamide
15