Chemistry 211
2013
Equilibrium Controlled Reactions:
Carbonyl Reactions - 11
A. Original Reactions:
In the Carbonyl Reactions-3 through -10, we have explored fifteen examples of three general types of reactions 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-3-10.
1. Carbonyl Addition Reactions.
2. Carbonyl Addition-Elimination Reactions.
Acid-Catalyzed
Uncatalyzed
O
a.
C
CH3
H3O
+
+
H
O
H
CH3
CH3
CH3
Base-Catalyzed
C
H
H2O
+
H
H
C
N
O
C
C
N
C
CH2
O
H
+ H2O
CH3
j.
CH3
CH3
H2O
HN
H
C
H2O +
+
C
CH2
N
N
H
H
NH3
Base-Catalyzed
O
CH3
CH3
NH3OH
HN
CH2
Base-Catalyzed
CH2
CH3
NH2
O
H
d. 2
H2O
.
+ NH2OH
C
CH2
N
Uncatalyzed
O
b.
O
c.
C
H2O
CH3
O
H
OH
C
H
H2 O
CH3
CH
CH2
m.
C
CH2
CH3
+
C
CH2
H
O H
CH2
CH3
O
H
O
O
O
C
CH2
H
CH2
O
C
CH2
H
H
H2O
D
C
CH2
CH3
CH2
C
H
C
+ H 2O
CH3 CH2
CH3 CH2
Uncatalyzed
Base-Catalyzed
H
O
k.
+
C
H
Cl
H
O O
O
O ..
S O
C
Cl
S
n.
O
O
O
+
C
O + H2O
OH
D
H
H O
Base-Catalyzed
Uncatalyzed
N
l.
H2O
O
+ H
C
C
N
o.
O
H
O
C
N
H2O
C
+ NH2OH
CH3
NH3OH
CH3
H
O
+ H2O
2
Carbonyl Reactions – 11
3. Acyl Substitution Reactions.
Acid-Catalyzed
f.
Base-Catalyzed
O
O
C NH + H3O
2
C
O
+
O
H + NH4
C
2
h.
O
OCH3
CH3
O
O
C
C
CH3
O
+ HOCH3
Acid-Catalyzed
Uncatalyzed
O
O
p.
O
H3O
H +
+ H2O
O
r.
OH
O
O
O
CH3 C
O
+
H
CH3O
CH3 C
+
C
O CH3
CH3OH
H
C
O
O
Uncatalyzed
O
O
i. CH3
C
H
Cl
+
2 CH3CH2N
H
CH3
CH2
C
+
Cl
N
CH3
H
+ CH3CH3NH3
So far we have been working with reactions that provide structures of products as well as structures of 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 we discovered 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 reactions like the example above.
Carbonyl Reactions - 11
3
General Mechanisms for Reactions of Carbonyl Compounds
= H or a carbon atom group
Nu: = Nucleophile
= group with O, N, Cl, Br
H-A & H-B = potential acid catalysts B:- & A:- = potential base catalysts
Base Catalyzed Addition
H
B
Nu
H
1
O
O
Nu
+
H B
C
C
2
O
C
3
+
B
+
B
Nu
Nu
Base Catalyzed Acyl Substitution
B
Nu
H
1
Nu
+
O
O
O
C
C
2
C
3
Nu
+
Nu
Base Catalyzed Addition-Elimination
H
H B
Nu
H
H
B
1
Nu
H
+
O
O
O
H B
C
C
2
C
3
Nu H
Nu H
4
H O
H
+ H A
C
Nu
O
C
5
Nu
+ H B
4
Carbonyl Reactions – 11
O
O
Nu
+
Uncatalyzed addition
H
O
H Nu:
C
2
C
C
1
H
Nu
H
+
Nu
H
Nu:
O
C
3
Nu:
H
Uncatalyzed Acyl Substitution
Nu
+
O
O
O
C
C
1
C
2
Nu
+
Nu
Uncatalyzed Addition-Elimination
H
Nu
H
+
O
O
O
H A
C
C
1
C
+
A
2
Nu H
Nu H
3
H O
H
+ H A
C
Nu
4
O
C
Nu
+ H A
+ Nu
H
Carbonyl Reactions - 11
5
Acid Catalyzed Addition
..O ..
C
+
+
+
H
H
A
Nu:
1
H
O
C
+
Nu :
H
+
A:
2
Nu
C
3
Nu :
2
.. O
..
H
+
.. H
+ .O
.
H
C
+ Nu
+
H
A
Nu
H
Acid Catalyzed Acyl Substitution
H
.. O
+
H
+
:A
+
..
.+ H
+ H .O
H 1
H Nu:
.. + H
O
C
O
C
+
..O ..
C
H
O
H
. .+
+ H O
C
3
H
H
Nu ..
H
4
+
.. O
.. ..
O
C
Nu: = Nucleophile
+
H
C
5
Nu ..
H
+
Nu ..
H-A & H-B = potential acid catalysts B:- &A:- = potential base catalysts
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 – 11
2. Examine the first step of all of the base-catalyzed reactions:
 Where are the HEE in each base catalyzed reaction on pp. 1 & 2?

What bond is made by the HEE in the first step of the corresponding base catalyzed general mechanism for each reaction (p. 3)?
3. Examine the first step of all of the uncatalyzed reactions:
 Where are the HEE in each uncatalyzed reaction on pp. 1 & 2?

What bond is made by the HEE in the first step of the corresponding uncatalyzed general mechanism for each reaction (p. 4)?

Where does the uncatalyzed catalyzed reaction’s first reaction step occur in the base-catalyzed general mechanisms (p. 3)?
4. Examine the first step of all of the acid-catalyzed reactions:
 Where are the HEE in each acid catalyzed reaction on pp. 1 & 2?

What bond is made by in the first step of the corresponding acid catalyzed general mechanism for each reaction (p. 5)?

Where does the acid catalyzed reaction’s first reaction step occur in the base-catalyzed general mechanisms (p. 3)?

Where does the acid catalyzed reaction’s first reaction step occur in the uncatalyzed general mechanisms (p. 4)
Carbonyl Reactions - 11
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; provide your warrant for your choice of
mechanism and first step. 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 one of the three mechanisms first begins to differ from the others two. Provide your warrant for the choice

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? Provide your warrant for the choice of mechanism and why the step is reasonable for
the reaction that changes path and not for the others.

In which step do the other two mechanisms begin to diverge? What is happening in that step? What structural difference appears to be
responsible for this change in mechanism? Provide your warrant for your choice of step and why the different paths are reasonable for
each reaction.
7. Now examine the three uncatalyzed general mechanisms for carbonyl reactions on p. 4.
 Identify the first step where one of the three mechanisms first begins to differ from the others. Provide your warrant for the choice


Which mechanism changes path first? What is happening in that step? What structural difference appears to allow the mechanism that is
changing to follow a different reaction path from the other two? Provide your warrant for the choice of mechanism and why the step is
reasonable for this reaction and not for the others.
In which step do the other two mechanisms begin to diverge? 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.
8. Finally examine the two acid catalyzed general mechanisms for carbonyl reactions on p. 5.
8

Carbonyl Reactions – 11
Identify the step where the two mechanisms first begin to diverge. What is happening in that step? What structural difference appears to
be responsible for this change in mechanism? Provide your warrant for the choice of step why the different paths are reasonable for each
reaction.
9. Review your responses to questions 6-8. (Base catalyzed, uncatalyzed and acid catalyzed mechanisms.)
 Among all mechanistic types, is there any pattern in the identity of the reaction that diverges first (Addition, Addition-Elimination or Acyl
Substitution)? Provide your warrant.

Is there any pattern in the aspect of reactant structure that seems to be responsible for this first change in path? Provide your warrant.

Is there any pattern in the point of variation between the remaining mechanisms? Provide your warrant.

Is there any pattern in the aspect of reactant structure that seems to be responsible for the divergence in path? Provide your warrant.
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. Provide your warrant.
O
O +
NH2
O
11. Apply your experience in this activity to first develop a series of questions to consider in discovering a reasonable mechanism and then
applying the questions to develop reasonable mechanisms for the following reactions, classify the catalytic type (acid, base, un) and reaction
Carbonyl Reactions - 11
9
type (addn, addn-elim, acyl-sub) and identify the step in your mechanism where the reaction type (the nature of the final product) was
determined.
Question 1:
Question 2:
Question 3:
a.
O
CH3
+
CH3
H2O
H
CH3
Answer to Question 1:
Answer to Question 2:
Answer to Question 3:
Completed mechanism:
b.
C
N
10
Carbonyl Reactions – 11
H
O +
N
H
H
O
H
H
N H
H
Answer to Question 1:
Answer to Question 2:
Answer to Question 3:
Completed mechanism:
Reflector’s Report Discussion:
Identify the most important concepts you learned from this activity:
What questions remain?
Carbonyl Reactions - 11
11
Strategy Analyst’s Report Discussion:
How did grouping the mechanisms with various types of catalysis for the three different carbonyl reactions help your group to begin to develop
an approach for using mechanisms to predict products of reactions?
How did the series of questions developed in #11. assist your group in working a new reaction through a mechanism to a reasonable product?
12
Carbonyl Reactions – 11
Carbonyl Reactions - 11
Out of Class Applications
A. Additional Nucleophiles for Carbonyl Reactions:
1. Organometallic Reagents (See Also CGW pp. 132-133 & 182-185 & 189-194)
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
Br
Grignard Reagents
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.
+2
CH3
CH2 : Mg Br
CH3
CH2 Mg
Br
Potential reactions:
(1.) Forming a bond to a proton -- Strong Base – Not very useful
(2.) Addition to a carbonyl carbon atom – High energy HEE, effective nucleophile (uncatalyzed)
– very useful!!
O
+
H
Br
Mg
1.
Dry
Ether
O
2.
-O
2+
Mg Br
Dilute
H2SO4
H
+
H2O
2+
Mg +
Br
-
Carbonyl Reactions - 11
13
14
Carbonyl Reactions – 11
2. Metal Hydrides: CGW pp. 130-132, 530-534.
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.) In 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:
+
C
H
O H
CH3 CH2
H
O
H B H + Na
H
O Na H
C
+
B H
H
H
H
O H
C
H H
H
+
CH3CH2O B H
H
(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.
Example:
O
H
+
C
H
H Al H + Li
H
1.
Dry
Ether
O
Li
C
+
H
H
H
2.
Al H Dilute
H
H2SO4 H2O
O H
C
H H
H
+
H Al OH
H
Carbonyl Reactions - 11
15
3. Wittig Reagents -- Phosphorus Ylides (See CGW pp. 237-238 & 689-693)
a. 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.
CH2 CH3
P
+
P
C
H
CH2 CH3
CH2 CH3
CH
P
+
C
P
CH2 CH3
C -
b. Reactivity: The HEE 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
4-membered ring transition-states and intermediate structures.
O
O
+
P
P
P
O
+
The net effect of a Wittig reaction is an addition-elimination in which the carbon ligand on the phosphorus replaces the carbonyl oxygen
atom and the carbonyl oxygen atom replaces the carbon that was attached to the phosphorus of the Wittig reagent. So a ketone is
converted to an alkene.
16
Carbonyl Reactions – 11
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-11 to develop reaction mechanisms and predict final products for the following reactions.
O
-O
(1.)
CH2
CH3
D
O
O
(2.)
+
1. Dry Ether
Mg
O
Cl
2. H3O H2O
O
(3.)
Cl
H2 O
+
O
(4.)
Br
excess
O
2. H3O+ H2O
H
(5.)
N
+
O
(6.)
1. Dry Ether
Mg
+
H3O+
O
H2O
NaBH4
H2O
Text Applications of Carbonyl Reactions:

References:
CGW
Chapters:
6, 10, 11, 26 & 29
CGW ONLINE http://www.oup.com/uk/orc/bin/9780199270293/:
Chapter 6: Problems 1, 6-8 & 10; Chapter 10:
Problems
2-4, 6-7-9, 11-12;
Carbonyl Reactions - 11
Chapter 11: Problems
1-3, 5-7, 9; Chapter 26:
Problems
17
1, 2
18
Carbonyl Reactions – 11
B. Nomenclature of Amides
Tutorials:
a.
http://chemistry.boisestate.edu/people/richardbanks/organic/nomenclature/organicnomenclature1.htm
Developed by Richard C. Banks, Professor of Chemistry, Boise State University
Provides questions with answers
Section
Amides
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
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
H
O
N
N
H 2N
O
O
b. Draw structural formulas for the following compounds:
N-(2-butyl)-2-methylpentanamide
N-ethyl-2-hydroxy-3-methylbutanmide
Carbonyl Reactions - 11
N-propylbenzamide
2-chloro-4-ethylhexanamide
19