Chemistry 212
Fall 2013
Carbonyl Reactions - 10
Summary of Class Discussion
Mechanisms for Substitution for an -Atom group in Carbonyl Compounds:
N-H -bond broken
4 O
i.
C
CH3 2
Cl
+
1
3
C-Cl -bond broken
5
CH3CH2NH2
4 O
HEE
C-N -bond made
C
CH2CH3 + Cl 3
2
N
+ 5
N-H -bond made
H CH3CH2NH3
6
CH3
1
6
CH3CH2NH2
N-H -bond made
-> WHAT OVERALL CHANGE OCCURS (Bonds made and
broken)? Illustrate on the given structures.
->
WHERE ARE THE HIGHEST ENERGY ELECTRONS?
Circle on original structures.
-> WHAT BOND CAN THE HIGHEST ENERGY ELECTRONS MAKE TO MOVE THE STRUCTURE OF THE ATOM HOLDING
THEM TOWARD ITS STRUCTURE IN THE PRODUCTS? Propose a reaction step with original structures using arrows. Write
intermediate product structures below:
Proposed First Steps
CH3CH2
The most obvious step for HEE on N5 is to make the C2-N5
5
HEE
O 4
6
-bond (Step A1), a bond that is present in the products; this
N
H
5
O
+
CH
CH
NH
is the first step in uncatalyzed addition and addition
+
CH3CH2NH2
3
2
2
C
4
C H
CH3 2
elimination mechanisms and moves HEE from neutral N5 to
Step A1 HEE
Cl
+
2 Cl 3
CH3
6
1
3
negative O4, a reasonable increase in energy. (~6 pK units)
1
CH3CH2NH2
A second option suggested was to use one ethylamine
molecule to remove a proton from the other (Step A2), again
this is a bond that must be broken to reach the products; this
is the first step of base catalyzed addition, additionelimination and acyl substitution mechanisms. However this
moves HEE from neutral N5 to negative N5, large increase in
energy. (~27 pK units)
A third option discussed was to use an ethyl amine molecule
to protonate the carbonyl oxygen, O4 (Step A3), again this
removes a proton from N5; this is the first step of acid
catalyzed addition, addition-elimination and acyl substitution
mechanisms. However this again moves HEE from neutral
O4 to negative N5, another large increase in energy.
O 4
CH3
1
C
2
Cl
+
3
O 4
CH3
1
C
2
5 HEE
CH3CH2NH2
Step A2
6 H
CH3CH2NH
O 4
CH3
1
5 H
CH3CH2NH
+
3
Step A3
6
CH3CH2NH2
CH3
1
Cl
+
3
O
HEE
Cl
C
2
5
CH3CH2NH
C
2
CH3CH2N
6
H
H
H
H
4
5
CH3CH2NH
Cl
HEE
HEE
+
3
6
CH3CH2NH2
Carbonyl Reactions – 10
2
Choice of Most likely First step
As we discussed in class, Step A1-results in an acceptable
energy increase for HEE. The other two options we
HEE
O 4
5
5
could find, created the negative on N on a structure with
CH3CH2NH2
C
no electron withdrawing inductive effects, which would
2
CH
Step A1
Cl
3
+
have higher energy than O4- in the products of Step A1.
6
1
3
So this mechanism begins with an uncatalyzed addition.
CH3CH2NH2
HEE are now on the negative oxygen, O4, created in
step A1. The most productive bond for the HEE on O4
to make is to reform the -bond with C2. This will also
lead to elimination of Cl3 (Step B1). At first, this step
seemed to be unlikely since it might be more likely that
reformation of the C=O bond would lead to loss of a
neutral ethylamine molecule (Step B2) rather than a
negative chloride ion. However when we considered
that the pKaH for Cl- (pKa of H-Cl) is about - 6 and that
for N5 is about 10, we decided that Step B1 is actually
the better & more productive next step.
CH3CH2
HEE
O
4
CH3
C
2
H
5
6
N
H
+ +
CH3CH2NH2
Cl 3
CH3CH2
HEE
CH3
1
HEE
O
4
CH3
1
C
2
N
5
6
H
+ + CH3CH2NH2
C H
2 Cl 3
4 O
Step B1
CH3
1
CH3CH2
-
O
4
C
5
2
N
+
+
H
CH2CH3 + Cl
H
6
CH3CH2NH2
-
3
HEE
4 O
5 H
N
H +
Cl 3
6
CH3CH2NH2
Step B2
CH3
1
C
2
+
H
Cl
3
5N
+
CH2CH3
HEE
H
6
CH3CH2NH2
Step B1 places HEE on neutral N6. They can complete
4 O
4 O
the reaction by removing the most acidic proton from
C
CH2CH3 + Cl 4
C
Step C
CH2CH3 + Cl 3
positive N5.
2
2
CH3
O
3
CH3
5O
+ 5+
+
Again in this reaction, we see the substitution for the
H
+
1
1
CH3CH2OH 6
-atom group occurring through an addition to the
CH
CH
OH
HEE
3
2
2 6
carbonyl, Step A1, and subsequent elimination of the
-atom group, Steps B & C. Since there is no proton
transfer before the addition step, this mechanism is
considered an Uncatalyzed Acyl Substitution
Mechanism
NOTE: As mentioned earlier in class, these reactions which we have descriptively termed “substitution for the  –atom group” are generally
referred to as
ACYL SUBSTITUTION REACTIONS or SUBSTITUTION AT ACYL CARBON.
The carbon of a carbonyl group is called an acyl carbon atom while saturate carbon atoms are called alkyl carbons.
3
Complex Equilibrium Controlled Reactions
CGA 17
Comparison of Mechanisms in Carbonyl Reactions 8, 9 and 10
Draw the mechanisms for the reactions explored in carbonyl Reactions 8, 9 and 10 using the starting materials provided below:
Carbonyl 8: Base Catalyzed Acyl Substitution
H
7
H
h.
HEE
O
9 OCH3
H
8
5 6 O CH3 HEE
Step A
Carbonyl 9
1
7
2 O4 CH3 HEE
Addition
12
8
5 6 O CH3
Step B
9
O
O
CH3
6 O8
5
Step C
9
4 .. .
O.
C .. + H
2 NH 3
2
..
H2O
.. 5
H2O 6
+
O
5 H
H
HEE
H
CH3
1
Step A1
Step B1
H
H
5
.O.
C ..
Addition
2 NH
2 3
CH3
1
C
2
5 .. O
+
4 +
O..
.. 4
O
..
.. 3
HEE
NH2
OCH3
+
H
H
Step F
..
CH3
1
+ NH3 3
O
4 ..+
Step E
CH3
1
C
2
HEE
H
+ H
H
H
+
NH3
3
4
O
.. H
H
Step D
CH3
1
+
O
7 H
H
..
+ O5 H
C
2
..
+
NH3
3
4
O
.. H
+
H2O
.. 7
HEE
..
O
4 ..
C
2
H
7
+
..O
Step C
..
+ NH4
CH
3 + 4
O
5 6 8 HEE
9
H
O5 H
..
5 .. O
..
..
3
7
O
+ HOCH3
..
C
2
3
f. Acid Catalyzed Acyl Substitution
ACIDIC CONDITIONS
1
CH3
1 2
+ HOCH3
+ HOCH3
HEE
CH3
1
4 CH3
O
O
O7
3
3O
Carbonyl 10 Uncatalyzed Acyl Substitution
O 4
i.
CH3
1
C
2
CH3CH2
HEE
5
CH3CH2NH2
Cl
6
+ CH3CH2NH2
3
Step A1
HEE
O
4
CH3
C
2
H
5
6
N
H
+ +
CH3CH2NH2
Cl 3
4 O
Step B1
CH3
1
C
2
O
+ 5+
HEE
CH3CH2OH 6
4 O
CH2CH3
H
Step C
-
+ Cl 4
3
C
CH2CH3
2
CH3
O
5
1
+
+ CH3CH2OH2 6 + Cl 3
Carbonyl Reactions – 10
4
Are there any similarities in the mechanisms you devised for the three reactions in Carbonyl Reactions – 8, 9 and 10 and how are they
different? Provide your warrant.
Similarities:
All involve a nucleophile adding to a carbonyl carbon to yield an addition intermediate (tetrahedral carbon with three heteroatoms). The Addition
intermediate eliminates the original a-group. They also all involve proton transfer steps to help control the energies of the HEE.
Differences:
The number and order of reaction steps varies since the HEE do not always start on the nucleophile that must add. Reactions under basic conditions
(higher energy HEE) require the fewest steps and those under acidic conditions require the largest number of steps.