REACTION SITE SELECTION IN CARBONYL COMPOLINDS

by Dr. Donna
J.
Nelson
Tel.
(405)321-1309
The reactions of carbonyl compounds are some of the most confusing reactions of organic chemistry. This is because there
are four possible sites at which reactions can occur in these compounds, often with each site yielding different types of
products in different types of carbonyl compounds. Moreover, reactions at these sites are in competition with each
other, which makes the reactions of carbonyl compounds more difficult to learn.
First, it is essential to learn the four sites, which are identified and
discussed below. The dashed line in between the two terminal carbons is
meant to indicate that there may or may not be a double bond there. If
there is a single bond, abstraction of a proton at position 3 by a base is
possible and attack at position 4 is not. If there is a double bond, attack at
position 4 by a nucleophile is possible and attack at position 3 is not.
4- - - +
3-------) H
o H + 2
Thc'possible types of reactions at each of the sites are given below. Generally, the method used to divert the reaction to
one of the reaction sites other than the carbonyl C=O
(which is considered the default reaction) is to use a reactant
which is selective for a different site. The reaction positions and the reactants used to select them are reviewed on the
SUMMARY SHEET
(page
3), and the logic behind the selection process is outlined in the DECISION TREE (page 4).
l. ATTACK AT C=O. Reaction at position 1 will involve attack upon the carbon atom of the carbonyl group by a
nucleophile and is considc.red the default reaction. Generally, this will lead to addition in the case of aldehydes
R'(C=O)H and ketones R'(C=O)R, and to substitution in carboxylic acid derivatives which have a good Leaving Group
R'(C=O)LC. Whether addition or substitution is undergone, the first step in the mechanism is attack by Nu- at the
carbonyl carbon.
H, R"LG -------->
Ho r R
/
g;rrcr aildit t^
/
(add H+)
/
o H /
I
to
r,.,*,
I
eliminaticm
|
(lose LG)
Y
o
r.' H, R
Nu
\,,\N'
Tl're course of the second step is determined by the groups on the carbonyl. If both groups is H or R
(if
the carbonyl
compound is R'(C=O)H or R'(C=O)R), then the intermediate in which oxygen bears a negative charge will not react
iurther, and usually dilute acid will be added to protonate the intermediate, yielding the alcohol; the overall reaction
is addition across the carbonyl. lf at least one group is a leaving group, such as Hal, OAc, OR, or in some cases NR2,
then the intermediate in which oxygen bears a negative charge is not stable. Then the leaving group is eliminated or
lost; thc overall reaction is a substitution reaction in which Nucleophile Nu has been substituted for Leaving Group LG.
ln summary, the reaction observed from attack at position 1 will be:
(1)
addition to R'(C=O)H or R'(C=O)R, and
(2)
substitution R'(C=O)LC where LG is a leaving group, such as Hal, OAc, OR, or in some cases NR2.
2. ACID PROTON ABSTRACTION. Reaction at position 2 involves proton abstraction by a base upon a carboxylic
acicl or an amide. The acidic proton is so rcactive under neutral or basic conditions that this is the site of the reaction.
a. A carboxylic acid
(R'COOH)
has a pKa of about 4.8; a weak base such as NR3 is strong enough to deprotonate
it. Since this site is so reactivc, this means that there will be little competition due to proton abstraction at position 3
or nucleophilic attack at positions 1 or 4. (However, under acidic conditions, attack at C=O is possible).
Phone 405-325-2288
or*/,-->
An amide
(R'CONH2) has a pKn of approximately 15.0; a stronger base is necessary for deprotonation. While it can
undergo deprotonation similarly to the carboxylic acid, it is less acidic, and stronger bases are required. This leads to
the possibility of competing reactions. The proton at position 2 is much more acidic
(pQ -15.0)
than that at position 3
(pKn -19.0)
so proton abstraction at position 3 should not give competition, but the stronger base required for proton
abstraction at position 2 of an amide could also act as a nucleophile and attack at position 1 or at position 4 (if
the
compound is an cr,B-unsaturated carbonyl).
b. There are a few additional reactions, such as those of anhydrides and carbamates, which also provide the
stable leaving group R'COO- or a similar moiety. Examples of a typical first step in the mechanism for each are shown
bel ow.
o
\ J, ] . n
- N-
- O_ l / _ Du
R
3. u-PROTON ABSTRACTION. If one group attached to the carbonyl is Ot{" NR2, R, or H and the other group has an
o.-proton, the compound can give abstraction of the proton via the mechanism shown below. This usually requires a
basc which is strong and/or very hindered sterically. Here, the reactant is a base which will deprotonate rather than
do a nucl eophi l i c attack.
\s
H
Othcr groups on such a carbonyl generally yield different reactions: OH and NH undergo deprotonation at O and N
respectively (position 2), as discussed in part 2 above; carboxylic acid halides and anhydrides are so reactive that they
usually undergo substitution of Hal or OAc in which the base behaves as a nucleophile to attack at the carbonyl carbon
(position
1), as discussed in part 1 above. Esters and amides are unreactive enough that they can survive this
dcprotonation at position 3
(since usually a base, which is not a good nucleophile, is used) leaving the COOR or CONR2
group intact. A common additional precaution is to use a base identical to the potential leaving group
(i.e., -OR-
to
cleprotonate R'COOR) so that even if substitution competes, it makes no practical difference.
4. ATTACK AT
B-CARBON.
lf the compound is an o,
B-unsaturated
carbonyl, attack at C=C, the
"soft"
(low
charge
clensity) end of the n system, will be obtained with a soft Nu-. However, if the soft Nu- reacts with an o,,
B-unsaturated
carboxylic acid derivative, the acid derivative is usually reactive enough to cause attack at the carbonyl, as discussed
in part 1 above. The C=C double bond is esser-rtially ignored.
A
"hard"
(high
charge density) Nu- will give addition or substitution directly at C=O
(the hard site in the n system)
in aldehydes and ketones, as well as carboxylic acid derivatives, as discussed in part L above, again essentially
i gnori ng the C=C.
OR, NR2 & H
1700 Winding Itidgc I{oad, Norman, OK 73072
Cff
@1.996.7999Dr. Donna T. Nelson
DECISIONTREE
o
"\oA-*
ti
DEPROTONATE AT N OR O
B
io-
I
o
t l
i*"
I
o
il
i**
I
DEFAULT FGACTION
(ATTACK
AT C=O)
ATTACK AT G POSITION
o
t l
*"-ji1*'"
DEPROTONATE a PROTONS
o
t l
--
R,H,OR,NR'
I
At each decision diamond, the structural
features and the reaction conditions which
must both be met in order to deviate from the
default reaction are given.
@1996,1999 Dr. Donna J. Nelson
X=OH,NHR,NHT;
a,B-UNSATURATION)
Nu
(Mow charge
concentration)
X=R,H,OR,N&
a-PROTONS; BASE
SUMMARYSHEET
| .
Attack at C=O
o
t l
alR,H,LG
, l
01996, 1999. Dr. Donna J. Nelson
Ttre mechanism at the left is the default reaction.
The following entries are examples of the basic
ways to divert from the default reaction.
examples explanation
C-arborylic acid deprotonation
o
acidic conditions
give attack at C=O
5.
91,
-Proton
abstraction
H\
l l
n) AoH
: B- -
I
A
basic conditions
I
t*" be weak)
o
"\A
H1
H\
l l
"?
R,H,oR,NR2
t
4. Aftack at
p-carbon
NH^
->
H * >
-Hzo
- oH
>
R' Li
-+
RLi
+
o-
+NH4
R,H,OR,NR2
\<
o
4
: B-
(strong
bar-/
bulkiness helps)
/o
R,H,OR,NR2
/ R '
o
t l
t-
t
ReCuli
+
o-
I

I
R/
o-
-'+\
l l R
rD 0
protons,
+
Nu-, or weak base
gives attack at CO
Nu
(lowchargeconc.);
attacks low charge end
Nu-
(highcharge conc.);
gives attack at CO;
attacks high charge site