Summary Sheet: Two Key Concepts for Nucleophilic Substitution on Carbonyls plus a third bonus concept.

Predicting the rate of reaction at a carbonyl and the fate of the resulting tetrahedral intermediate depend on understanding two key concepts: 1. The electronic nature of the atoms adjoining the carbonyl. 2. Steric bulk around the carbonyl.

Key Concept #1: The importance of electronic factors
The presence of donating groups makes the carbonyl carbon less electrophilic and
Take the simplest carbonyl: formaldehyde the carbonyl oxygen more nucleophilic. Recall these resonance forms
It undergoes one type of reaction: nucleophilic addition. O O O O
Key concept #2: The importance of steric factors
Formaldehyde again: as the hydrogens are replaced with progressively
O O bulkier groups, the reaction rate goes down.

O O M O O O O
δ OH OH OR OR NH2 NH2
Nu M > > >
H H H Nu The carbonyl is the most nucleophilic (and Lewis basic) site. Therefore, it is protonated first. H H H CH3 H3C CH3 H3C t-Bu
H
δ slower rate of reaction with nucleophiles
A good proxy for donating ability is pKa, especially when the atom attached
What happens when you substitute one of the hydrogens to the carbonyl is the same. increasing steric hindrance adjacent to the carbonyl
on formaldehyde for a different functional group?
Example:
O X= OH, OR, OAc, NH2, NHR, NR2, NHAc, Cl NO2
Cl, Br, I, CH3, R, CCl3, SR, etc. O O O O Why? Recall the antibonding (π*) orbitals of the carbonyl group.
H X
The rate of the reaction will depend on two key factors. Me OMe Me O Me O Me O O The alkyl groups stand in the way of the trajectory of the
C nucleophile toward the carbonyl's empty π* orbital.
increasing susceptibility toward nucleophilic attack
1) Electronegative functional groups make the carbonyl carbon
more electropositive, which increases the rate of reaction with 9.4 7 Nucleophile attacks here
nucleophiles. pKa of ~16 10
alcohol The same concept applies for the rate of reaction of nucleophiles with esters and
O O O O amides:
< < <
H CH2I H CH2Br H CH2Cl H CH2F The tetrahedral intermediate can undergo further reaction O O Me O O Me
Me
> >
Increasing reaction rate w/ nucleophiles Me NMe2 Me N Me Me OMe Me O Me
O O M O
Nu M
2) Donation of π-electrons by the X group makes the carbonyl H X H Nu H Nu Me Me
carbon less electropositive, which decreases the rate of reaction X –MX
with nucleophiles. faster slower faster slower
How can you predict what will happen?
O O O O
Leaving group ability is directly related to the pKa of
H Cl H Cl H NMe2 H NMe2 the conjugate acid. A final important concept.: Lewis acids make carbonyls more electrophilic
Cl is poor π-donor NMe2 is strong π-donor I > Br > Cl > OAc > OAr > OH*, OMe > NRAc > NR2 > H > CH3, R H H
relatively unimportant this is an important good these groups O O X– O Lewis acid promotes greater
resonance form resonance form moderate poor H+X–
never leave contribution from this more
–11 –9 –7 4 10 15 17 35 ~40 ~50 H R H R H R reactive resonance form
Does this discussion seem familiar from electrophilic aromatic
substitution? It should! It's the same principle! X–
Recall from electrophilic aromatic substitution:
pKa of conjugate acid
For example, in the Fischer esterification, the first step is protonation of the carboxylic acid:
Strongly activating Moderately deactivating *remember, however, that under basic conditions OH will be O– which
NH2, NHR, NR2, OH, O CO2H, CO2R, CN means it would have to leave as O2–: an extremely bad leaving group O OH O
CHO, COR H+X– not
Moderately activating Advice: Know your pKa's cold. They are a great measure of leaving group H
ability and also of the electron donating ability of the conjugate base,
OH OH X–O X–
NHCOCH3, NHCOR, OCH3, OR Strongly Deactivating*
CF3, CCl3 which comes up again and again when discussing chemical reactivity. H
Weakly activating The protonated carbonyl, which is now more electrophilic, reacts with the relatively weak
CH3, C2H5, R, C6H5 *I left off NO2 and SO3H, which are nucleophile, the alcohol:
important in electrophilic aromatic
Weakly Deactivating* substitution but not here; Aldehydes and ketones: OH X– H OH OH2 X– OH X–
ROH
F, Cl, Br, I in general, carbonyl groups attached to R' RO RO
deactivating due to these functional groups are too O OH N promoted Me OH X– OH OH RO Me
RNH2 [–H2O] Me Me [–H2O]
electronegativity but unstable toward hydrolysis to be NHR by acid
are π-donors H R H R H R
synthetically useful. Note in this example that the reaction between the Lewis acid (HCl) and nucleophile (EtOH)
aminal (a.k.a. hemiaminal) imine (CH ) is reversibile under the reaction conditions, whereas using , say, a Grignard reagent would
2 n
O OH result in irreversible protonation of the nucleophile (i.e. no reaction). Compatibility between
Note: look at the postition of OH and O . They are extremely strong π-donors. HO(CH2)nOH [–H2O] O O note: Lewis acids and nucleophiles is treated with more detail in advanced level organic chemistry
This is why carboxylic acids are resistant to attack under basic conditions; O(CH2)nOH courses.
H R H R H R requires
strong π-donation by O into the carbonyl makes it extremely resistant acid
toward nucleophilic attack. acetal (a.k.a. hemiacetal) acetal
O OH
Just like with electrophilic aromatic substitution, π-donation trumps HCN
CN
electronegativity. The stronger the π-donor, the more resistant the H R H R
carbonyl will be towards nucleophilic attack. cyanohydrin
version 1.0, 3/25/10
copyright James Ashenhurst, 2010.
more nucleophilic = less electrophilic = faster rate of reaction with electrophiles = higher electron density = more Lewis basic *= less Lewis acidic* = more electron rich = less electropositive suggestions/questions/comments?
In general james@writechem.com
more electrophilic = less nucleophilic = faster rate of reaction with nucleophiles = lower electron density = less Lewis basic* = more Lewis acidic* = less electron rich = more electropositive
masterorganicchemistry.wordpress.com
* caveat: acidity/basicity is the position of a thermodynamic equilibrium, while nucleophilicity is measured by reaction rate