Hydration of Ketones and Aldehydes

H
H
H O
O
H H
H H HO OH
H2O
O O HO OH

O
a hydrated ketone
H H

O HO OH
H2O
Keq = 2000 uncrowded

H H H H
Aldehydes exist as partial
hydrates in aqueous solution:
O H2O HO OH
Keq = 1 more crowded
Me H Me H

O
H2O HO OH
Ketones generally do not favor hydration: Keq = 0.002 very crowded
Me Me Me Me
 Nucleophilic Addition of "O–" to Carbonyl Groups

Na
O OH
O O
H+ (workup)
HO Na + H2O
Me Me Me Me Me Me
OH Me Me
OH

A hydrated ketone Starting material!

pKa of H2O: approx. 16
pKa of alkoxide: 16-20

Na
O O OH
H+ (workup) O

MeO Na + MeOH
Me Me Me Me Me Me
OMe OMe Me Me

A hemiacetal Starting material!

(usually unstable)
pKa of MeOH: approx. 15
pKa of alkoxide: 16-20
 Hydration of Ketones and Aldehydes

O 18O
H218O

Me Me H+ cat. Me Me

H
H 18O
H
18O

H H H
Me Me H H Me
18O
O O H18O OH
H H
Me 18O Me Me
H H H18O OH

H
Me Me
18O
H
a hydrated ketone

Me Me H
H18O OH2
18O 18O

Me Me Me Me
 Addition of Alcohols to Carbonyl Groups:
Acetal Formation

O RO OR
ROH, H+

Me Me Me Me

An acetal

MeOH

H+
Me Me H H Me
O O MeO OH
H+
Me Me Me
MeOH
MeO OH

MeOH Me Me

a hemiacetal
MeO OMe
H Me Me Me
MeO OH2
Me Me MeO OMe O

Me Me
An acetal Me MeOH Me
H2O
 Acetals as Carbonyl Protecting Groups
O OH
MeMgCl

Me Me Me Me
Me

MeO OMe MeMgCl

No reaction
Me Me

O Br O O
Li–Bu
P(Ph)3
Br
Me
(Ph)3P
Me
X (Ph)3P
Me

Butyllithium will react with the ketone,

and the reagent will react with itself!

O MeO OMe
MeOH, H+ MeO OMe
(Ph)3P
Br Br
Me
Me Me

A stable reagent

O MeO OMe
H2O, H+

Me Me
 Cyclic Hemiacetals
MeOH

H+
Me Me H H Me MeO OH
MeOH
O O MeO OH
Me Me
Me Me Me
MeOH
a hemiacetal
(usually unstable for ketones,
sometimes stable for aldehydes)

O
O catalytic H+ O H
HO HO H
H
H H OH

OH OH

O O
solvent
a cyclic hemiacetal H

(usually stable for 5- and 6-membered rings)

 Cyclic Hemiacetals in Biological Systems:
Carbohydrates

OH OH OH
OH OH
H catalytic H+ H HO
HO OH
HO
(not necesary, but
OH OH O accelerates formation) OH
OH OH O
H HO
D-glucose (linear form)
O
H

OH
H
CH2OH HO
H OH
HO O
OH
HO O
H HO
OH
H
OH

β-D-glucose (cyclic form) a hemiacetal

 Cyclic Hemiacetals in Biological Systems:
Mutarotation in Carbohydrates
H OH
CH2OH
H HO
HO O
OH OH
HO
H OH O
H H HO

OH OH

β-D-glucose (cyclic form) HO OH OH

OH H2O H
OH HO
HO
OH OH O
O
OH H D-glucose (linear form)
H
CH2OH
H HO
HO O
H OH
HO
H O
OH
H OH HO

OH

α-D-glucose (cyclic form)

The process of equlibration (epimerization) at the hemiacedtal (anomeric) carbon is called mutarotation.
 The Nitrogen-Equivalent of a Carbonyl Group:
Imines and Hydrazones
H
O NH3 N

Me Me Me Me

an imine

NHR
O H2N–NHR N

Me Me Me Me

a hydrazone

Basic conditions:

H
proton transfer H H
O NH3 H3N O (via solvent molecules) H2N OH OH N
N

Me Me Me Me Me Me Me Me
Me Me
a carbinolamine

Acidic conditions:

H H
proton transfer H H
O NH3 H3N OH (via solvent molecules) H2N OH2 NH3 N
N

Me Me Me Me Me Me Me Me
Me Me
a carbinolamine
 The Nitrogen-Equivalent of a Carbonyl Group:
Imines and Hydrazones
O
OH
N
hydroxylamine H2N OH an oxime

NH2
N
hydrazine H2N NH2 a hydrazone

Ph
H
phenylhydrazine H2N N NH
N a phenylhydrazone

NO2

H
2,4-dinitrophenylhydrazine (2,4-DNP) H2N N NO2 a 2,4-dinitrophenylhydrazone
NO2

NH
O2N N

O NH2
O
H
semicarbazide H2N N NH a semicarbazone
N
NH2