8.AN a aldeídos e cetonas QUI02015 4

Esta é uma pré-visualização de arquivo. Entre para ver o arquivo original

07/09/14 
1 
195 
 
Prof. Dr. José Eduardo Damas Martins 
Adição de cianeto a aldeídos e 
cetonas 
196 
 
Prof. Dr. José Eduardo Damas Martins 
A adição do íon cianeto, 
−CN, a uma aldeído ou 
c e t o n a , g e r a u m a 
cianoidrina. 
07/09/14 
2 
197 
 
Prof. Dr. José Eduardo Damas Martins 
Filling antibonding orbitals breaks bonds and, as the electrons enter the antibonding π* of the car-
bonyl group, the π bond is broken, leaving only the C–O σ bond intact. But electrons can’t just vanish,
and those that were in the π bond move off on to the electronegative oxygen, which ends up with the
negative charge that started on the nucleophile. You can see all this happening in the diagram below.
Notice how the trigonal, planar sp2 hybridized carbon atom of the carbonyl group changes to a
tetrahedral, sp3 hybridized state in the product. For each class of nucleophile you meet in this chap-
ter, we will show you the HOMO–LUMO interaction involved in the addition reaction.
Cyanohydrins from the attack of cyanide on aldehydes and
ketones
Now that we’ve looked at the theory of how a nucleophile attacks a carbonyl group, let’s go back to
the real reaction with which we started this chapter: cyanohydrin formation from a carbonyl com-
pound and sodium cyanide. Cyanide contains sp hybridized C and N atoms, and its HOMO is an sp
orbital on carbon. The reaction is a typical nucleophilic addition reaction to a carbonyl group: the
electron pair from the HOMO of the CN– (an sp orbital on carbon) moves into the C=O π* orbital;
the electrons from the C=O π orbital move on to the oxygen atom. The reaction is usually carried out
in the presence of acid, which protonates the resulting alkoxide to give the hydroxyl group of the
composite functional group known as a cyanohydrin. The reaction works with both ketones and
aldehydes, and the mechanism below shows the reaction of a general aldehyde.
Cyanohydrins from the attack of cyanide on aldehydes and ketones 137
!
The HOMO of the nucleophile will
depend on what the nucleophile
is, and we will meet examples in
which it is an sp or sp3 orbital
containing a lone pair, or a B–H or
metal–carbon σ orbital. We shall
shortly discuss cyanide as the
nucleophile; cyanide’s HOMO is
an sp orbital on carbon.
O
O
Nu
O
C O
C O C O
Nu
Nu
Nu
C O C O
Nu
electrons in HOMO begin to 
interact with LUMO
new σ bond
sp3 hybridized carbon
curly arrow representation:
orbitals involved:
HOMO
sp2 hybridized carbon
LUMO = π*
electrons from π bond end up 
as negative charge on oxygen
while at the same time...
filling of π* causes 
π bond to break
N
N C
orbitals of the cyanide ion
two pairs of p orbitals make 
two orthogonal πbonds
HOMO = sp
orbital on C
containing 
lone pair
C–N σ orbital 
(not shown)
sp orbital on 
N contains 
lone pair
C
NaCN
HR
O
HR
O
HR
ONC
HR
OHNC
CN
aldehyde cyanohydrin
H
H2O, HCl
C O
N
C HOMO = sp orbital
LUMO = π*
orbitals involved in the addition
of cyanide
Aldeído Cianoidrina 
Filling antibonding orbitals breaks bonds and, as the electrons enter the antibonding π* of the car-
bonyl group, the π bond is broken, leaving only the C–O σ bond intact. But electrons can’t just vanish,
and those that were in the π bond move off on to the electronegative oxygen, which ends up with the
negative charge that started on the nucleophile. You can see all this happening in the diagram below.
Notice how the trigonal, planar sp2 hybridized carbon atom of the carbonyl group changes to a
tetrahedral, sp3 hybridized state in the product. For each class of nucleophile you meet in this chap-
ter, we will show you the HOMO–LUMO interaction involved in the addition reaction.
Cyanohydrins from the attack of cyanide on aldehydes and
ketones
Now that we’ve looked at the theory of how a nucleophile attacks a carbonyl group, let’s go back to
the real reaction with which we started this chapter: cyanohydrin formation from a carbonyl com-
pound and sodium cyanide. Cyanide contains sp hybridized C and N atoms, and its HOMO is an sp
orbital on carbon. The reaction is a typical nucleophilic addition reaction to a carbonyl group: the
electron pair from the HOMO of the CN– (an sp orbital on carbon) moves into the C=O π* orbital;
the electrons from the C=O π orbital move on to the oxygen atom. The reaction is usually carried out
in the presence of acid, which protonates the resulting alkoxide to give the hydroxyl group of the
composite functional group known as a cyanohydrin. The reaction works with both ketones and
aldehydes, and the mechanism below shows the reaction of a general aldehyde.
Cyanohydrins from the attack of cyanide on aldehydes and ketones 137
!
The HOMO of the nucleophile will
depend on what the nucleophile
is, and we will meet examples in
which it is an sp or sp3 orbital
containing a lone pair, or a B–H or
metal–carbon σ orbital. We shall
shortly discuss cyanide as the
nucleophile; cyanide’s HOMO is
an sp orbital on carbon.
O
O
Nu
O
C O
C O C O
Nu
Nu
Nu
C O C O
Nu
electrons in HOMO begin to 
interact with LUMO
new σ bond
sp3 hybridized carbon
curly arrow representation:
orbitals involved:
HOMO
sp2 hybridized carbon
LUMO = π*
electrons from π bond end up 
as negative charge on oxygen
while at the same time...
filling of π* causes 
π bond to break
N
N C
orbitals of the cyanide ion
two pairs of p orbitals make 
two orthogonal πbonds
HOMO = sp
orbital on C
containing 
lone pair
C–N σ orbital 
(not shown)
sp orbital on 
N contains 
lone pair
C
NaCN
HR
O
HR
O
HR
ONC
HR
OHNC
CN
aldehyde cyanohydrin
H
H2O, HCl
C O
N
C HOMO = sp orbital
LUMO = π*
orbitals involved in the addition
of cyanide
198 
 
Prof. Dr. José Eduardo Damas Martins 
Filling antibonding orbitals breaks bonds and, as the electrons enter the antibonding π* of the car-
bonyl group, the π bond is broken, leaving only the C–O σ bond intact. But electrons can’t just vanish,
and those that were in the π bond move off on to the electronegative oxygen, which ends up with the
negative charge that started on the nucleophile. You can see all this happening in the diagram below.
Notice how the trigonal, planar sp2 hybridized carbon atom of the carbonyl group changes to a
tetrahedral, sp3 hybridized state in the product. For each class of nucleophile you meet in this chap-
ter, we will show you the HOMO–LUMO interaction involved in the addition reaction.
Cyanohydrins from the attack of cyanide on aldehydes and
ketones
Now that we’ve looked at the theory of how a nucleophile attacks a carbonyl group, let’s go back to
the real reaction with which we started this chapter: cyanohydrin formation from a carbonyl com-
pound and sodium cyanide. Cyanide contains sp hybridized C and N atoms, and its HOMO is an sp
orbital on carbon. The reaction is a typical nucleophilic addition reaction to a carbonyl group: the
electron pair from the HOMO of the CN– (an sp orbital on carbon) moves into the C=O π* orbital;
the electrons from the C=O π orbital move on to the oxygen atom. The reaction is usually carried out
in the presence of acid, which protonates the resulting alkoxide to give the hydroxyl group of the
composite functional group known as a cyanohydrin. The reaction works with both ketones and
aldehydes, and the mechanism below shows the reaction of a general aldehyde.
Cyanohydrins from the attack of cyanide on aldehydes and ketones 137
!
The HOMO of the nucleophile will
depend on what the nucleophile
is, and we will meet examples in
which it is an sp or sp3 orbital
containing a lone pair, or a B–H or
metal–carbon σ orbital. We shall
shortly discuss cyanide as the
nucleophile; cyanide’s HOMO is
an sp orbital on carbon.
O
O
Nu
O
C O
C O C O
Nu
Nu
Nu
C O C O
Nu
electrons in HOMO begin to 
interact with LUMO
new σ bond
sp3 hybridized carbon
curly arrow representation:
orbitals involved:
HOMO
sp2 hybridized carbon
LUMO = π*
electrons from π bond end up 
as negative charge on oxygen
while at the same time...
filling of π* causes 
π bond to break
N
N C
orbitals of the cyanide ion
two pairs of p orbitals make 
two orthogonal πbonds
HOMO = sp
orbital on C
containing 
lone pair
C–N σ orbital 
(not shown)
sp orbital on 
N contains 
lone pair
C
NaCN
HR
O
HR
O
HR
ONC
HR
OHNC
CN
aldehyde cyanohydrin
H
H2O, HCl
C O
N
C HOMO = sp orbital
LUMO = π*
orbitals involved in the addition
of cyanide
O Íon cianeto 
Carga negativa 
sobre o carbono 
07/09/14 
3 
199 
 
Prof. Dr. José Eduardo Damas Martins 
Filling antibonding orbitals breaks bonds and, as the electrons enter the antibonding π* of the car-
bonyl group, the π bond is broken, leaving only the C–O σ bond intact. But electrons can’t just vanish,
and those that were in the π bond move off on to the electronegative oxygen, which ends up with the
negative charge that started on the nucleophile. You can see all this happening in the diagram below.
Notice how the trigonal, planar sp2 hybridized carbon atom of the carbonyl group changes to a
tetrahedral, sp3 hybridized state in the product. For each class of nucleophile you meet in this chap-
ter, we will show you the HOMO–LUMO interaction involved in the addition reaction.
Cyanohydrins from the attack of cyanide on aldehydes and
ketones
Now that we’ve looked at the theory of how a nucleophile attacks a carbonyl group, let’s go back to
the real reaction with which we started this chapter: cyanohydrin formation from a carbonyl com-
pound and sodium cyanide. Cyanide contains sp hybridized C and N atoms, and its HOMO is an sp
orbital on carbon. The reaction is a typical nucleophilic addition reaction to a carbonyl group: the
electron pair from the HOMO of the CN– (an sp orbital on carbon) moves into the C=O π* orbital;
the electrons from the C=O π orbital move on to the oxygen atom. The reaction is usually carried out
in the presence of acid, which protonates the resulting alkoxide to give the hydroxyl group of the
composite functional group known as a cyanohydrin. The reaction works with both ketones and
aldehydes, and the mechanism below shows the reaction of a general aldehyde.
Cyanohydrins from the attack of cyanide on aldehydes and ketones 137
!
The HOMO of the nucleophile will
depend on what the nucleophile
is, and we will meet examples in
which it is an sp or sp3 orbital
containing a lone pair, or a B–H or
metal–carbon σ orbital. We shall
shortly discuss cyanide as the
nucleophile; cyanide’s HOMO is
an sp orbital on carbon.
O
O
Nu
O
C O
C O C O
Nu
Nu
Nu
C O C O
Nu
electrons in HOMO begin to 
interact with LUMO
new σ bond
sp3 hybridized carbon
curly arrow representation:
orbitals involved:
HOMO
sp2 hybridized carbon
LUMO = π*
electrons from π bond end up 
as negative charge on oxygen
while at the same time...
filling of π* causes 
π bond to break
N
N C
orbitals of the cyanide ion
two pairs of p orbitals make 
two orthogonal πbonds
HOMO = sp
orbital on C
containing 
lone pair
C–N σ orbital 
(not shown)
sp orbital on 
N contains 
lone pair
C
NaCN
HR
O
HR
O
HR
ONC
HR
OHNC
CN
aldehyde cyanohydrin
H
H2O, HCl
C O
N
C HOMO = sp orbital
LUMO = π*
orbitals involved in the addition
of cyanide
Orbitais moleculares 
envolvidos na adição 
nucleofílica 
Vantagem: formação de ligação C−C 
200 
 
Prof. Dr. José Eduardo Damas Martins 
Obtem-se maiores rendimentos quando se 
usa HCN como solvente da reação, no 
entanto devido à alta toxidade do gás, 
prefere-se formar o HCN durante a reação 
adicionando-se pequenas porções de um 
ácido forte. 
07/09/14 
4 
201 
 
Prof. Dr. José Eduardo Damas Martins 
Mecanismo com HCN 
R
C
H
O
+ HCN
R
C
H
NC OH
KCN
R
C
H
O
CN
R
C
H
NC O H CN
202 
 
Prof. Dr. José Eduardo Damas Martins 
 A reação, geralmente, é conduzida 
sob condições básicas moderadas, 
pH 6−8, a fim de evitar a produção 
excessiva de HCN. 
07/09/14 
5 
203 
 
Prof. Dr. José Eduardo Damas Martins 
O Excesso de base causa reversibilidade da reação Cyanohydrin formation is reversible: just dissolving a cyanohydrin in water can give back the alde-
hyde or ketone you started with, and aqueous base usually decomposes cyanohydrins completely.
Cyanohydrin formation is therefore
an equilibrium between starting materi-
als and products, and we can only get
good yields if the equilibrium favours
the products. The equilibrium is more
favourable for aldehyde cyanohydrins
than for ketone cyanohydrins, and the
reason is the size of the groups attached
138 6 . Nucleophilic addition to the carbonyl group
Cyanohydrins in synthesis
Cyanohydrins are important synthetic
intermediates—for example, the cyanohydrin
formed from this cyclic amino ketone forms the first
step of a synthesis of some medicinal compounds
known as 5HT3 agonists, which were designed to
reduce nausea in chemotherapy patients.
Cyanohydrins are also components of many natural
and industrial products, such as the insecticides
cypermethrin (marketed as ‘Ripcord’, ‘Barricade’,
and ‘Imperator’) and fluvalinate.
Cl
ClO
O
H
N
Cl
CF3O
OPh
H H
HO
CN
OPh
H
O
CN
H
O
CN
H H
OPh
OPh cypermethrin
fluvalinateNaCN
H+
other reagents
other reagents
N
O
N
OH
CNNaCN, H2O
95% yield
other reagents
5HT3 agonists
!
This is because the cyanide is a
good leaving group—we’ll come
back to this type of reaction in
much more detail in Chapter 12.
R R
O
R R
HO CN
R R
O CN
R R
O CNH
OH
CN
NaOH, H2O
ketonecyanohydrin
H2O, HClRR
O
RR
OHNC
120° 109°
sp2 sp3
substituents move 
closer together
NaCN
RR
O
RR
OHNC
O
HCN
+
aldehyde or 
ketone Keq
Keq PhCHO 212
28
Some equilibrium constants
Cyanohydrins and cassava
The reversibility of cyanohydrin formation is of more than
theoretical interest. In parts of Africa the staple food is
cassava. This food contains substantial quantities of the
glucoside of acetone cyanohydrin (a glucoside is an acetal
derived from glucose). We shall discuss the structure of
glucose later in this chapter, but for now, just accept that
it stabilizes the cyanohydrin.
The glucoside is not poisonous in itself, but enzymes in
the human gut break it down and release HCN. Eventually
50 mg HCN per 100 g of cassava can be released and this
is enough to kill a human being after a meal of
unfermented cassava. If the cassava is crushed with
water and allowed to stand (‘ferment’), enzymes in the
cassava will do the same job and then the HCN can be
washed out before the cassava is cooked and eaten.
The cassava is now safe to eat but it still contains some
glucoside. Some diseases found in eastern Nigeria can be
traced to long-term consumption of HCN. Similar
glucosides are found in apple pips and the kernels inside
the stones of fruit such as peaches and apricots. Some
people like eating these, but it is unwise to eat too many
at one sitting!
OHO
HO
HO
OH
O CN HO CN O + HCN
glucoside of acetone 
cyanohydrin found in 
cassava
β-glucosidase
hydroxynitrile 
lyase
(an enzyme) (another enzyme)
Cianoidrina Cetona 
Cyanohydrin formation is reversible: just dissolving a cyanohydrin in water can give back the alde-
hyde or ketone you started with,
and aqueous base usually decomposes cyanohydrins completely.
Cyanohydrin formation is therefore
an equilibrium between starting materi-
als and products, and we can only get
good yields if the equilibrium favours
the products. The equilibrium is more
favourable for aldehyde cyanohydrins
than for ketone cyanohydrins, and the
reason is the size of the groups attached
138 6 . Nucleophilic addition to the carbonyl group
Cyanohydrins in synthesis
Cyanohydrins are important synthetic
intermediates—for example, the cyanohydrin
formed from this cyclic amino ketone forms the first
step of a synthesis of some medicinal compounds
known as 5HT3 agonists, which were designed to
reduce nausea in chemotherapy patients.
Cyanohydrins are also components of many natural
and industrial products, such as the insecticides
cypermethrin (marketed as ‘Ripcord’, ‘Barricade’,
and ‘Imperator’) and fluvalinate.
Cl
ClO
O
H
N
Cl
CF3O
OPh
H H
HO
CN
OPh
H
O
CN
H
O
CN
H H
OPh
OPh cypermethrin
fluvalinateNaCN
H+
other reagents
other reagents
N
O
N
OH
CNNaCN, H2O
95% yield
other reagents
5HT3 agonists
!
This is because the cyanide is a
good leaving group—we’ll come
back to this type of reaction in
much more detail in Chapter 12.
R R
O
R R
HO CN
R R
O CN
R R
O CNH
OH
CN
NaOH, H2O
ketonecyanohydrin
H2O, HClRR
O
RR
OHNC
120° 109°
sp2 sp3
substituents move 
closer together
NaCN
RR
O
RR
OHNC
O
HCN
+
aldehyde or 
ketone Keq
Keq PhCHO 212
28
Some equilibrium constants
Cyanohydrins and cassava
The reversibility of cyanohydrin formation is of more than
theoretical interest. In parts of Africa the staple food is
cassava. This food contains substantial quantities of the
glucoside of acetone cyanohydrin (a glucoside is an acetal
derived from glucose). We shall discuss the structure of
glucose later in this chapter, but for now, just accept that
it stabilizes the cyanohydrin.
The glucoside is not poisonous in itself, but enzymes in
the human gut break it down and release HCN. Eventually
50 mg HCN per 100 g of cassava can be released and this
is enough to kill a human being after a meal of
unfermented cassava. If the cassava is crushed with
water and allowed to stand (‘ferment’), enzymes in the
cassava will do the same job and then the HCN can be
washed out before the cassava is cooked and eaten.
The cassava is now safe to eat but it still contains some
glucoside. Some diseases found in eastern Nigeria can be
traced to long-term consumption of HCN. Similar
glucosides are found in apple pips and the kernels inside
the stones of fruit such as peaches and apricots. Some
people like eating these, but it is unwise to eat too many
at one sitting!
OHO
HO
HO
OH
O CN HO CN O + HCN
glucoside of acetone 
cyanohydrin found in 
cassava
β-glucosidase
hydroxynitrile 
lyase
(an enzyme) (another enzyme)
204 
 
Prof. Dr. José Eduardo Damas Martins 
Mecanismo ? 
O
NaCN
H2O, HCl
OH
CN
07/09/14 
6 
205 
 
Prof. Dr. José Eduardo Damas Martins 
R
C
R
O
+ HCN
R
C
R
NC OH
Keq
Cyanohydrin formation is reversible: just dissolving a cyanohydrin in water can give back the alde-
hyde or ketone you started with, and aqueous base usually decomposes cyanohydrins completely.
Cyanohydrin formation is therefore
an equilibrium between starting materi-
als and products, and we can only get
good yields if the equilibrium favours
the products. The equilibrium is more
favourable for aldehyde cyanohydrins
than for ketone cyanohydrins, and the
reason is the size of the groups attached
138 6 . Nucleophilic addition to the carbonyl group
Cyanohydrins in synthesis
Cyanohydrins are important synthetic
intermediates—for example, the cyanohydrin
formed from this cyclic amino ketone forms the first
step of a synthesis of some medicinal compounds
known as 5HT3 agonists, which were designed to
reduce nausea in chemotherapy patients.
Cyanohydrins are also components of many natural
and industrial products, such as the insecticides
cypermethrin (marketed as ‘Ripcord’, ‘Barricade’,
and ‘Imperator’) and fluvalinate.
Cl
ClO
O
H
N
Cl
CF3O
OPh
H H
HO
CN
OPh
H
O
CN
H
O
CN
H H
OPh
OPh cypermethrin
fluvalinateNaCN
H+
other reagents
other reagents
N
O
N
OH
CNNaCN, H2O
95% yield
other reagents
5HT3 agonists
!
This is because the cyanide is a
good leaving group—we’ll come
back to this type of reaction in
much more detail in Chapter 12.
R R
O
R R
HO CN
R R
O CN
R R
O CNH
OH
CN
NaOH, H2O
ketonecyanohydrin
H2O, HClRR
O
RR
OHNC
120° 109°
sp2 sp3
substituents move 
closer together
NaCN
RR
O
RR
OHNC
O
HCN
+
aldehyde or 
ketone Keq
Keq PhCHO 212
28
Some equilibrium constants
Cyanohydrins and cassava
The reversibility of cyanohydrin formation is of more than
theoretical interest. In parts of Africa the staple food is
cassava. This food contains substantial quantities of the
glucoside of acetone cyanohydrin (a glucoside is an acetal
derived from glucose). We shall discuss the structure of
glucose later in this chapter, but for now, just accept that
it stabilizes the cyanohydrin.
The glucoside is not poisonous in itself, but enzymes in
the human gut break it down and release HCN. Eventually
50 mg HCN per 100 g of cassava can be released and this
is enough to kill a human being after a meal of
unfermented cassava. If the cassava is crushed with
water and allowed to stand (‘ferment’), enzymes in the
cassava will do the same job and then the HCN can be
washed out before the cassava is cooked and eaten.
The cassava is now safe to eat but it still contains some
glucoside. Some diseases found in eastern Nigeria can be
traced to long-term consumption of HCN. Similar
glucosides are found in apple pips and the kernels inside
the stones of fruit such as peaches and apricots. Some
people like eating these, but it is unwise to eat too many
at one sitting!
OHO
HO
HO
OH
O CN HO CN O + HCN
glucoside of acetone 
cyanohydrin found in 
cassava
β-glucosidase
hydroxynitrile 
lyase
(an enzyme) (another enzyme)
Cianoidrinas de aldeídos 
possuem maior constante de 
equilíbrio do que cianoidrinas 
de cetonas. 
Equilíbrio ceto−cianoidrina 
206 
 
Prof. Dr. José Eduardo Damas Martins 
R
C
R
O
+ HCN
R
C
R
NC OH
Keq
O
O
H
O
H
O
Cl
(a) (b) (c) (d)
Coloque os compostos abaixo em ordem 
CRESCENTE de constante de equilíbrio 
de formação de cianoidrina. 
07/09/14 
7 
207 
 
Prof. Dr. José Eduardo Damas Martins 
 Fatores estéricos também contribuem 
para a ma io r es tab i l idade de 
cianoidrinas obtidas à partir de 
aldeídos. 
Cyanohydrin formation is reversible: just dissolving a cyanohydrin in water can give back the alde-
hyde or ketone you started with, and aqueous base usually decomposes cyanohydrins completely.
Cyanohydrin formation is therefore
an equilibrium between starting materi-
als and products, and we can only get
good yields if the equilibrium favours
the products. The equilibrium is more
favourable for aldehyde cyanohydrins
than for ketone cyanohydrins, and the
reason is the size of the groups attached
138 6 . Nucleophilic addition to the carbonyl group
Cyanohydrins in synthesis
Cyanohydrins are important synthetic
intermediates—for example, the cyanohydrin
formed from this cyclic amino ketone forms the first
step of a synthesis of some medicinal compounds
known as 5HT3 agonists, which were designed to
reduce nausea in chemotherapy patients.
Cyanohydrins are also components of many natural
and industrial products,
such as the insecticides
cypermethrin (marketed as ‘Ripcord’, ‘Barricade’,
and ‘Imperator’) and fluvalinate.
Cl
ClO
O
H
N
Cl
CF3O
OPh
H H
HO
CN
OPh
H
O
CN
H
O
CN
H H
OPh
OPh cypermethrin
fluvalinateNaCN
H+
other reagents
other reagents
N
O
N
OH
CNNaCN, H2O
95% yield
other reagents
5HT3 agonists
!
This is because the cyanide is a
good leaving group—we’ll come
back to this type of reaction in
much more detail in Chapter 12.
R R
O
R R
HO CN
R R
O CN
R R
O CNH
OH
CN
NaOH, H2O
ketonecyanohydrin
H2O, HClRR
O
RR
OHNC
120° 109°
sp2 sp3
substituents move 
closer together
NaCN
RR
O
RR
OHNC
O
HCN
+
aldehyde or 
ketone Keq
Keq PhCHO 212
28
Some equilibrium constants
Cyanohydrins and cassava
The reversibility of cyanohydrin formation is of more than
theoretical interest. In parts of Africa the staple food is
cassava. This food contains substantial quantities of the
glucoside of acetone cyanohydrin (a glucoside is an acetal
derived from glucose). We shall discuss the structure of
glucose later in this chapter, but for now, just accept that
it stabilizes the cyanohydrin.
The glucoside is not poisonous in itself, but enzymes in
the human gut break it down and release HCN. Eventually
50 mg HCN per 100 g of cassava can be released and this
is enough to kill a human being after a meal of
unfermented cassava. If the cassava is crushed with
water and allowed to stand (‘ferment’), enzymes in the
cassava will do the same job and then the HCN can be
washed out before the cassava is cooked and eaten.
The cassava is now safe to eat but it still contains some
glucoside. Some diseases found in eastern Nigeria can be
traced to long-term consumption of HCN. Similar
glucosides are found in apple pips and the kernels inside
the stones of fruit such as peaches and apricots. Some
people like eating these, but it is unwise to eat too many
at one sitting!
OHO
HO
HO
OH
O CN HO CN O + HCN
glucoside of acetone 
cyanohydrin found in 
cassava
β-glucosidase
hydroxynitrile 
lyase
(an enzyme) (another enzyme)
208 
 
Prof. Dr. José Eduardo Damas Martins 
R
C
R
NC OH
R
C
H
NC OH
Cianoidrina à 
partir de aldeído
Cianoidrina à 
partir de cetona
)( )(
M a i o r r e p u l s ã o 
espacial entre os 
grupos. 
07/09/14 
8 
209 
 
Prof. Dr. José Eduardo Damas Martins 
R
C
R
NC OH
R
C
R
HO2C OH
R
C
R
OH
H2N
α-Hidroxi-ácido β-Amino-álcool
H3O
+ Redução
Cianoidrina
Cianoidrinas são importantes intermediários 
sintéticos 
210 
 
Prof. Dr. José Eduardo Damas Martins 
Hidrólise de cianoidrinas 
Mecanismo ? 
The bisulfite compound of formaldehyde (CH2O) has special significance. Earlier in this chapter
we mentioned the difficulty of working with formaldehyde because it is either an aqueous solution
or a dry polymer. One readily available monomeric form is the bisulfite compound. It can be made
in water (in which it is soluble) but addition of ethanol (in which it isn’t) causes it to crystallize
out.
The compound is commercially available
and, together with the related zinc salt, is
widely used in the textile industry as a reduc-
ing agent.
The second reason that bisulfite compounds are useful is that they are soluble in water. Some
small (that is, low molecular weight) aldehydes and ketones are water-soluble—acetone is an exam-
ple. But most larger (more than four or so carbon atoms) aldehydes and ketones are not. This does
not usually matter to most chemists as we often want to carry out reactions in organic solvents rather
than water. But it can matter to medicinal chemists, who make compounds that need to be com-
patible with biological systems. And in one case, the solubility of bisulfite adduct in water is literally
vital.
Dapsone is an antileprosy drug. It is a very effective one too, especially when used in combination
with two other drugs in a ‘cocktail’ that can be simply drunk as an aqueous solution by patients in
tropical countries without any special facilities, even in the open air. But there is a problem! Dapsone
is insoluble in water.
The solution is to make a bisulfite compound from it. You may ask how this is possible since dap-
sone has no aldehyde or ketone—just two amino groups and a sulfone. The trick is to use the
formaldehyde bisulfite compound and exchange the OH group for one of the amino groups in dap-
sone.
Now the compound will dissolve in water and release dapsone inside the patient. The details of
this sort of chemistry will come in Chapter 14 when you will meet imines as intermediates. But at this
stage we just want you to appreciate that even the relatively simple chemistry in this chapter is useful
in synthesis, in commerce, and in medicine.
Bisulfite addition compounds 149
Other compounds from cyanohydrins
Cyanohydrins can be converted by simple reactions
into hydroxyacids or amino alcohols. Here is one
example of each, but you will have to wait until
Chapter 12 for the details and the mechanisms of
the reactions. Note that one cyanohydrin was made
by the simplest method—just NaCN and acid—while
the other came from the bisulfite route we have just
discussed.
H2O
NaCN
O
Ph Me Ph Me
HO CN
Ph Me
HO CO2H
hydroxyacids by hydrolysis of CN in cyanohydrin
HCl, Et2O
HCl
NaHSO3
O
H H
HO CN
H
HO NH2
amino alcohols by reduction of CN in cyanohydrin
LiAlH4
NaCN, H2O
saturated aqueous
HO SO3 Na
H H
O
crystalline
NaHSO3
ice bath
S
H2N NH2
O O
HO SO3 Na S
H2N N
H
O O
SO3 Na
formaldehyde bisulfite 
adduct
water-soluble "pro-drug"dapsone: antileprosy drug; insoluble in water