CURLY ARROWS

1
 After studying this topic, you should be able to…

• Use curly-arrow notation to denote the movement of electrons

in the progress of simple reactions
• Errata - at 17:30 I say "nucleophiles like the charge you find on
nucleus: that is they like negative charge" - I mean they like
positive charge

2
 A reaction is the rearrangement of electrons
• Breaking bonds requires energy
• Making bonds releases energy

break old bond

O
O
H H
H
H

O make new bond

O
H H
H H

3
 The movement of electrons is shown by curly arrows

Homolytic cleavage Heterolytic cleavage

• Half-headed arrows
• Generates free radicals
• Bonded pair becomes two unpaired
electron
• Peroxide fission
• Full headed arrows
• Generates ions
• Bonded pair becomes a lone pair on an
anion
• Acetic acid dissociation

H O
H O

O O H3C C H3C C
O O
H O H O H
H

4
 Free radicals are highly reactive chemical
species with an unpaired electron Sildenafil (Viagra®)
prolongs the effect of
• Dangerous, lipid-oxidising, DNA- NO signalling
wrecking…
– Superoxide radical O2−·
– Hydroxyl (not hydroxide!) radical HO·

• …but also cell-signalling

– Nitric oxide NO·

O N CC-BY-SA-3.0 SElefant@Wikimedia, but

contains trademarked content
5
The curly arrow goes from a source of electrons to a sink

Source Sink
• Breaking of old bond • Formation of new bond
• Lone pair • New lone pair
• Formal negative charge • "New" negative formal charge
• Neutralisation of formal positive
charge
O O
H H H
H

O O
H H H H
6
 SN2 (bimolecular nucleophilic substitution) reaction

Hydroxide ion Methanol

‡
H H H
H H
H
H O C Br H O C Br H O C Br

H H
H

Bromomethane Transition state Bromide

7
8
BIOCHEMICAL REACTIONS

9
 After studying this topic, you should be able to…

• Define the jargon terms of reactions and reactants –

nucleophile, electrophile, addition, substitution, elimination,
heterolytic, homolytic, rearrangement
• Be able to recognise addition, elimination, substitution and
rearrangement reactions in simple systems (e.g. alkaline
hydrolysis of an ester); and when one of the reactants is a
larger chemical species such as a cofactor or enzyme

10
 Nucleophiles− are electron-richδ− chemical species
O
H H
• Alcohols (–OH) O OH • Hydride (H−)
C - NH2
– serine H C CH2 O – NADH
N
NH2 H

• Carboxylate (COO−) O O
O OH
• Amines (–NH2) C - – Acetate 3H C C H3C C

H C (CH2)4 N – (resonance can be shown

O O
– lysine
NH2 H H using curly arrows)

O OH H H
C - • Olefins & arenes (C=C)
• Thiols (–SH) C C
H C CH2 S – ethene
– cysteine NH2 H H H

11
 Electrophiles+ are electron-deficientδ+ chemical species

H
CH3
• Proton sources O
C
OH
O
• Imines R
N
C
C C

– aspartic acid H C CH2 C – retinal/opsin H

NH2 O H conjugate
 

• Carbonyl carbons

– Glucose O H
C 
• Methyl groups
– (C=O is a carbonyl H C OH – S-adenosyl
group) HO C H methionine
NH2
H C OH
N HO O
N CH3 C
H C OH
N CH2 S+ CH2 CH2 C H
CH2OH N O
NH2

OH OH 12
 The alkaline hydrolysis of an ester
Addition Elimination
• doublesingle • single double
• A+BC • CD+E
O
O R2
Carbonyl carbon R2 O
is an electrophile R2
R1 O
R1 O R1 OH
OH
O H+ OH
Hydroxide ion is
a nucleophile H Note "arrow pushing"

Overall the reaction corresponds to an acyl substitution

13
 The enzymatic hydrolysis of an ester is a double addition-
elimination reaction
Nucleophilic O
O
O
R2

attack of ester R2
R2

by O− on serine R1 O
R1 O
R1 OH

in enzyme's O H+ O O
Acylated
active site R1-alcohol
Ser Ser
eliminated
Ser enzyme

R2 R2
R2 R2-acid
O

Nucleophilic O
O

O
eliminated
O
O
attack of H H H

acetylated O O O

enzyme by OH− Ser Ser Ser

Regenerated
14
enzyme
 Methylation of DNA is an bimolecular nucleophilic substitution
(SN2) reaction
Hydroxide ion Bromomethane Methanol Bromide O H
H H C C NH2
H
H HO
H O C Br H O C Br CH2

H H CH2

S+
H3C

H CH2
H R1 H+ H H R1 OH
H O
+ OH
R N C S R N C S
N N
H R2 H R2
H H
H2N N

DNA base S-adenosyl methylated S-adenosyl N

methionine DNA base homocysteine 15

keto-enol tautomery is a very common form of
rearrangement reaction (isomerisation)
enol = double bond + OH keto = single bond + C=O

O H O H O H+

C C C C C C

H+ H H

Electrophilic
addition of Note H+ is
proton across regenerated: acid
the double bond catalysis

16
Amino-imino tautomery is the equivalent for amines and
is critical in DNA
H N
N N
double bond + NH2 N single bond + C=NH N
O H
H
H H N N
N N N N
H H
N
N N
H H
N O
N O

(amino-)cytosine : imino-cytosine : adenine

guanine base-pair base-mispair  mutation!

17
18
 These additional resources may help you meet the intended
learning outcomes of these topics…
• Self-test materials on Blackboard
– End of topic quiz
– Worksheets

19