Lecture notes
Organic Chemistry notes
- Module
- BIOL1026 (BIOL1026)
- Institution
- University Of Southampton (UOS)
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Nucleophilic AdditionNucleophilic Substi tuti on in Biochemistry
Biosynthesis of S- adenosylmethionine (SAM):
Nucleophilic Substi tuti on at Saturated Carbon
Nucleophile- Friend of positive charges
- highly electronegative atom charged NEGATIVE- one of its pair of electrons will attack some who has
positive density charge
Electrophile- Friend of negative charges
- C atom who had density positive charge and good leaving group
1) Nucleophile adds first, then leaving group departs- Impossible
a. Impossible since intermediate stage including pentavalent
carbon (5 bonds- 10 bonding shell (shared) electrons) would be
involved
2) Leaving group departs first, then nucleophile adds- Possible- SN1
The nucleophile
S Na
mechanism
Leaving
a. Two step mechanism H H
Cl
Group
Departs
H + Cl
S
i. Step 1: Leaving group departs- SLOW H
Nucleophile
Arrives
H H
ii. Step 2: Nucleophile arrives- FAST The electrophile Intermediate
Carbocation
+ Na
b. Rate of reaction depends only on [PhCH2Cl] and rate
isn’t increased by increasing [nucleophile] – step involving PhCH2Cl is rate determining- STEP 1
c. Rate determining step is unimolecular- electrophile only- mechanism is SN1
bonds partly
3) Nucleophile arrives whilst leaving group departs- The nucleophile formed/broken
Possible- SN2 mechanism S
H H
Nucleophile
Arrives - H H -
AND S Cl
a. One-step mechanism: +
Cl Transition state
Electrophile
i. Rate is dependent on both [nucleophile] Na
The electrophile
Departs
and [electrophile]
b. Rate determining step is biomolecular-
S
electrophile and nucleophile- mechanism is SN2
+ Cl + Na
Deciding which Mechanism occurs:
There are two possibilities- SN1 and SN2
, Many factors control which mechanism occurs but one of main factors is structure of
ELECTROPHILE X
X is the leaving group
Methyl Primary Secondary Tertiary
Electrophile H H H H R H R R
Structure H X R X R X R X
If R = alkyl H H R R
SN1 No ? H H R H R H R R
No Yes
SN2 Yes Yes ? No carbocation stability increases
SN1 is favoured for ELECTROPHILE that form stable carbocation intermediate
SN2 is favoured for ELECTROPHILE that has fewer ‘R groups’ since these hinder attack by nucleophile-
STERIC HINDRANCE
Stereochemistry and Substi tuti on
Consider SN2 mechanism:
Nucleophile approaches on opposite side of electrophile to side where leaving group is departing
Stereochemistry of tetrahedral carbon
where substitution has occurred is
INVERTED in product
o Leads to inversion of
configuration for chiral electrophile The nucelophile can add
to either face of the flat
carbocation
+ Br Me
Consider SN1 mechanism:
Br
SN1 leads to RACEMIC MIXTURE of products leaving group
PLANAR
carbocation
Ph
Et
departs
CH3 CH3
H3C S + Br S AND S S
CH3
(S)-enantiomer (R)-enantiomer
50% 50%
Selecti vity in Nucleophilic Substi tuti on
Several possible ‘leaving groups’- can accept electron pair from breaking bond
If a molecule contains two possible sites for nucleophilic substitution- i.e. two possible leaving groups
(how can we predict at which site of reaction will occur?)
H3C S
O Path B
Path A
O Br
O
S Br O S
O
+ + Br
O
bromide ion
carboxylate ion
Stability of anion product of leaving group- plays important role in control of rate of reaction
o e.g. Carboxylate or Bromide
, o
Steric hindrance to nucleophilic attack in SN2 and Carbocation stability in SN1- important factors
along with specific reaction conditions used
Compare two reactions in which leaving group differs- Which is fastest?
Anion product is formed from leaving group in rate determining step of SN1 and SN2 reaction
o So, Fastest reaction- is the one in which more stable anion (e.g. Bromide or Carboxylate) is formed
Compare stability of two anions by comparing acidity of HBr with CH 3CO2H:
Stronger acids- have lower pKa value
o HBr is stronger acid than CH3CO2H
o HBr is more dissociated – equilibrium is more to
LEFT
Br- ion is more stable anion
Anions from strong acids are STABLE – tend to make
good leaving groups
Substi tuti on of Alcohols
HO- is very poor leaving group- H2O is weak acid with pKa= 16
OH Cl + HO
Cl
But H2O is very good leaving group- H3O+ is strong acid
with pKa=-1.7
o So nucleophilic substitution of alcohols REQUIRES
protonation of oxygen to take place first
Comparing Nucleophiles- DELOCALISATION
Species is MORE STABLE- LESS REACTIVE- of multiple
resonance forms are shown
Nucleophilic strength is DECREASED – if nucleophilic
lone pair can be shared by multiple electronegative
atoms- DELOCALISATON
Comparing Nucleophiles- ELECTRONEGATIVITY
Amines are more nucleophilic than Alcohols
o Oxygen is more electrophilic than Nitrogen
SLOWER
o Outer shell electrons are held more tightly by Oxygen H H
H
O H O
H Br
OH H H
than by Nitrogen H H
+ Br
- HBr H
o Oxygen lone pair electrons are LESS AVAILABLE to
participate in Substitution reactions FASTER
H H
H H H
H N H N
NH2 Br H H
+ Br
H H - HBr H
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