Transcript Slide 1

Part 3iv
Substitution Reactions:
Nucleophile
There is some correlation between basicity and nucleophilicity.
remember both a base (B:) and a nucleophile (Nu:) are
electronically very similar.
Both have a lone pair of electrons on an atom within the molecule
Content of Part 3iv
The Nucleophile and SN1 Reactions
The Nucleophile and SN2 Reactions
How to Estimate the Nucleophilicity of a Nucleophile
Some Guidelines for Estimating Nucleophilicity
Caution on Correlating Basicity with Nucleophilicity!
Hard Base/Soft Base
CHM1C3
– Introduction to Chemical Reactivity of Organic
Compounds–
– Learning
Objectives Part 5iv –
Substitution Reactions:
Nucleophile
After completing PART 4iv of this course you should have an understanding of, and be able to demonstrate, the following
terms, ideas and methods.
(i)
Changing the Nu: in which the substrate undergoes nucleophilic substitution via an SN1 mechanism will have
no effect on the rate,
(ii)
Changing the Nu: in which the substrate undergoes nucleophilic substitution via an SN2 mechanism will have
an effect on the rate,
(iii)
The effectiveness of a nucleophile is dependent on its ability to donate a lone pair of electrons into a s*
orbital (could also be a p* orbtial in the case of addition reactions (see a later course)),
(iv)
pKa data can be used as a guide to correlate basicity with nucleophilicity by considering the conjugate base
which is equivalent to the nucleophile,
(v)
Correlations of basicity and nucleophilicity should be done with care as acid/base reactions are
thermodynamically controlled and are little effected by steric influences, whereas electrophile/nucleophile
reactions are generally under kinetic control and are influenced by steric factors,
(vi)
Correlations of basicity and nucleophilicity should only be carried out when considering the same
heteroatom carrying a lone pair (i.e. compare like with like, EtO-, PhO-, CH3C(O)O-).
(vii)
The concept of hard and soft bases is useful for evaluating the differences in nucleophilicity between
different heteroatoms carrying lone pairs, where the assesment is made on the difference in
electronegativities of the atoms and the degree of polarisability of the lone pair of electrons,
(viii)
Some nucleophiles carry lone pairs of electrons on more than one heteroatom and, therefore, can attack
electrophilic centres through both heteroatoms – ambident nucleophiles. The more electron rich heteroatom
(more lone pairs, higher charge) will react with electrophilic centres involving SN1 reaction conditions, whilst
the less electron rich heteroatom will react with the electrophilic centre under SN2 conditions, and
(ix)
One should not forget the role that solvent can have on the nucleophilicity of nucleophiles (see part 4ii)
The Nucleophile and SN1 Reactions
The rate of reaction for an SN1 reaction is…
Rate = k[R-Hal]
Thus, simply changing the nucleophile will have no effect on the rate of reaction
as the rate determining step (the slowest step) only involves the haloalkane.
The Nucleophile and SN2 Reactions
Conversely, in a SN2 reaction changing the nucleophile can have dramatic effects
on the rate of reaction as the rate determining step (the formation of the transition
state) is dependent on the nucleophile, having a rate equation described by…
Rate = k[R-Hal][Nu:]
So if nucleophile A: is better than nucleophile B: the reaction rate will be quicker
when A is used!
We refer to the relative degrees of nucleophile efficiency as NUCLEOPHILICITY
How to Estimate the Nucleophilicity of a Nucleophile
Nu
Br
Nu
Br
The nucleophilicity is all to do with the ease (or not) of a lone pair of electrons
being donated in to the s* orbital of an electrophilic atom centre
Some Guidelines for Estimating Nucleophilicity
There is some correlation between basicity and nucleophilicity.
remember both a base (B:) and a nucleophile (Nu:) are
electronically very similar.
Both have a lone pair of electrons on an atom within the molecule
Elimination Mechanisms
Base, B:
+
B:
H+

Cl
B:
+
H
+
+
The lone pair of electrons on a base
attack a electrophilic hydrogen atom.
Nucleophile, Nu:
Nu:
H
+
Cl
Substitution Mechanisms
Nu:
H
The lone pair of electrons on a nucleophile
attack a electrophilic atom other than hydrogen.
Thus, by considering pKa values one can estimate the nucleophilicity.
Of course, we will be considering the conjugate base as the nucleophile.
Thus, the higher the pKa the better the conjugate base will be as the
nucleophile
pKa
15.9
10.00
conjugate
base
OH2
OH2
+
+
OH
OH
OH3
+
O
OH3
+
O
OH
4.76
OH2
OH3
+
O
+
Nucleophilicity
Good
Intermediate
O
Bad
O
Caution on Correlating Basicity with Nucleophilicity!
An base-acid reaction is an equilibrium process.
That is to say that the reaction lies at its thermodynamically most stable state
A nucleophile-electrophile reaction is not an equilibrium process.
That is to say that the reaction is kinetically controlled (once the Nu-carbon
bond is formed it is generally not reversible).
An base-acid reaction is little effected by steric influences (a proton is small!)
A nucleophile-electrophile reaction is subject to steric factors.
Hard Base/Soft Base
Hard Base: this is a donor atom of high electronegativity
O and N
The lone pair of electrons are held ‘tightly’ by the donor atom
Thus, these electrons are not very polarisable
Therefore, more difficult to donate these electrons to the s* orbital
Soft Base: this is a donor atom of lower electronegativity
S, I, Br, and Cl
The lone pair of electrons are held ‘loosely’ by the donor atom
Thus, these electrons are polarisable
Therefore, much easier to donate these electrons to the s* orbital
Thus, softness promotes nucleophilicity
Harder
RO:-
F:-
3.0
3.5
4.0
R3P:
RS:-
Cl:-
2.1
2.4
3.0
Softer R3N:
Br:2.8
I:2.5
Softer
CHM1C3
– Introduction to Chemical Reactivity of Organic
Compounds–
– Summary
Sheet Part 3iv –
Substitution Reactions:
Nucleophile
It is no surprise that changing the nucleophile in reactions in which the substrate (the haloakane) ionises to the
carbocation (i.e. SN1 reactions in which the rate is independent of the Nu:) has no effect on the rate of the reaction,
whereas the rate can be dramatically effected in reactions which follow an SN2 reaction course.
The SN2 substitution reaction is driven by the ability of a lone pair of electrons to be donated from a nucleophilic species
into the s* orbital associated with an electrophilic atom (usually carbon). The ability of the the lone pair to do this
donation (the nucleophilicity) is dependent on several factors which include (i) the degree of solvation of the nucleophile
(high e or low e solvents (part 4ii)), (ii) the nature of the solvent (protic or non-protic (part 4ii)), the electronegativity of the
heteroatom carrying the lone pair of electrons, and (iv) the nature of the heteroatom (ROH compared to RO-).
An assessment of nucleophilicity between the same heteroatoms can be carried out utilising pKa (acid/base) date,
bearing in mind that the analysis is not a direct comparison because (i) acid/base reactions are thermodynamically
controlled (i.e. reversible equilibria) and are not influenced by sterics, whilst electrophile/nucleophile reactions are
generally kinetically controlled (i.e. unreversible equilibria) and are influenced by steric factors.
For considering the nucleophilicity of lone pairs of electrons on different heteroatoms it is useful to use the concept of
hard and soft bases, which is based on the electronegativity of the heteroatom. The lower the electronegativity, the
smaller the attraction of the nucleus for the outer valence electrons, and therefore the more easily the valence lone pairs
of electrons will be polarised by electrophiles. Thus, low electronegativity atoms – soft bases – are better nucleophiles
than hard bases.
Finally, ambident nucleophiles (CN-, NO2-) contain more than one heteroatom carrying a lone pair of electrons. Thus,
they can react with elecrophilic centres in two fashions. Under SN1 reaction conditions the more electron rich
heteroatom react with the electrophilic centre, whereas under SN2 reaction conditions the less electron rich heteroatom
reacts with the electrophilic centre.
Exercise 1: Substitution Reactions
Me
Me
Nu Nu
D
SN1
or
SN2
Me
Nu
Me
Nu
Nu
Br
D
D
R
R
Complete the table and comment on
the difference in rates between the
reactions when R = H and Ph.
R = Ph
R= H
R
Relative Rate of Reaction
Rate
Eqn
(1 = fastest, 6 = slowest)
R=H
R = Ph
O
O
O
S
O
N
O
O
N
O
Nu
O
O
O
O
Comments
D
R
N
O
Complete the table and comment on
the difference in rates between the
reactions when R = H and Ph.
Exercise 1: Substitution Reactions
Me
Me
Nu Nu
D
SN1
or
SN2
R=H
R = Ph
SN2
SN1
Me
Nu
Nu
Br
D
D
R
R
Me
Nu
R = Ph
D
R
R= H
R
Relative Rate of Reaction
Rate
Eqn
(1 = fastest, 6 = slowest)
k[R-Br][Nu}
2
6
k[R-Br]
O
1
3
rates all the same
1O
O
5
S
Nu
N
O
O
N
O
O
4
O
O
O
O
N
O
When R = Ph the carbocation can be formed, as this produces the stablised benzyl cation, thus reaction
goes by SN1 Mechanism. Rate equation for SN1 process is not dependant on Nu concentration, as rate
determining step is formation of carbocation. Thus, relative rates are all the same.
When R = H the cabocation can not be formed, as this would produce the highly unstable primary
carbocation, hence reaction proceeds via SN2 mechanism. SN2 mechanism is dependent on Nu
concentration, hence rates will be dependant on effectiveness of nucleophiles, which we can correlate to
pKas of the corresponding acids of the nucleophiles.
Exercise 1: Substitution Reactions
Identify the products and rationalise the differences in product outcome.
1
NaNO2
H
EtOH
Rate = k[R-Br][NaNO2]
Br
AgNO2
EtOH
2(+/-)
Answer 1: Substitution Reactions
Identify the products and rationalise the differences in product outcome.
NaNO2
1
AgNO2
Br
H
EtOH
Rate = k[R-Br][NaNO2]
2(+/-)
EtOH
Rate = k[R-Br]
O
O N O
H
N
H
O
Look up
ambident nucleophiles
O
O
N
N
O
O
H
O
N
H
Br
O
H
Br
Ag
H
Br Ag