Download Chapter Seven - U of L Class Index

Nucleophilic
Substitution
Reactions
These reactions are polar and usually involve negatively charged nucleophiles.
X:
Br
X
Br
The organic substrates for such reactions are usualy alcohols of alkyl halides.
Electrophilic centers exist by virtue of the electronegativity difference between
carbon and leaving group bond.
The Leaving Group
Generally, good leaving groups are WEAK BASES.
X
Br
X:
Br
All of the halides are good leaving groups except fluoride.
Hydroxide is very basic, and a woeful leaving group.
X
OH
X:
OH
One solution…
O
O
Cl
S
N
S
OH
CH 3
X:
O
A su lfo n at e est er .
"Mesyla te - OMs"
O
O
S
CH 3
CH3
O
Mesyl Ch lo r id e
O
O
O
X
O
S
O
CH 3
Other sulfonates…
O
O
H
H
S
S
CF3
OTf
Tr iflat e
O
O
H
S
CH 3
O
O
H
CF3
O
O
H
O
O
H
p -To lu en esu lfo n at e
o r To sy lat e
OTs
O
S
Br
O
OBs
Br osy lat e
Neutral molecules are spiffy leaving groups…
X:
X
OH
OH
H
H
Br
OH
O
H
H
Br
O
H
Br
H
O
H
The Nucleophile…
Good nucleophiles are usually basic, or polarizable.
Rules to Remember…
1) A negatively charged species is usually more nucleophilic than its conjugate base.
2) For a given atom and charge, nucleophilicity parallels basicity.
O
H 3 CH 2 C
H
O
O
O
C
O
H3 C
3) Within a group of the periodic table, bigger is better in terms of nucleophilic
character of the attacking atom.
4) Steric effects can effect nucleophilicity…
H 3 CH 2 C
O
H3 C
H3 C
C
O
N
H3 C
Classify your substrate!
Structural features determine whether certain reactions will take place which
mechanism operates.
H
CH 3 CH3 CH2 OH
CH 3 CH 3 CH 2 Cl
H3 C
H 3 CH 2 C
CH2 Cl
CH 3
Br
CH2 OH
CH 3
H2 C
H2 C
C
OH
H3 C
CH 3
Br
H3 C
C
C
H
H2 C
OH
C
H
H3 C
H
CH 2 CH 2 Cl
C
Br
Br
OH
H2 C
C
H
Alkyl halides
mechanisms:
(and many alcohols)
undergo
substitution
by t w o
Sn 1 and Sn 2 .
The Sn 1 mechanism involves the formation of a carbocation intermediate in the ratedetermining step.
3°, benzylic and allylic substrates undergo Sn 1 reaction because they form relatively
stable carbocations.
1° substrates undergo Sn2 reaction because they are sterically uncluttered.
2° substrates undergo both reaction types, but sluggishly.
The Sn 1 Reaction
H3 C
H3 C
H2 O
C
H3 C
H3 C
Br
C
OH
+ HBr
H3 C
H3 C
Rea ct ion s in wh ich t h e solv en t p a r tici p at es as a n u celo p h ile ar e called
solv oly sis r ea ct io n s.
The Mechanism…
H3 C
C
CH3
Br
H3 C
H3 C
C
H3 C
H
H3 C
Br
CH3
H
C
H3 C
H3 C
H
Br
O
H
H3 C
C
H3 C
H3 C
The reaction profile…
O
OH
+ HBr
Since the SN1 reaction involves carbocations that are formed in the RDS, then only
those substrates that form relatively stable carbocations will undergo this reaction.
What makes for a stabilized
H2
C
CH 2
Cl
H 2C
H 2C
carbocation?
Br
CH 2
C
H 2C
C
H
H3 C
H
H2
C
O
H3 C
CH 2
O
Cl
Alkyl carbocations
bonds.
are stabilized
by hyperconjugation
to adjacent
3°
1°
H
H
C
H
C
H
H
H
C
H
C
H
C
H
H H
C
H
H
H
Vinyl (and aryl) carbocations cannot be stabilized by resonance.
H
Cl
C
H
H
C
C
H
C
H
=
H
H
H
So, the order of stability of carbocations is:
Benzyl = allyl > 3° > 2° > 1° > CH3 + > vinyl, aryl
C
C
H
C-H
The Hammond Postulate – a useful and oft used tool to rationalize
relative rates of reactions.
the
“The structure of a transition state tends to resemble that species to which it is closer
in energy.”
For endothermic processes…
For exothermic processes…
the TS is closer in energy to the p r o d u c t s
and therefore said to be "product-like" i n
structure. As a result, we can i n f e r
something about the energy of t h e
transition state from the stability of t h e
product.
H 3C
CH 3
C
H3 C
H 3C
Br
C
H 3C
Nu :
H 3C
H3 C
Br
CH 3
the TS is closer in energy to the reactants a n d
therefore said to be "reactant-like" in s t r u c t u r e .
As a result, we can infer something about t h e
energy of the transition state from the stability
of the r e a c t a n t .
C
H3 C
H3 C
Nu
CH 3
C
H
H
Br
C
H3C
C
Br
H
Nu
H
H
H
Nu :
Therefore, when comparing reactions that involve carbocation intermediates, the one
involving the more stable carbocation intermediate will be…
Reactions Involving Carbocations
Substitution
H3 C
CH3
C
H3 C
C
Nu
Nu
H3 C
H3 C
CH3
Elimination
OH2
CH 3
H3 C
CH3
H
C
C
H
C
H3C
CH 2
H
Addition
CH 3
CH 3
H2 C
H3 C
C
C
C
CH3
H3 C
H2
C
CH3
C
H3 C
CH 3
CH 3
CH 3
Rearrangement
H3 C
H3 C
C
H3 C
H3 C
CH3
C
C
H3 C
H
CH3
C
CH 3
H
Carbocation rearrangments are often promoted by the presence of Lewis Acids. In
this case, the intermediates are said to be “carbocation-like” if not carbocations.
Cl
H3 C
H3 C
C
H
Cl
C
H
H
AlCl 3
H3 C
H3 C
C
H
Cl
C
AlCl 3
H3 C
H
H
C
H3 C
AlCl 3
H
H
C
H
Carbocation Rearrangements are always possible when group migration can lead to a
more stable carbocation. Generally, this is a pain…
H3 C
H3 C
C
C
H3 C
H3 C
H3 C
C
CH3
I
H 2 O,
CH3 OH, ∆
H3 C
H3 C
C
H
C
H3 C
H3 C
H3 C
H3 C
C
CH3
I
H
H3 C
C
H
C
C
H3 C
CH3
H
CH3
H3 C
CH 3
C
C
HO
CH 3
C
H3 C
H
H3 C
H3 C
C
H3 C
H3 C
C
CH3
OH
CH3
H
CH3
OH
H3 C
H3 C
C
H
HO
C
CH3
H
CH3
Another case…
H
Cl
H
H
H 2 O,
CH3 OH, ∆
Yet another example…
H3 C
CH 3
C
H3 C
C
CH 3
CH 3
H3 C
CH3
CH
CH2 Cl
CH 3
Cl
Al Cl 3
H3 C
AlCl3
C
CH 3
CH 3
Stereochemistry
of the SN 1 reaction
Br
C
H3 C
NaI
CH2 CH 3
Ph
Acet o n e
H 3 CH 2 C
Ph
H3 C
C
CH2 CH3
Ph
I
I
C
C
CH 3
H3 C
CH2 CH 3
Ph
Reactions in which the configuration of an asymmetric center is scrambled are said to
occur with
Sometimes (depending on conditions), reactions occur with only partial
racemization…
Br -
Br
C
H3 C
NaI
CH2 CH 3
Ph
Ac et o n e
H 3 CH 2 C
Ph
H3 C
C
CH2 CH3
Ph
I
I
C
C
CH 3
H3 C
CH2 CH 3
Ph
The SN 2 Reaction
Best for 1° subtrates. And methyl, of course.
H3 C
I
Br
CH 3
I
Br
The mechanism involves a single elementary process that is bimolecular.
Stereochemistry
of the SN 2 Reaction
The collision in this reaction must occur such that the nucleophile attacks the
back side of the C-LG bond.
H
I
H
H
C
I
Br
H
C
Br
H
H
In chiral substrates, this means that the reaction occurs exclusively
H3 C
S
H3 C
H 3 CH2 C
C
Br
H
inversion of the absolute stereochemistry.
reaction.
H3 C
S
with
CH3
CH2 CH3
C
Br
H
This is an example of a stereospecific
Stereospecific:
stereoisomeric
A reaction in which the mechanism dictates that different
reactants give different stereoisomeric
products.
Why?
H
H
H
C
I
Br
structure
C
Br
H
H
Substrate
I
H
and SN 2
Relat iv e r at e
o f r eac tion
CH3 Br
100
CH3 CH 2 Br
1 .3 1
CH3 CH 2 CH 2 Br
0 .8 1
Su b st r at e
H3 C
CHBr
0 .0 1 5
H3 C
CH3
H3 C
C
Br
0 .0 0 4
CH3
So, the order of reactivity for SN 2 is:
CH 3 > 1° > 2° >>3° > vinyl, aryl
The effect of branching
100
1 .3 1
0 .8 1
0 .5 2
CH3 Br
CH3 CH 2 Br
CH3 CH 2 CH 2 Br
CH3 CH 2 CH 2 CH 2 Br
Neopentyl
next to the 1° carbon…
Br
0 .0 52
Br
0 .0 00 0 1
substrates
H2
C
H3 C
C
H3 C
are prone to rearrangement…
OTs
CH 3 OH/ H2 O
H2
C
H3 C
C
CH 3
H3 C
H2
C
H3 C
C
CH 3
CH 3
OH
CH 3
Solvent dependence
of SN 1 and SN 2 reactions…
SN 1 reactions are facilitated by using polar, protic solvents – solvents that are capable
of stabilizing ionic intermediates.
Examples:
SN 2 reactions are facilitated by using polar, aprotic solvents – solvents that will not
mask the nucleophile with a large solvation sphere.
Examples:
Making alkyl iodides – the Finkelstein Reaction
Aceton e
R
Br
R
NaI
I
Pitfalls in the synthesis of amines…
CH3 CH 2 Br
:NH 3
CH3 CH 2 NH 2
:NH 3
CH3 CH 2 NH 3 Br
CH3 CH 2 NH 2
CH3 CH 2 NH 3 Br
NH 4 Br
Br
CH3 CH 2 NH 2 CH 2 CH 3
CH3 CH 2 Br
OK for preparing 3° amines from 2° amines…
Cl
NH
HO
+
N
Cl
70 %
and quaternary ammonium compounds.
CH 3
N
CH 3
CH 3 I
N
CH 3
H3 C CH 3
Preparing alkyl halides from alcohols – SN 1 or SN 2.
3° alcohols react via SN1…
H 3C
H3 C
H
C
H3 C
Br
H3 C
H 3C
OH
H
C
H3 C
H3 C
O
CH 3
CH 3
C
H
O
H
H3 C
H3 C
C
H3 C
Br
H
1° alcohols by SN 2
H 2 SO 4 , NaBr
CH3 CH 2 CH 2 CH 2 OH
CH3 CH 2 CH 2 CH 2 Br
sometimes facilitated by Lewis acids
Zn Cl 2 , HCl
CH 3 CH2 CH2 CH2 OH
CH 3 CH2 CH2 CH2 Cl
H
H3 CH2 CH 2 CH 2 C
O
Zn Cl 2
Some other reagents…
OH
OH
PBr 3
SOCl2
Br
60%
Cl
78%
Both these reactions operate on the principal of converting OH into a better leaving
group…
Br
Br
P
P
OH
Br
O
Br
Br
H
Br
OR
P
P
O
O
OR
H
Br
Br
OR
OR
P
P
O
Br
OR
H
O
OR
H
SOCl 2
O
OH
Cl
S
O
Cl
Ethers in substitution
Making them…
reactions:
The Williamson ether synthesis
O
O
H
O
Br
NaH, DMF
This is just an SN 2 reaction, so the substrate dependence for SN 2 applies.
and breaking
them…
HI
O
I
H
I
I
O
O
H
H
TMSI, Trimethylsilyl Iodide
I
Me 3 Si
H3 C
O
I
H3 C
SiMe 3
O
CH 3
SiMe 3
O
Epoxides are good substrates
for substitution
reactions
With good nucleophiles and neutral conditions, it is an SN 2 reaction, and occurs w i t h
inversion at the reaction center…
O
O
Nu
Nu :
H
H
N3
NaN 3 , Et OH, H 2 O
H
OH
OH
H
O
H
N
N
N3
H
N
N
N
H
N
H
O
O
H
H
OH
H
In SN 2 ring-opening of epoxides, the nucleophile tends to attack the least hindered
end of the epoxide.
O
HO
Ph SH, Ph S
H3 C
89 %
H3 C
H
H
SPh
Under acidic conditions, the nucleophile adds to the most substituted end. This is a
little complicated. This resembles, but is not, an SN 1 process.
O
H3 C
H3 C
CH3 OH, H3 O+
H3 C
H3 C
OH
H 3 CO
The intermediate – carbocation, or not
H
O
O
O
CH2
H3 C
H3 C
H
H
=
CH2
H3 C
H3 C
CH2
H3 C
H3 C
H
H
H
O
O
O
=
H3 C
H3 C
CH2
CH2
H3 C
H3 C
CH2
H3 C
H3 C
Attack occurs at that carbon that is best able to stabilize positive charge
development.
H
O
-H+
CH 2
H3 C
H3 C
H3 C
H3 C
H3 CO
O
H
CH 3
OH
A Comparison
of SN 1 and SN 2
SN 1
Mechanism
Kinetics
Substrate
dependence
SN 2
2 or more steps involving a 1 step bimolecular process
carbocation intermediate
first order in substrate
second order over all, first
only
order in substrate and
nucleophile
Those substrates capable
Those substrates that are
of forming stabilized
sterically unhindered at
carbocations
the substitution site.
Stereochemistry
Occurs with racemization
or partial racemization at
the reaction center
Occurs exclusively with
inversion at the reaction
center
Importance o f
nucleophile
Not involved in RDS, but
better if less basic form of
nucleophile is employed
Leaves in RDS therefore it
is important
Polar protic solvents are
best.
Involved in RDS therefore
reactivity is important
Importance
group
Solvent
of leaving
Leaves in RDS therefore it
is important
Polar aprotic solvents are
best.