Transcript Nucleophilic Substitution and b

An alternative to making the halide:
ROH  ROTs
CH3
CH3
Preparation from
alcohols.
ROH +
O
S
O
O
S
O
Cl
p-toluenesulfonyl
chloride
Tosyl chloride
TsCl
The configuration of
the R group is
unchanged.
O
R
Tosylate
group, -OTs,
good leaving
group,
including the
oxygen.
Example
CH3
CH3
TsCl
H
H
OTs
C3H7
CH3
OH
C3H7
CH3
C2H5
Preparation of tosylate.
Retention of configuration
C2H5
Substitution on a tosylate
The –OTs group is an excellent leaving group
Acid Catalyzed Dehydration of an Alcohol,
discussed earlier as reverse of hydration
Secondary and tertiary alcohols, carbocations
Protonation,
establishing of good
leaving group.
Elimination of water to
yield carbocation in
rate determining step.
Expect tertiary faster
than secondary.
Rearrangements can
occur.
Elimination of H+
from carbocation to
yield alkene.
Zaitsev Rule
followed.
Primary alcohols
Problem: primary carbocations are not observed. Need a modified, non-carbocation
mechanism.
Recall these concepts:
1. Nucleophilic substitution on tertiary halides invokes the carbocation but nucleophilic
substitution on primary RX avoids the carbocation by requiring the nucleophile to
become involved immediately.
2. The E2 reaction requires the strong base to become involved immediately.
Note that secondary and tertiary protonated alcohols eliminate the water to yield a
carbocation because the carbocation is relatively stable. The carbocation then
undergoes a second step: removal of the H+.
The primary carbocation is too unstable for our liking so we combine the departure of
the water with the removal of the H+.
What would the mechanism be???
Here is the mechanism for acid catalyzed
dehydration of Primary alcohols
1. protonation
2. The
carbocation is
avoided by
removing the
H at the same
time as H2O
departs (like
E2).
As before,
rearrangements can
be done while
avoiding the primary
carbocation.
Principle of Microscopic Reversibility
Same mechanism in either
direction.
Pinacol Rearrangement: an example of
stabilization of a carbocation by an adjacent lone
pair.
Overall:
Mechanism
Reversible
protonation.
Elimination of
water to yield
tertiary
carbocation.
1,2
rearrangement
to yield
resonance
stabilized cation.
Deprotonation.
This is a
protonated
ketone!
Oxidation
Primary alcohol
RCH2OH
Na2Cr2O7
Na2Cr2O7
RCH=O
RCO2H
Na2Cr2O7 (orange)  Cr3+
(green) Actual reagent is
H2CrO4, chromic acid.
Secondary
Na2Cr2O7
R2CHOH
R2C=O
KMnO4 (basic) can also be
used. MnO2 is produced.
Tertiary
R3COH
NR
The failure of an attempted
oxidation (no color change) is
evidence for a tertiary alcohol.
Example…
OH
OH
Na2Cr2O7
acid
HO
CH2OH
O
CO2H
Oxidation using PCC
Primary alcohol
PCC
RCH2OH
RCH=O
Secondary
PCC
R2CHOH
R2C=O
Stops here, is not oxidized to
carboxylic acid
Periodic Acid Oxidation
OH
O
OH
HIO4
glycol
O
+
HIO3
two aldehydes
OH
O
O
HIO4
HO
O
+
aldehydes
carboxylic acid
O
O
O
HO
HIO4
O
+
OH
carboxylic acid
HIO3
carboxylic acid
OH
O
O
2 HIO4
+ 2 HIO3
HO
O
OH
OH
O
HIO3
Mechanistic Notes
Cyclic structure is formed during
the reaction.
Evidence of cyclic intermediate.
Sulfur Analogs, Thiols
Preparation
RI +
HS-
 RSH
SN2 reaction. Best for primary, ok secondary, not tertiary (E2 instead)
Oxidation
Acidity
H2S pKa = 7.0
RSH
pKa = 8.5
Ethers, Sulfides, Epoxides
Variety of ethers, ROR
Aprotic solvent
Reactions of ethers
Ethers are inert to (do not react with)
•Common oxidizing reagents (dichromate, permanganate)
•Strong bases
HX protonates ROH, set-up leaving group
followed by SN2 (10) or SN1 (20 or 30).
•Weak acids. But see below.
Ethers do react with conc. HBr and HI. Recall how HX reacted with ROH.
Look at this reaction and attempt to predict the mechanism…
Characterize this reaction:
Fragmentation
Substitution
Regard as
leaving
group.
Compare to
OH, needs
protonation.
Expectations for mechanism
Protonation of oxygen to establish
leaving group
For 1o alcohols: attack of halide, SN2
For 2o, 3o: formation of carbocation, SN1
Mechanism
H
+
H
R-O-R
H
XO
R
R
O
R
primary R
R
X
Inversion of this
R group
Secondary,
Tertiary R
H
X-
O
R
This alcohol is
protonated, becomes
carbocation and
reacts with halide.
This alcohol will
now be
protonated and
reacted with
halide ion to yield
RX. Inversion will
occur.
R
R
X
Loss of chirality at reacting
carbon. Possible
rearrangement.
Properties of ethers
Aprotic Solvent, cannot supply the H in Hbonding, no ether to ether hydrogen
bonding
Ethers are polar and have boiling points
close to the alkanes.
propane (bp: -42)
dimethyl ether (-24)
ethanol (78)
Hydrogen Bonding
R
Requirements of
Hydrogen Bonding:
Need both H acceptor
and donor.
R
O
H
O
protic
H
H acceptor
Ethers are not protic, no ether to
ether H bonding
However, ethers can function as
H acceptors and can engage in H
bonding with protic compounds.
Small ethers have appreciable
water solubility.
H donor
Synthesis of ethers
Williamson ether synthesis
RO- + R’X
 ROR’
nucleophile electrophile
Characteristics
• RO-, an alkoxide ion, is both a strong nucleophile (unless bulky and hindered)
and a strong base. Both SN2 (desired) and E2 (undesired side product) can
occur.
• Choose nucleophile and electrophile carefully. Maximize SN2 and
minimize E2 reaction by choosing the R’X to have least substituted carbon
undergoing substitution (electrophile). Methyl best, then primary, secondary
marginal, tertiary never (get E2 instead).
• Stereochemistry: the reacting carbon in R’, the electrophile which
undergoes substitution, experiences inversion. The alkoxide undergoes no
change of configuration.
Analysis (devise reactants and be
mindful of stereochemistry)
C2H5
Provide a
synthesis starting
with alcohols.
H3C
H
D
H
Use Williamson ether synthesis.
•Which part should be the nucleophile?
•Which is the electrophile, the compound
undergoing substitution?
O
H
CH3
H
CH3
C2H5
Electrophile should ideally be 1o.
Maximizes subsitution and minimizes
elimination.
We can set it up in two different ways:
C2H5
C2H5
Electrophile, RX
undergoing
1o
substitution
3
H3C
H
D
H
or
O
Nucleophile
H
2o
Nucleophile
H C
H
Remember: the electrophile (RX) will
D inversion.
H
experience
Must1oallow for
that!
O
H
CH3
H
CH3
CH3
H
CH3
C2H5
C2H5
Electrophile, RX
undergoing
substitution
2o
C2H5
C2H5
Electrophile
(RX)
1o
H3C
H
D
H
H3C
H
H
D
SN2
X
Note allowance
for inversion
O
Nucleophile
H
2o
CH3
O
H
CH3
H
CH3
H
CH3
C2H5
Preferably use tosylate as the
leaving group, X. Thus….
C2H5
C2H5
C2H5
C2H5
H3C
H3C
H
H
D
TsCl
H3C
H
H
D
H
D
H
O
H
CH3
H
CH3
C2H5
SN2
{
inversion
retention
Done!
OTs
OH
OH
O
H
CH3
H
CH3
C2H5
K
retention
H
CH3
H
CH3
C2H5
Acid catalyzed dehydration of alcohols to yield
ethers.
H
2 ROH
ROR + H2O
Key ideas:
•Acid will protonate alcohol, setting up good leaving group.
•A second alcohol molecule can act as a nucleophile. The nucleophile
(ROH) is weak but the leaving group (ROH) is good.
Mechanism is totally as expected:
•Protonation of alcohol (setting up good leaving group)
•For 2o and 3o ionization to yield a carbocation with alkene formation as side
product. Attack of nucleophile (second alcohol molecule) on carbocation.
• For 1o attack of nucleophile (second alcohol molecule) on the protonated
alcohol.
Mechanism
For primary alcohols.
RCH2OH
RCH2OH
RCH2OCH2R
RCH2OCH2R
RCH2 - OH2
primary
alcohols
ether
H
For secondary or tertiary alcohols.
ROH
ROH2
H2O + carbocation
ROH
- H+
ether
alkene
E1 elimination
SN1 substitution
H-O-H leaves,
R-O-H attached.
Use of Mechanistic Principles to Predict Products
acid
C10H22O
OH
H+
H
OH
OH2+
protonate
H
Have set-up leaving
group which would yield
secondary carbocation.
Check for
rearrangements. 1,2 shift
of H. None further.
O
OH
O
H
Carbocation
reacts with
nucleophile,
another alcohol.
deprotonate
H
H
Acid catalyzed addition of alcohol to
alkene
Recall addition of water to an alkene (hydration). Acid catalyzed, yielded
Markovnikov orientation.
Using an alcohol instead of water is really the same thing!!
OH
OR
HOH
ROH
acid
acid
alcohol
ether
Characteristics
Markovnikov
Alcohol should be primary to avoid carbocations being formed from the alcohol.
Expect mechanism to be protonation of alkene to yield more stable
carbocation followed by reaction with the weakly nucleophilic alcohol.
Not presented.