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C ClH3CH2C
H
H3C
CH3S- Na+
CH3CNCH3CS
CH2CH3H
CH3
+ NaCl
C OHH3C
H3C
H3C
HBr, ∆C Br
H3CH3C
H3C
+ H2O
H3CH2C Br:N(CH3)3
OSO2CH3NaI, acetone
I
+ NaOSO2CH3
H3CH2C N(CH3)3Br
Substitution Reactions of Alkyl Halides
• involve displacement of a heteroatom from carbon -- the "leaving group"
• the leaving group is always more EN than carbon making the carbon electrophilic
• the carbon is always sp3 hybridized
• there is always a nucleophile present, either -ve or d -
SN1 reactions in which the solvent participates as a nucleophile are called solvolysis reactions.
C CH3C C CH3C CH3
Important Synthetic Reactions that are Substitutions
Many important functional groups can be prepared by using Substitution reactions.
O2N CH2
Examples involving C-C bond formation: Result
CH3CH2Br + NaCN CH3CH2CN
Nucleophile
CH3I +
Examples involving C-O bond formation:
PhCH2Cl +
CH3I + PhO CH3OPh
CH3CH2CH2CH2Cl + HO CH3CH2CH2CH2OH
Examples involving C-S bond formation:
CH3CH2Br + NaSH CH3CH2SH
CH3I + CH3CH2CH2S
PhCH2CH2NO2
CH3CH2CH2SCH3
(CH3)3C—Br + H2O (CH3)3C—OH
(CH3)3C—Br + HOCH3 (CH3)3C—OCH3
Examples involving C-H bond formation:
CH3(CH2)8CH2Cl + LiAlH4 CH3(CH2)8CH3
Examples involving C - halogen bond formation:
CH3CH2CH2CH2Cl + KNCO CH3CH2CH2CH2NCO
Examples involving C-N bond formation:
CH3CH2CH2CH2Cl + H3N CH3CH2CH2CH2NH3
PhCH2Cl + N(CH3)3 PhCH2N(CH3)3 Cl
CH2Br + NaI CH2I
+ NaN3
Br N3
What makes a good nucleophile?
It is hard to derive an accurate order of nucleophilic strength because, among other things, solvent plays an important role in SN2 reactions. Having said that, the following trends are a useful guide.Strong bases are good nucleophiles... so:
A nucleophile with a negative charge is always a more powerful nucleophile than its conjugate acid. So, HO- is more nucleophilic than H2O, and H2N- is more nucleophilic than H3N:.
Overall: R3C- > H2N- > RO- > HO- > R2NH > AcO- > ArO- > H3N: > F- > H2O.
For the same atom with the same charge, nucleophilicity parallels basicity:
CH3CH2O > HO > PhO > CH3CO2 > H2O
For atoms in the second row of the periodic table, and with the same charge, nucleophilicity parallels basicity:
H3C > H2N > HO > F
Going down the periodic table, nucleophilicity increases, though basicity decreases. Therefore, for halides:
I- > Br- > Cl- > F-
Group VIA: RSe - > RS - > RO -
Group VA: R3P > R3N
Steric bulk around the basic atom suppresses nucleophilicity...
CH3CH2O > CH3C
H3CH3C
Ot-butoxide
H2N >N
Diisopropylamide(LDA)
pKa conj. acid:
CH3CH2CH2OH CH3CH2CH2ClH3CH2C
BrH
CH3 H3CC
CH3H3C
OH
CH2Cl CH2OH
C CH
H CH2Br
HC C
H
H C
H
H3CCH3
OH
CH3C
CH3
OHCH2CH2Cl Br
C CH
H
H
Br
To determine which, if either, mechanism is operating, you must learn to...
Alkyl halides and alcohols undergo substitution by two mechanisms: SN1 and SN2.
The SN1 reaction involves a the formation of a carbocation reaction intermediate in rate determining step. SN2 involves the collision of the nucleophile with the carbon that bears the leaving group.
3°, benzylic and allylic substrates undergo SN1 reactions because they form relatively stable carbocations.
1° substrates undergo SN2 reaction because they are sterically uncluttered at the reaction site.
2° substrates undergo both reaction types but slowly.
The SN1 Reaction
H3C
C
H3CH3C Br
H2O
H3C
C
H3CH3C OH + HBr
SN1 reactions in which the solvent participates as a nucleophile are called solvolysis reactions.
The Mechanism...
H3C
CH3C
H3C Br
H3CC CH3
H3C
BrOH
HH3C
CH3C
H3C OH
H
H3C
CH3C
H3C OH
HBr
Br
HOH3C
Br
HO CH3
HO
H3C
HO
CH3H3C C
CH3
CH3
HO
CH3
HO
H3C
The reaction profile...
This mechanism operates when:• the substrate forms a relatively stable carbocation• the nucleophile is a weak base, preferably a neutral molecule like H2O, ROH etc.• the reaction is done in a polar, protic (OH)solvent (water, alcohols, acetic acid etc.)
Factors that stabilize carbocations.
Since the SN1 reaction involves the formation of carbocations in the rate determining step, only those species that form relatively stable carbocations will undergo this reaction in a timely fashion.
H2C
C C
H
H H2C
H
Br
H3CO
H2C
Cl
Cl
Alkyl carbocations are stabilized by electron donation from adjacent C-H bonds, something that is known as hyperconjugation.
H
C
HH
CHH
1° 3° H
C
HH
CC
C
H
H
HH
HH
So for alkyl carbocations, the order of stability is...
Vinyl and aryl carbocations cannot be stabilized by resonance...
C CHH H
C
H
H
C H
H
or by hyperconjugation.
So, the order of stability of carbocations is:
Usually, SN1 reactions are practical for benzylic, allylic and 3° substrates.
The Hammond Postulate - a useful and oft used tool to rationalize the relative rates of analogous reactions.
"The structure of a transition state tends to resemble that species to which it is closer in energy."For endothermic reactions... For exothermic reactions...
the transition state is closer in energy to the products and therefore said to be "product-like" in structure. From this, we infer something about the energy of the transition state from the stability of the product.
the transition state is closer in energy to the reactants and therefore said to be "reactant-like" in structure. From this, we infer something about the energy of the transition state from the stability of the reactants.
H3C
C
H3C
H3C Br
H3CC CH3
H3C BrNu:
H3CC
H3CH3C Nu
H3CC
H
H3C BrH3C
C CH3H
Br
H3CC
HH3C Nu
Nu:
Therefore, when comparing reactions that involve the formation of carbocation intermediates in the RDS, the one involving the more stable carbocation intermediate will be formed ...
H3C
C
H3CH3C Br
H3C
C CH3
H3C
O
H
H
Br
Reactions Involving Carbocations
H3C CC
CH3
H
HH
H3C CC
CH3
H
H
H3C
C CH3
H3C H2C C
CH3
CH3 H3CC
CH3
H3C H2C C
CH3
CH3
H3CC
CH3
H3C HC CH3
H3C C
CH3
CH3
CHCH3
Substitution (SN1 - the last step is a Lewis acid/base reaction).
Elimination (E1 - the last step is a Brønsted acid/base reaction.)
Addition
Rearrangement
H3CC
CH3
H CH2 ClAlCl3
H3CC
CH3
H CH2 Cl AlCl3
Carbocation rearrangements are often promoted by the presence of Lewis acids. In this case, the intermediates are said to be "carbocation-like" if not actual carbocations.
H3C C
CH3
CH3AlCl4
C
H3C
H3CCH3
C
CH3I
H
H2O/CH3OH, ∆ C
H3C
H3CCH3
C
CH3OH
HC
H3C
H3COH
C
CH3H
CH3
C
H3C
H3CCH3
C
CH3I
H
C
H3C
H3CCH3
C
CH3
H
C
H3C
H3CCH3
C
CH3OH
H
C
H3C
H3CC
CH3H
CH3
C
H3C
H3COH
C
CH3H
CH3
Carbocation rearrangements are always possible when group migration can lead to a more stable carbocation. Generally this is an unwanted complication.
Another case...
Cl H2O/CH3OH, ∆
H H H
Yet another case...
AlCl3C
CH3
CH3
CH3
C
H3CH3C
H3C
Cl C
H3CH3C
H
CH2Cl
AlCl3C
CH3
CH3
CH3
Stereochemistry of the SN1 Reaction
C
PhCH2CH3H3C
BrNaI/Acetone
C PhCH2CH3H3C
C
PhCH2CH3H3C
I
C
PhH3CH2C CH3
I
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.
C
PhCH2CH3H3C
BrNaI/Acetone
C PhCH2CH3H3C
C
PhCH2CH3H3C
I
C
PhH3CH2C CH3
I
Br-
The SN2 reaction
Best for 1° and methyl substrates.
I H3C Br CH3I Br
The mechanism consists of a single elementary process.
The Stereochemistry of the SN2 reaction
The reaction geometry is such that the collision must occur with the nucleophile attacking the back side of the C—LG bond.
H3C Br CH3I Br
When attack occurs at an asymmetric carbon, the reaction occurs exclusively with inversion of the absolute stereochemistry. This is an example of a stereospecific reaction.
C Br
H3CH3CH2C
HCS
CH3CH2CH3
H
BrH3C
Why backside attack?
C Br
HH
HH3C S CS
HH
H
BrH3C
Substrate structure and the rate of SN2
Substrate Relative rate
CH3Br
0.004
CH3CH2CH2Br
C
H3C
H3CBr
H
C
H3C
H3CBrCH3
100
1.31
0.81
0.015
CH3CH2Br
So the substrate structure dependence on rate is...
More data...
CH3Br
CH3CH2CH2Br
100
1.31
0.81
CH3CH2Br
CH3CH2CH2CH2Br 0.52
C
CH3
H3CH2C
Br
H
C
CH3
H3CH2C
Br
H3C
0.052
0.00001
Neopentyl substrates are prone to rearrangement.
C
CH3
H3CH2C
OTs
H3C H2O/CH3OH, ∆
C
OH
H3CH2C
CH3
H3C
CH3C
CH2
CH3
H3C
The effect of solvent on the rate of SN1 and SN2 reactions...
SN1 processes are fastest in polar, protic solvents due to ion-dipole stabilization of the developing charge in the transition state.
Polar protic solvents...
H3CC
OH
OOH CH3CH2OH CH3OH H2OOH
t-Butanol (t-BuOH)
Isopropanol (iPrOH)
Ethanol (EtOH)
Methanol(MeOH)
WaterAcetic AcidAcOH
Polar aprotic solvents are best for SN2 because the nucleophile is not as solvated.
H3CC
CH3
O
H3C C N CH3OCH2CH2OCH3 HC
N(CH3)2
O
H3CS
CH3
O
H3CH2CO
CH2CH3
N
O
Acetone Acetonitrile(MeCN)
Dimethoxyethane(DME) Dimethylformamide
(DMF)
Dimethyl sulfoxide(DMSO)
Ethyl ether(Et2O)
Pyridine(Pyr) Tetrahydrofuran
(THF)
OK for the preparation of 3° amines from 2° amines...
NHCl
OH
N
OH
70%
and quaternary ammonium compounds...
NCH3
CH3
CH3I N CH3
CH3
CH3
I
Preparation of Amines vis SN2
But pitfalls in the synthesis of 1° or 2° amines...
H3N: CH3CH2Br CH3CH2NH3Br
CH3CH2NH3Br H3N: CH3CH2NH2 NH4Br
CH3CH2NH2 CH3CH2Br CH3CH2NH2CH2CH3 Br
Wtih 16 eq. NH334% 1°57% 2°1% 3°
Comparing SN2 and SN1
No. Steps 1 2 or 3
SN2 SN1
Reactionorder
2nd 1st
Substrate structure dependence
CH3, 1° best. 2° OK but slow.Watch for b-branching.3°, vinyl, aryl do not react.
Allylic, benzylic > 3°.2° very slow. 1°, vinyl, aryldo not react.
Intermediate None Carbocation.
Stereochemical consequences StereospecificInversion
Racemization orpartial racemization
Solvent Polar, aprotic. Polar protic
Competing reaction E2 E1, E2, rearrangement.
Importance of nucleophile on rate
Very important.NR for weak nucleophileslike H2O, ROH.
Unimportant.
Substrateclassification
Weak base/good Nu
Moderate/strong base/good Nu
Weak base/weak Nu
Methyl, CH3X SN2 SN2 NR
1°
2°
3°
SN2
SN2 and SN1
SN1
SN2
E2
SN1
E2
SN1
SN1
1° Benzylic
2° Benzylic
3° Benzylic
1° Allylic
2° Allylic
3° Allylic
Aryl
Alkenyl(Vinyl)
NR NR NR
NRNRNR
SN2 and SN1
SN1
SN1
E2
E2
SN1SN2
SN1
SN1
SN2 and SN1
SN1
SN1
E2
E2
SN1SN2
SN1
SN1