Section20 Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions
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Transcript of Created by Professor William Tam & Dr. Phillis Chang Chapter 6 Ionic Reactions Nucleophilic...
Created byProfessor William Tam & Dr. Phillis
ChangCopyright © 2014 by John Wiley & Sons, Inc. All rights reserved.
Chapter 6
Ionic ReactionsNucleophilic
Substitution and Elimination Reactions of
Alkyl Halides
© 2014 by John Wiley & Sons, Inc. All rights reserved.
About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents (hyperlinked)1. Alkyl Halides2. Nucleophilic Substitution Reactions3. Nucleophiles4. Leaving Groups5. Kinetics of a Nucleophilic Substitution Reaction: An SN2
Reaction6. A Mechanism for the SN2 Reaction7. Transition State Theory: Free-Energy Diagrams8. The Stereochemistry of SN2 Reactions9. The Reaction of tert-Butyl Chloride with Water: An SN1
Reaction10. A Mechanism for the SN1 Reaction11. Carbocations12. The Stereochemistry of SN1 Reactions13. Factors Affecting the Rates of SN1 and SN2 Reactions14. Organic Synthesis: Functional
Group Transformations Using SN2 Reactions15. Elimination Reactions of Alkyl Halides16. The E2 Reaction17. The E1 Reaction18. How to Determine Whether Substitution or Elimination Is
Favored19. Overall Summary
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents1. Alkyl Halides2. Nucleophilic Substitution Reactions3. Nucleophiles4. Leaving Groups5. Kinetics of a Nucleophilic Substitution Reaction: An SN2
Reaction6. A Mechanism for the SN2 Reaction7. Transition State Theory: Free-Energy Diagrams8. The Stereochemistry of SN2 Reactions9. The Reaction of tert-Butyl Chloride with Water: An SN1
Reaction10. A Mechanism for the SN1 Reaction11. Carbocations12. The Stereochemistry of SN1 Reactions13. Factors Affecting the Rates of SN1 and SN2 Reactions14. Organic Synthesis: Functional Group Transformations Using
SN2 Reactions15. Elimination Reactions of Alkyl Halides16. The E2 Reaction17. The E1 Reaction18. How to Determine Whether Substitution or Elimination Is
Favored19. Overall Summary
© 2014 by John Wiley & Sons, Inc. All rights reserved.
In this chapter we will consider:
What groups can be replaced (i.e., substituted) or eliminated
The various mechanisms by which such processes occur
The conditions that can promote such reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
1. Alkyl Halides An alkyl halide has a halogen
atom bonded to an sp3-hybridized (tetrahedral) carbon atom
The carbon–chlorine and carbon–bromine bonds are polarized because the halogen is more electronegative than carbon
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Iodine does not have a permanent dipole, but the bond is easily polarizable
Iodine is a good leaving group due to its polarizability, i.e. its ability to stabilize a negative charge due to its large atomic size
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Halogens are more electronegative than carbon
C X
X = Cl, Br, I
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Different Types of Organic Halides Alkyl halides (haloalkanes)
Cl Br Ia 1o chloride a 2o bromide a 3o iodide
Attached to1 carbon atom
C
Attached to2 carbon atoms
C
C
Attached to3 carbon atoms
C
C
C
sp3
C X
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Vinyl halides (Alkenyl halides)
Aryl halides
Acetylenic halides (Alkynyl halides)
sp2
X
sp2
X
benzene or aromatic ring
sp
X
© 2014 by John Wiley & Sons, Inc. All rights reserved.
C X
sp3
Alkyl halides
Prone to undergo Nucleophilic Substitutions (SN) and Elimination Reactions (E) (the focus of this Chapter)
sp2
X X X
sp2sp
Different reactivity than alkyl halides, and do not undergo SN or E reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Nu + C X
CNu + X
(nucleophile) (substrate) (product) (leavinggroup)
The Nu⊖
donates
an e⊖ pairto thesubstrate
The bondbetweenC and LGbreaks,giving both
e⊖ from thebond to LG
The Nu⊖ uses
its e⊖ pair toform a newcovalent bondwith thesubstrate C
The LGgains the
pair of e⊖
originallybondedin thesubstrate
2. Nucleophilic Substitution Reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Two types of mechanisms●1st type: SN2 (concerted
mechanism)
R
C Br
RR
HO
R
C
RR
BrHO
transition state (T.S.)+ Br
R
CHO
RR
Timing of The Bond Breaking & Bond Making Process
© 2014 by John Wiley & Sons, Inc. All rights reserved.
RC BrRR
RCRR
Br(k1)
Step (1):
+slowr.d.s.
H2O(k3)
RCRR
OH
H RCRR
OH H3O
Step (3)
+ +
RCRR
H2O(k2)
RCRR
OH
HStep (2)
+
k1 << k2 and k3
fast
fast
●2nd type: SN1 (stepwise mechanism)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A reagent that seeks a positive center
Nucleophile – “nucleus” “loving”
“phile” – derived from the Greek word philia meaning “loving”
3. Nucleophiles
© 2014 by John Wiley & Sons, Inc. All rights reserved.
C X
Has an unshared pair of e⊖
e.g.:
HO , CH3O , H2N
(negative charge)
H2O, NH3 (neutral)
This is the positivecenter that theNu⊖ seeks
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Examples:
HO + CCl
ClH H
CH3
(substrate) (product) (L.G.)(Nu )
COH
H H
CH3
+
O + CCl
ClH H
CH3(substrate) (L.G.)(Nu )
CO
H H
CH3
+H H H
H
COH
H H
CH3
H3O+(product)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
To be a good leaving group, the substituent must be able to leave as a relatively stable, weakly basic molecule or ion e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3
OMs =
OTs = O SO
OCH3
O SO
OCH3
(Tosylate)
(Mesylate)
4. Leaving Groups
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The rate of the substitution reaction is linearly dependent on the concentration of HO⊖ and CH3Br
Overall, a second-order reaction bimolecular
HO + CH3 Br HO CH2 +
Rate = k[CH3Br][HO ]
Br
5. Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The rate of reaction can be measured by● The consumption of the reactants
(HO⊖ or CH3Cl) or● The appearance of the products
(CH3OH or Cl⊖) over time
HO + C Cl HO C +
(Nu )
ClH
H
H
H
H
H
(substrate) (product)(leavinggroup)
e.g.:
5A.How Do We Measure the Rate of This Reaction?
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Time, t
Con
cen
trati
on
, M
[CH3Cl] ↓[CH3OH] ↑
Graphically…
Rate =Δ[CH3Cl]
Δt= −
[CH3Cl]t=t − [CH3Cl]t=0
Time in seconds
[CH3Cl] ↓[CH3OH] ↑
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Time, t
Con
cen
trati
on
, M
[CH3Cl]
Initial Rate[CH3Cl]t=0
[CH3Cl]t=t
Initial Rate(from slope)
= −[CH3Cl]t=t − [CH3Cl]t=0
Δt
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Example:
HO + Cl CH3 HO CH3 + Cl60oCH2O
[OH⊖]t=0 [CH3Cl]t=0
Initial ratemole L-1, s-
1
Result
1.0 M 0.0010 M 4.9 × 10-7
1.0 M 0.0020 M 9.8 × 10-7 Doubled
2.0 M 0.0010 M 9.8 × 10-7 Doubled
2.0 M 0.0020 M 19.6 × 10-7 Quadrupled
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Conclusion:
HO + Cl CH3 HO CH3 + Cl60oCH2O
●The rate of reaction is directly proportional to the concentration of either reactant.
●When the concentration of either reactant is doubled, the rate of reaction doubles.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The Kinetic Rate Expression
Rate α [OH⊖][CH3Cl]
HO + Cl CH3 HO CH3 + Cl60oCH2O
[OH⊖][CH3Cl]
Initial Ratek =
= 4.9 × 10-7 L mol-1 s-1
Rate = k[OH⊖][CH3Cl]
© 2014 by John Wiley & Sons, Inc. All rights reserved.
5B.What is the Order of This Reaction?
This reaction is said to be second order overall
We also say that the reaction is bimolecular
We call this kind of reaction an SN2 reaction, meaning substitution, nucleophilic, bimolecular
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
C Br
HH
HO
H
C
HH
BrHO
transition state (T.S.)+ Br
H
CHO
HH
negative HO⊖
brings an e⊖ pair to δ+C; δ–Br begins to move away with an
e⊖ pair
O–C bond partially formed; C–Br bond partially broken. Configuration of C begins to invert
O–C bond
formed; Br⊖ departed. Configuration of C inverted
6. A Mechanism for the SN2 Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A reaction that proceeds with a negative free-energy change (releases energy to its surroundings) is said to be exergonic
A reaction that proceeds with a positive free-energy change (absorbs energy from its surroundings) is said to be endergonic
7. Transition State Theory: Free-Energy Diagrams
© 2014 by John Wiley & Sons, Inc. All rights reserved.
At 60oC (333 K)
CH3 Br + HO CH3 OH + Cl
DGo = -100 kJ/mol
●This reaction is highly exergonic
●This reaction is exothermic
DHo = -75 kJ/mol
© 2014 by John Wiley & Sons, Inc. All rights reserved.
●Its equilibrium constant (Keq) is
DGo = –RT ln Keq
ln Keq =–DGo
RT
=–(–100 kJ/mol)
(0.00831 kJ K-1 mol-1)(333 K)
= 36.1
Keq = 5.0 x 1015
CH3 Br + HO CH3 OH + Cl
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A Free Energy Diagram for a Hypothetical SN2Reaction That Takes Place with a Negative DGo
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The reaction coordinate indicates the progress of the reaction, in terms of the conversion of reactants to products
The top of the energy curve corresponds to the transition state for the reaction
The free energy of activation (DG‡) for the reaction is the difference in energy between the reactants and the transition state
The free energy change for the reaction (DGo) is the difference in energy between the reactants and the products
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A Free Energy Diagram for a HypotheticalReaction with a Positive Free-Energy Change
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A 10°C increase in temperature will cause the reaction rate to double for many reactions taking place near room temperature
7A.Temperature & Reaction Rate
Distribution of energies at twodifferent temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The relationship between the rate constant (k) and DG‡ is exponential :
Distribution of energies at twodifferent temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve.
k = k0 e G‡/RT
e = 2.718, the base of natural logarithms
k0 = absolute rate constant, which equals the rate at which all transition states proceed to products (At 25oC,k0 = 6.2 ╳ 1012 s-1 )
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A reaction with a lower free energy of activation (DG‡) will occur exponentially faster than a reaction with a higher DG‡, as dictated byDistribution of energies at two
different temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve.
k = k0 e G‡/RT
© 2014 by John Wiley & Sons, Inc. All rights reserved.
HO- + CH3Br
T.S.
CH3OH + Br-
Free
Ene
rgy
Reaction Coordinate
Go
GG =
Go =
free energy of activationfree energy change
Exothermic (DGo is negative) Thermodynamically favorable
process
Free Energy Diagram of SN2 Reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
(R)
(S)
CH3
C Br
CH2CH3
HHO +
+ BrCH3
CHO
CH2CH3
H
(inversion)
Inversion of configuration
8. The Stereochemistry of SN2 Reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3 OCH3 + I
Example:
CH3 I + OCH3
Nu⊖ attacks from the TOP face.
(inversion of configuration)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
+BrNC H
(R)
Example:
+ CNBrH
(S)
Nu⊖ attacks from the BACK side.
(inversion ofconfiguration)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
C ClCH3
CH3
H2OCH3
C OHCH3
CH3
HCl+ +
9. The Reaction of tert -Butyl Chloride with Water: An SN1 Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
C ClCH3
CH3
H2OCH3
C OHCH3
CH3
HCl+ +
The rate of SN1 reactions depends only on concentration of the alkyl halide and is independent of concentration of the Nu⊖
Rate = k[tBuCl]In other words, it is a first-order reaction unimolecular nucleophilic substitution
© 2014 by John Wiley & Sons, Inc. All rights reserved.
In a multistep reaction, the rate of the overall reaction is the same as the rate of the SLOWEST step, known as the rate-determining step (r.d.s)
For example:Reactant Intermediate
1Intermediate
2Product
(slow)
k1 k2 k3
(fast) (fast)
k1 << k2 or k3
9A.Multistep Reactions & the Rate-Determining Step
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The opening A is much smaller than openings B and C
The overall rate at which sand reaches to the bottom of the hourglass is limited by the rate at which sand falls through opening A
Opening A is analogous to the rate-determining step of a multistep reaction
A
B
C
Fig. 6.5
© 2014 by John Wiley & Sons, Inc. All rights reserved.
A multistep process
CH3
C BrCH3
CH3
CH3
CCH3
CH3
Br(k1)
Step (1):
+
(ionization ofalkyl halide)
slowr.d.s.
10.A Mechanism for the SN1 Reaction
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of SN1 Reactions
T.S. (1)
(CH3)3C-OH+ Br
Free E
nerg
y
Reaction Coordinate
T.S. (2)
T.S. (3)
(CH3)3C -OH2
+ Br
(CH3)3C+ Br
(CH3)3CBr
+ H2O
G1
intermediate
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
CCH3
CH3
H2O(k2)
CH3
CCH3
CH3
OH
H
Step (2)
+fast
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of SN1 Reactions
intermediate
T.S. (1)
(CH3)3C-OH+ Br
Free E
nerg
y
Reaction Coordinate
T.S. (2)
T.S. (3)
(CH3)3C -OH2
+ Br
(CH3)3C+ Br
(CH3)3CBr
+ H2O
G1
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H2O(k3)
CH3
CCH3
CH3
OH
H CH3
CCH3
CH2
OH
H3O
Step (3)
+
+
CH3
CCH3
CH3
H2O(k2)
CH3
CCH3
CH3
OH
H
Step (2)
+fast
fast
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Free Energy Diagram of SN1 Reactions
intermediate
T.S. (1)
(CH3)3C-OH+ Br
Free E
nerg
y
Reaction Coordinate
T.S. (2)
T.S. (3)
(CH3)3C -OH2
+ Br
(CH3)3C+ Br
(CH3)3CBr
+ H2O
G1
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
CCH3
CH3
H2O(k2)
CH3
CCH3
CH3
OH
H
Step (2)
+
k1 << k2 and k3
fast
fastH2O
(k3)CH3
CCH3
CH3
OH
H CH3
CCH3
CH2
OH
H3O
Step (3)
+
+
© 2014 by John Wiley & Sons, Inc. All rights reserved.
2 intermediates and 3 transition states (T.S.)
CH3
CCH3
CH3
Br
The most important T.S. for SN1 reactions is T.S. (1) of the rate-determining step (r.d.s.)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Carbocations are trigonal planar
The central carbon atom in a carbocation is electron deficient; it has only six e⊖ in its valence shell
The p orbital of a carbocation contains no electrons, but it can accept an electron pair when the carbocation undergoes further reaction
11A. The Structure of Carbocations
11.Carbocations
CH3C
H3C CH3
© 2014 by John Wiley & Sons, Inc. All rights reserved.
General order of reactivity (towards SN1 reaction)●3o > 2o >> 1o > methyl
The more stable the carbocation formed, the faster the SN1 reaction
11B. The Relative Stabilities of Carbocations
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Stability of cations
Resonance stabilization of allylic and benzylic cations
CH2 CH2etc.
R
CR R
R
CR H
R
CH H
H
CH H
> > >
most stable (positive inductive effect)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Ph
BrCH2CH3
CH3
CH3OH
(S)
Ph
C
CH2CH3CH3
(trigonal planar)
CH3OHattack from left
CH3OHattack from right
CH3OHPh
CCH3 OCH3
CH2CH3
(R) and (S)racemic mixture
50:50chance
12. Stereochemistry of SN1 Reactions
Ph
CH3OCH2CH3
CH3
(R)Ph
OCH3CH2CH3
CH3
(S)
(1 : 1)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Example:
Br
(R) H2O
(SN1)
slowr.d.s.
(one enantiomer)
(carbocation)
H2O
attack from TOP face
H2O attack from BOTTOM face
OH H
OH H
OH
(R)
OH
(S)+
H2O
H2O
racemic mixture
( 1 : 1 )
© 2014 by John Wiley & Sons, Inc. All rights reserved.
tBuCH3
tBu
O
Me
Me H
tBu
Me
O H
Me
tBu
I
Me MeOH
Example:
slowr.d.s.
MeOH
MeOH
trigonal planar
tBu
OMe
Me tBu
Me
OMe+
MeOH
MeOH
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The structure of the substrate
The concentration and reactivity of the nucleophile (for SN2 reactions only)
The effect of the solvent
The nature of the leaving group
13. Factors Affecting the Rates of SN1 and SN2 Reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
13A. The Effect of the Structure of the Substrate
General order of reactivity (towards SN2 reaction)
● Methyl > 1o > 2o >> 3o > vinyl or aryl
DO NOT undergo
SN2 reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Relative Rate (towards SN2)
methyl 1o 2o neopentyl
3o
2 106 4 104 500 1 < 1
Most reactiv
e
Least reactiv
e
CH3 Br CH3CH2 Br CH3CH BrCH3
C CH2BrCH3
CH3
CH3 C BrCH3
CH3
CH3
R Br HO+ R OH Br+
For example:
© 2014 by John Wiley & Sons, Inc. All rights reserved.
HC Br
CH3
CH3
HC Br
HH
Compare
HO + BrH
CHO
HHfaster
HO + BrH
CHO
CH3
CH3slower
HO
© 2014 by John Wiley & Sons, Inc. All rights reserved.
+ BrCH3
CHO
CH3
CH3extremely
slow
+ BrH
CHO
H
tBuveryslow
HC Br
H
tBu
CH3
C Br
CH3
CH3
HOHO
HOHO
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Note NO SN2 reaction on sp2 or sp carbons
e.g.
H
H
H
I+Nu No reaction
No reaction+NuI
I No reaction+Nu
sp2
sp2
sp
© 2014 by John Wiley & Sons, Inc. All rights reserved.
General order of reactivity (towards SN1 reaction)●3o > 2o >> 1o > methyl
The more stable the carbocation formed, the faster the SN1 reaction
Reactivity of the Substrate in SN1 Reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Stability of cations
R
CR R
R
CR H
R
CH H
H
CH H
> > >
most stable (positive inductive effect)
Allylic halides and benzylic halides also undergo SN1 reactions at reasonable rates I
Br
an allylic bromide a benzylic iodide
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Resonance stabilization for allylic and benzylic cations
CH2 CH2
CH2CH2
© 2014 by John Wiley & Sons, Inc. All rights reserved.
For SN1 reactionRecall: Rate = k[RX]●The Nu⊖ does NOT participate
in the r.d.s.●Rate of SN1 reactions are NOT
affected by either the concentration or the identity of the Nu⊖
13B. The Effect of the Concentration& Strength of the Nucleophile
© 2014 by John Wiley & Sons, Inc. All rights reserved.
For SN2 reactionRecall: Rate = k[Nu⊖][RX]●The rate of SN2 reactions
depends on both the concentration and the identity of the attacking Nu⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Identity of the Nu⊖
●The relative strength of a Nu⊖ (its nucleophilicity) is measured in terms of the relative rate of its SN2 reaction with a given substraterapid
CH3O + CH3I CH3OCH3 + IGood Nu⊖
Veryslow
CH3OH + CH3I CH3OCH3 + I
Poor Nu:
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The relative strength of a Nu⊖ can be correlated with 3 structural features● A negatively charged Nu⊖ is always
a more reactive Nu⊖ than its conjugate acid e.g. HO⊖ is a better Nu⊖ than
H2O and RO⊖ is better than ROH● In a group of Nu⊖s in which the
nucleophilic atom is the same, nucleophilicities parallel basicities e.g. for O compounds,
RO⊖ > HO⊖ >> RCO2⊖ > ROH > H2O
© 2014 by John Wiley & Sons, Inc. All rights reserved.
●When the nucleophilic atoms are different, then nucleophilicities may not parallel basicities e.g. in protic solvents HS⊖,
NC⊖, and I⊖ are all weaker bases than HO⊖, yet they are stronger Nu⊖s than HO⊖
HS⊖ > NC⊖ > I⊖ > HO⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.
SN2 reactions are favored by polar aprotic solvents (e.g., acetone, DMF, DMSO)
SN1 reactions are favored by polar protic solvents (e.g., EtOH, MeOH, H2O)
13C. Solvent Effects in SN2 & SN1 Reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Solvents
Non-polar solvents(e.g. hexane, benzene)
Polar solvents
Polar protic solvents(e.g. H2O, MeOH)
Polar aprotic solvents(e.g. DMSO, HMPA)
Classification of solvents
© 2014 by John Wiley & Sons, Inc. All rights reserved.
SN2 Reactions in Polar Aprotic Solvents●The best solvents for SN2
reactions are Polar aprotic solvents, which
have strong dipoles but do not have OH or NH groups
ExamplesOS
CH3 CH3
O
H NCH3
CH3
OP
Me2N NMe2NMe2
CH3CN
(DMSO) (DMF) (HMPA) (Acetonitrile)
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Polar aprotic solvents tend to solvate metal cations rather than nucleophilic anions, and this results in “naked” anions of the Nu⊖ and makes the e⊖ pair of the Nu⊖ more available
NaDMSO
+ DMSO Na"naked anion"
CH3O CH3O
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3Br +NaI CH3I +NaBr
SolventRelative Rate
MeOH 1
DMF 106
Tremendous acceleration in SN2 reactions with polar aprotic solvent
© 2014 by John Wiley & Sons, Inc. All rights reserved.
H
Nu HH
H
OR
OR
ORRO
SN2 Reactions in Polar Protic Solvents●In polar protic solvents, the Nu⊖
anion is solvated by the surrounding protic solvent which makes the e⊖ pair of the Nu⊖ less available and thus less reactive in SN2 reactions
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Halide Nucleophilicity in Protic Solvents●I⊖ > Br⊖ > Cl⊖ > F⊖
Thus, I⊖ is a stronger Nu⊖ in protic solvents, as its e⊖ pair is more available to attack the substrate in the SN2 reaction.
H
H
H
HH
H
OR
OR
ORRO
RO
RO
(strongly solvated)
F- H
H
H
RO
OR
OR(weakly solvated)
I-
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Halide Nucleophilicity in Polar Aprotic Solvents (e.g. in DMSO)●F⊖ > Cl⊖ > Br⊖ > I⊖
Polar aprotic solvents do not solvate anions but solvate the cations
The “naked” anions act as the Nu⊖
Since F⊖ is smaller in size and the charge per surface area is larger than I⊖, the nucleophilicity of F⊖ in this environment is greater than I⊖
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Solvent plays an important role in SN1 reactions but the reasons are different from those in SN2 reactions
Solvent effects in SN1 reactions are due largely to stabilization or destabilization of the transition state
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Polar protic solvents stabilize the development of the polar transition state and thus accelerate this rate-determining step (r.d.s.):
CH3
CCH3 ClCH3
slowr.d.s.
C Cl
H
H
OR
OR
ORH
CH3
CCH3
CH3
CH3
CH3
CH3
+Cl
© 2014 by John Wiley & Sons, Inc. All rights reserved.
13D.The Nature of the Leaving Group
Leaving groups depart with the electron pair that was used to bond them to the substrate
The best leaving groups are those that become either a relatively stable anion or a neutral molecule when they depart
© 2014 by John Wiley & Sons, Inc. All rights reserved.
The better a species can stabilize a negative charge, the better the LG in an SN2 reaction
C Xslowr.d.s.
C X
C X
C X+
slowr.d.s.
C XNu
Nu:
C X+Nu
SN1 Reaction:
SN2 Reaction:
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CH3O + CH3–X CH3–OCH3 + X
HO, H2N, RO
F Cl Br I TsO
~ 0 1 20010,00
030,00
060,00
0
Relative Rate:
<< < < < <Worst X⊖ Best X⊖
Note: Normally R–F, R–OH, R–NH2, R–OR’ do not undergo SN2 reactions.
Examples of the reactivity of some X⊖:
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NuR OH +R Nu HO
R OH
H Nu+R Nu H2O
H
a strong
basic aniona poor
leaving group
weakbase
✔a good
leaving group
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Other weak bases that are good leaving groups:
O
S R
O
O
O
S O
O
O R
O
S
O
O CH3
an alkanesulfonateion
An alkylsulfonate ion
p-Toluenesulfonateion
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14.Organic Synthesis: Functional Group Transformation Using SN2 Reactions
HO
Br
OH
MeO
OMe
HS
SH
MeS
SMe
NCCN
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Br
C CMe
Me
MeCOO
O Me
O
Me3N
NMe3 Br
N3
N3
II
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Examples:
Br O
??NaOEt, DMSO
I SMe
??NaSMe, DMSO
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Examples:
I CN
(optically active, chiral) (optically active, chiral)
??
● Need SN2 reactions to control stereochemistry
● But SN2 reactions give the inversion of configurations, so how do you get the “retention” of configuration here??
● Solution: “double inversion” “retention”
© 2014 by John Wiley & Sons, Inc. All rights reserved.
Br
I CN
(optically active, chiral) (optically active, chiral)
??
(Note: Br⊖ is a stronger Nu thanI⊖ in polar aprotic solvent.)
NaBrDMSO
NaCNDMSO
(SN2 withinversion)
(SN2 withinversion)
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Vinylic and phenyl halides are generally unreactive in SN1 or SN2 reactions
14A. The Nonreactivity of Vinylic andPhenyl Halides
C
X
CX
vinylic halide phenyl halide
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Examples
I
BrNaCN
DMSO
NaSMe
HMPA
No Reaction
No Reaction
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Substitution
15.Elimination Reactions of AlkylHalides
Elimination
C CH
H
Br
H
H
HBrC C
H
H
H H
OCH3
H+(acts as a
Nu )
OCH3
C CH
H
Br
H
H
HC C
H
H
H
HCH3OH Br(acts as a
base)
+ +OCH3
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Substitution reaction (SN) and elimination reaction (E) are processes in competition with each other
tBuOKtBuOH
e.g.
I +OtBu
SN2: 15% E2: 85%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
15A. Dehydrohalogenation
CH
CXhalide as LG
β carbon
β hydrogen carbon
H
BrtBuOK
tBuOH, 60oC+ KBr + tBuOHβ
LG
β hydrogen
⊖OtBu
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Conjugate base of alcohols is often used as the base in dehydrohalogenations
15B. Bases Used in Dehydro-halogenation
R−O⊖ + Na⊕ + H2
R−O−H
R−O⊖ + Na⊕ + H2
Na
NaH
EtO Nasodium ethoxide potassium t -butoxide
e.g.tBuO K
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Rate = k[CH3CHBrCH3][EtO⊖]
Rate determining step involves both the alkyl halide and the alkoxide anion
A bimolecular reaction
16.The E2 Reaction
Br
H
EtO + + EtOH + Br
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Mechanism for an E2 Reaction
Et O
C CBr
H
HH
CH3H
Et O
C CBr
H
HH
CH3H
C C
H
H
H
CH3
Et OH +Br
+β
α
EtO⊖ removes a b proton; C−H breaks; new p bond forms and Br begins to depart
Partial bonds in the transition state: C−H and C−Br bonds break, new p C−C bond forms
C=C is fully formed and the other products are EtOH and
Br⊖
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CH3CHBrCH3
+ EtO-
T.S.
CH2=CHCH3
+ EtOH + Br-
Free
Ene
rgy
Reaction Coordinate
Free Energy Diagram of E2 Reaction
DG‡E2 reaction has ONEtransition state
Second-order overall bimolecular
Rate = k[CH3CHBrCH3][EtO⊖]
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E1: Unimolecular elimination
C ClCH3
CH3
CH3 H2O
slowr.d.s
CCH3
CH3
CH3 H2O asnucleophile
(major (SN1))
C OHCH3
CH3
CH3
H2O asbase
+CH2 CCH3
CH3
(minor (E1))
17.The E1 Reaction
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Mechanism of an E1 Reaction
Cl
HH2O
slowr.d.s
.
carbonβ hydrogen
+ H3O(E1 product)fast
H2Ofast
OH
H H2O OH +H3O
(SN1 product)
Free Energy Diagram of E1 Reaction
T.S. (1)
Free E
nerg
y
Reaction Coordinate
T.S. (2)
(CH3)3C+ Cl
(CH3)3CCl
+ H2O
(CH3)2C=CH2+ H3O + Cl
G1
© 2014 by John Wiley & Sons, Inc. All rights reserved.
© 2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
C ClCH3
CH3
CH3
CCH3
CH3
Cl(k1)
Step (1):
+H2O
slowr.d. stepAided by the
polar solvent, a chlorine departs with the e⊖ pair that bonded it to the carbon
Produces relatively stable 3o carbocation and a Cl⊖. The ions are solvated (and stabilized) by surrounding H2O molecules
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Free Energy Diagram of E1 Reaction
T.S. (1)
Free E
nerg
y
Reaction Coordinate
T.S. (2)
(CH3)3C+ Cl
(CH3)3CCl
+ H2O
(CH3)2C=CH2+ H3O + Cl
G1
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H3C
CH3C
H2O(k2)
H OH
H
Step (2)
+C H CH2H3C
H3C
+
H
Hfast
H2O molecule removes one of the b hydrogens which are acidic due to the adjacent positive
charge. An e⊖ pair moves in to form a double bond between the b and a carbon atoms
Produces alkene and hydronium ion
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18. How To Determine Whether Substitution or Elimination Is Favoured
All nucleophiles are potential bases and all bases are potential nucleophiles
Substitution reactions are always in competition with elimination reactions
Different factors can affect which type of reaction is favoured
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CNu
C X
H
E2
(b)
(a)
SN2(b)
(a)
C
CNu
H+ X
C+ X
C+Nu H
18A. SN2 vs. E2
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With a strong base, e.g. EtO⊖
●Favor SN2
Primary Substrate
BrNaOEtEtOH
OEt
+
E2: (10%)
SN2: 90%
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With a strong base, e.g. EtO⊖
●Favor E2
Secondary Substrate
Br
NaOEtEtOH
OEt
+
+
E2: 80%
SN2: 20%
© 2014 by John Wiley & Sons, Inc. All rights reserved.
With a strong base, e.g. EtO⊖
●E2 is highly favored
Tertiary Substrate
Br OEt
NaOEtEtOH
+
E2: 91% SN1: 9%
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Unhindered “small” base/Nu⊖
Base/Nu⊖: Small vs. Bulky
Hindered “bulky” base/Nu⊖
BrKOtButBuOH
OtBu+
E2: 85%SN2: 15%
BrNaOMeMeOH OMe+
E2: 1%SN2: 99%
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Basicity vs. Polarizability
Br
O CH3
O
+
OCCH3 O
(weak base)E2: 0%SN2: 100%
EtO(strong base)
OEt
+
E2: 80%SN2: 20%
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Tertiary Halides: SN1 vs. E1 & E2
EtO
Br
OEt+
SN1: 0%E2: 100%
(strongbase)
EtOHheat
OEt+
SN1: 80%E1 + E2: 20%
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E2E1SN2SN1CH3X
RCH2X
RCHXR'
RCXR'
R"
Mostly SN2 withweak bases;e.g. with CH3COO⊖
Very favorablewith weak bases;e.g. with H2O;MeOH
Hindered bases givemostly alkenes;e.g. with tBuO⊖
Mostly
Very little;Solvolysis possible;e.g. with H2O;MeOH
Very littleStrong basespromote E2;e.g. with RO⊖, HO⊖
Strong basespromote E2;e.g. with RO⊖, HO⊖
──
─Always competeswith SN1
─Very fast ──
19.Overall Summary
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Review Problems
Br
DMF, 25oCtBu
Na(1) CN CN
tBu
NaHEt2OI O
H(2)
I O
O
H⊖
Intramolecular SN2
SN2 with inversion
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Cl
tBu
CH3
CH3
tBu
Cl
+
( 50 : 50 )
OH
tBu
HClCH3(3)
CH3
tBu
O
tBu
CH3
H
H
sp2 hybridizedcarbocation
Cl⊖ attacksfrom top face
Cl⊖ attacksfrom bottomface
SN1 with racemization
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END OF CHAPTER 6