four new mechanisms to learn: sn2 vs e2 and sn1 vs e1psbeauchamp/pdf_exams/314_sn_e_2013.pdf ·...
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Nucleophilic Substitution & Elimination Chemistry 1
y:\files\classes\314\314 Special Handouts\314 SN & E Spring 2013.doc
Four new mechanisms to learn: SN2 vs E2 and SN1 vs E1
Nucleophilic Substitution & Elimination Chemistry 2
y:\files\classes\314\314 Special Handouts\314 SN & E Spring 2013.doc
E1 approach comes from parallel C-H with either lobe of 2p orbital.
SN1 approach is from either the top face or the bottom face.
B
weak base
SN1 and E1 reactions are multistep reactions.
E1 products(pi bond forms)
X stableleaving group
Terms
S = substitution E = elimination H-Nu: = weak nucleophile H-B: = weak base X = leaving group
1 = unimolecular kinetics (first order reaction, the rate in the slow step depends only on RX)
R-X = R-Cl, R-Br, R-I, R-OTs, ROH2+
SN1 and E1 reactions begin exactly the same way. The leaving group, X, leaves on its own, forming a carbocation.
CC
X
H
The R-X bond ionizes with help from the polar, protic solvent, which is alsousually the weak nucleophile/base.
CC
H
X
solvated carbocation
addition of a weak nucleophile (SN1 type reaction)
Loss of a beta hydrogen atom, (C-H in most E1 reactions that we study).
rearrangement to a new carbocation of similar or greater stability
add Nu: (SN1)
lose beta H (E1)
rearrange
H
Nu H
weak nucleophile
CC
H
C
Nu
C
H
CC
H
Nu H
H
Nu H
Nu H
C C
CC
H
Nu
C
Nu
C
H
solvated carbocation
B
weak base
H Nu H
weak nucleophile
=
SN1
E1
Often a final proton transfer is necessary.
SN1 product (a nucleophile substitutes for a leaving group)
BHNu H = usually a polar, protic solvent (or mixture) of H2O, ROH or RCO2H=
NuH
BH
R
Nucleophilic Substitution & Elimination Chemistry 3
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C
H
H
XH C
H
H
XCH3 C
CH3
H
XCH3 C
CH3
CH3
XCH3
k 0t-butyl (tertiary)
k 0.025isopropyl (secondary)
k 30methyl (unique)
k 1 ethyl (primary)Reference compound
Relative Rates of SN2 Reactions - Steric hindrance at the C carbon slows down the rate of SN2 reaction.
140
(very low)
Primary substitution allows two easy pathsof approach by the nucleophile. It is the least sterically hindered "general" substitution pattern for SN2 reactions.
C XR
H
H
Nu
methyl RX primary RX secondary RX
Secondary substitution allows one easy path of approach by the nucleophile. It reacts slowest of the possible SN2 substitution patterns.
C X
R
R
H
Nu
Tertiary substitution has no easy path of approach by the nucleophile from the backside. We do not propose any SN2 reaction at tertiary RX centers.
C X
R
R
R
Nu =
When the C carbon is completely substituted the nucleophile cannot get close enough to make a bond with the C carbon. Even C-H sigma bonds block the nucleophile's approach
C
C
C
X
H
H
H
H
H H
H
H
H
Nu
tertiary RX
Methyl has three easy paths of approach by the nucleophile. It is the least sterically hindered carbon in SN2 reactions, but it is unique.
C X
H
H
H
Nu
C
CH2C
H
H
H
X CH2C
H
CH3
H
X CH2C
CH3
CH3
H
X CH2C
CH3
CH3
CH3
X
k 1 ethyl
k 0.4 propyl
k 0.03 2-methylpropyl
k 0.00001 2,2-dimethylpropyl (neopentyl)
All of these structures are primary R-X compounds at C, but substituted differently at C.
Reference compound
C
C
H
HX
CH3CH3
H
Nu
A completely substituted C carbon atom also blocks the Nu: approach to the backside of the C-X bond. A large group is always in the way at backside of the C-X bond.
If even one bond at C has a hydrogen then approach by Nu: to backside of the C-X bond is possible and anSN2 reaction is possible.
C
C
H
HX
CCH3
CH3HH
HNu
Nucleophilic Substitution & Elimination Chemistry 4
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These structures represent your hydrocarbon starting points to synthesize target molecules (TM) that are specified. You will need to propose a step-by-step synthesis for each target molecule from these given structures. Every step needs to show a reaction arrow with the appropriate reagent(s) above each arrow and the major product of each step. This is often accomplished by using retrosynthetic thinking. You start at the target molecule (the end) and work your way backwards (towards the beginning), one step at a time until you reach an allowed starting material. The starting material of each step becomes the target molecule for the next step until you reach the beginning. Allowed starting structures – our main sources of carbon – 1. free radical substitution of alkane sp3 C-H bonds to form sp3 C-Br bonds at the weakest C-H position and 2. Anti-Markovnikov addition to alkenes makes 1o R-Br
CH4
Br Br
BrWe need to make these 1o RBr from anti-Markovnikov free radical addition of H-Br (ROOR) to alkenes.
Br2 / h Br2 / h Br2 / h Br2 / h Br2 / h Br2 / h Br2 / h
H3CBr
Br
BrBr Br
Br
Br
HBrH2O2 / h
HBrH2O2 / h
HBrH2O2 / h
E2 reaction
O
K
E2 reaction
O
K
E2 reaction
O
K
E2 reaction
O
K
E2 reaction
O
K
Br2 / h
Br2 / h
Br2 / h
Br
Br
Br
Examples of allylic RBrcompounds: This is just free radical substitution
at allylic sp3 C-H positionof an alkene.
1. Mechanism for free radical substitution of alkane sp3 C-H bonds to form sp3 C-Br bonds at weakest C-H position
Nucleophilic Substitution & Elimination Chemistry 5
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H3C
H2C
CH3 H3CCH
CH3
Br
BrBr
overall reactionh
BrH
1. initiation
BrBrh BrBr H = 46 kcal/mole
2a propagation
H3CC
CH3
H H
Br BrH
H3CC
CH3
H
H = +7 kcal/mole
BE = +95 kcal/moleBE = -88 kcal/mole
2b propagation
H3CC
CH3
H
BrBr
H3CC
CH3
H Br
Br
H = -22 kcal/mole
BE = +46 kcal/moleBE = -68 kcal/mole
3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations
BrH3C
CCH3
H
H3CC
CH3
H Br
H3CC
CH3
H
CH3
CH3C
H
CH
CH3
H3C CHCH3
CH3
H = -68 kcal/mole
H = -80 kcal/mole
very minor product
2. Free radical addition mechanism of H-Br alkene pi bonds (alkenes can be made from E2 or E1 reactions at this
point in course) (anti-Markovnikov addition to alkenes)
H3C
H2C
CH2
Br
H3C
HC
CH2
HBrH2O2 (cat.)
h
overall reaction
1. initiation (two steps)
HO
OH h H
OO
H
BrHH
O HO
H Br
H = 40 kcal/mole
H = -23 kcal/mole
BE = +88 kcal/moleBE = -111 kcal/mole
(cat.)
reagent
2a propagation
H3C
HC
CH2Br
H3CC
CH2
Br
H
H = -5 kcal/mole
BE = +63 kcal/mole BE = -68 kcal/mole
Nucleophilic Substitution & Elimination Chemistry 6
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2b propagation
H3CC
CH2
Br
H
BrH H3C
H2C
CH2
BrBr
H = -10 kcal/mole
BE = +88 kcal/mole BE = -98 kcal/mole
3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations
H3CC
CH2
Br
H
Br
H3CCH
CH2
Br
Br
H = -68 kcal/mole
very minor product
Reagent list for our course (Chem 314)
What kind of mechanisms are possible? What is the major mechanism occuring? Be able to write in ALL mechanism details (lone pairs, formal charge, curved arrows, etc.) for each step of each reaction studied. Mechanism choices at this point in organic chemistry: SN2, E2, SN1, E1,acid/base reaction, free radical substitution, free radical addition to alkenes and no reaction.
Nuclephile/Bases (and other reagents) to choose from include:
Br2 h
Na HNasodium amide
OH Na
O
OH
CN NaSH Na
AlD
D
D
D
Li
NR2
sodiumhydroxide
water
ethanoic acid(acetic acid)
sodium hydride(only basic)
lithium aluminium hydride
(nucleophilic)
BD
D
D
D
Na
sodium borohydride(nucleophilic)
sodiumcyanide
monohydrogensulfide
K H potassium hydride
(only basic)
Na
sodiumazide
N3
purchase / given - You can invoke these whenever you need them. Some of these will disappear when we learn how to make them.
AlH
H
H
H
Li
lithium aluminium hydride
(nucleophilic)
BH
H
H
H
Na
sodium borohydride(nucleophilic)
O
propanone(acetone)
HO
H
ethanol
OH
HN
diisopropylamine
H3C
H2C
CH2
CH2
Lin-butyl lithium
t-butyl alcohol
OH
S
S
PhS
Ph
dithianediphenyl sulfide
(useful for making epoxides)triphenylphosphine
(used for making Wittig reagents)
PhP
PhPh
Cl2 h
strong acids: HCl, HBr, HI, H2SO4strong bases: NaOH, NaH, KH, n-BuLi, NaNR2, t-BuOKstrong nucleophiles: NaOH, NaOR, NaO2CR, LiAlH4, LiAlD4, NaBH4, NaBD4, NaCN, NaCCR, Li-enolates, Ph2S, Ph3P, Li-dithianeweak nucleophiles: H2O, ROH, RCO2Hcommon electrophiles: RX (= RCl, RBr, RI) free radical reactions: alkane C-H substitution (Br2/h), anti-Markovnikov addition to alkenes (HBr/ROOR (cat)/h)
Some of our reagents have to be made (often by acid/base reactions)
Make alkoxides and use as nucleophiles at Me-X and 1o RCH2-X in SN2 reactions.
OR
Na
alkoxides
OR H
alcohols
Na
H
BrR
O
SN2 ethers
Nucleophilic Substitution & Elimination Chemistry 7
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Make carboxylates and use as nucleophiles at Me-X, 1o RCH2-X and 2o R2CH-X in SN2 reactions.
O
O
Na
ethanoate(acetate)
O H
Na
O
Oethanoic acid(acetic acid)
HBr
O
O estersSN2
Make potassium t-butoxide and use as sterically large, strong base at 1o RCH2-X, 2o R2CH-X and 3o R3C-X in E2 reactions.
OK
K
OH
t-butyl alcohol
potassiumt-butoxide
HBr
H
R E2
R
alkenes
Make terminal acetylides and use as nucleophiles at Me-X and 1o RCH2-X in SN2 reactions.
CCR
Na
terminalacetylides
CCR
terminalalkynes
HNa
NR2
Br
SN2
R
alkynes
Make thiolates and use as nucleophiles at Me-X, 1o RCH2-X and 2o R2CH-X in SN2 reactions.
SR
Na
alkylthiolatesNa
SR H
thiols
O HBr
SN2R
S
sulfides
Synthesis of lithium diisopropyl amide, LDA, used to remove Cα-H proton of carbonyl groups. (acid / base reaction)
Keq =Ka1
Ka2
10-37
10-50= = 10+13
CH2 Li
N
H
NLi
Think - sterically bulky, very basic that goes after weakly acidic protons.
LDA = lithium diisopropyl amide
given
given
React ketone enolate (nucleophile) with R-Br electrophile (Me, 1o and 2o RX compounds)
O
HN
Li
N
H
CH2
O
Li
Keq =Ka1
Ka2
10-20
10-37= = 10+17
ketones (and other carbonyl compounds)
Make enolate (ketones)
LDA
ketone enolates(resonance stabilized)
given
-78oC
Nucleophilic Substitution & Elimination Chemistry 8
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H2C
O Li
ketone enolates(resonance stabilized)
React ketone enolate with RX compounds (methyl, 1o and 2o RX)
Br
O
1o RX key bondR
S Larger ketone made from smaller ketone.
SN2reactions
-78oC
React ester enolate (nucleophile) with R-Br electrophile (Me, 1o and 2o RX compounds)
O
OH
N
Li
N
H
CH2
O
O
Li
Keq =Ka1
Ka2
10-25
10-37= = 10+12
ketones (and other carbonyl compounds)
Make enolate (esters)
LDA
ketone enolates(resonance stabilized)
given
R R-78oC
H2C
O
O
Li
ester enolates(resonance stabilized)
React ester enolate with RX compounds (methyl, 1o and 2o RX)
Br
O
O
1o RX key bondR
S Larger ester made from smaller ester.
R RSN2reactions
-78oC
SN and E reactions (A is a pre-exponential term and can be considered to be the maximum possible rate constant when Ea = 0)
SN2 reactions = substitution nucleophilic bimolecularRate = kSN2[RX][Nu: ] bimolecular kinetics, both RX and Nu: participate in the slow step of the reaction; kSN2 = Ax10
- Ea(SN2)
2.3xRxT
E2 reactions = elimination bimolecularRate = kE2[RX][B: ] bimolecular kinetics, both RX and B: participate in the slow step of the reaction; kE2 = Ax10
SN1 reactions = substitution nucleophilic unimolecularRate = kSN1[RX] unimolecular kinetics, only RX participates in the slow step of the reaction; kSN1 = Ax10
E1 reactions = elimination unimolecularRate = kE1[RX] unimolecular kinetics, only RX participates in the slow step of the reaction; kE1 = Ax10
- Ea(E2)
2.3xRxT
- Ea(SN1)
2.3xRxT
- Ea(E1)
2.3xRxT
Nucleophilic Substitution & Elimination Chemistry 9
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R-X patterns - typical reaction patterns in our course (bold = atypical result)
Reagents methyl RX1o RX
primary2o RX
secondary3o RXtertiary
1o neopentyl RX
allylic RX benzylic RX
Na OH
O2CR
O-C(CH3)3t-butoxide
C N
C C R
N3
SH
Li AlH3H
BH3H
AlD3D
BD3D
Na
Na
K
Na
Na
Na
Na
Na
Na
Na
Li
SN2 > E2only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
only SN2
SN2 > E2
SN2 > E2
E2 > SN2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
only E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
SN2 > E2
E2 > SN2
E2 > SN2
OLi
ketone enolates
only SN2 SN2 > E2 SN2 > E2
E2 > SN2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
only E2
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
NA
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
very fast SN2 very fast SN2
OR
SR
1. NaN3 (SN2)2. LiAlH4 (SN2)3. workup (acid/base)
makes1o amines
makes1o amines
makes1o amines
makes1o amines
makes1o amines
no reactiononly E2
NA
O
O Li
ester enolates
only SN2 SN2 > E2 SN2 > E2 only E2 no reaction very fast SN2 very fast SN2R
The following are synthetic approaches to some of the target molecules above. They are presented as examples of how you might approach synthesis problems (these and others like them). You need to not only look at structures that I provide above but think about other possibilities using all of the structures available to you. I do not list every possibility (there are too many), but you need to be able to consider every possibility. The best strategy is to work backwards from the target molecule to an allowed starting structure (cover up everything but the target structure and write out an answer for how you could make that molecule, then start all over on target molecule minus one, which is called ‘retrosynthetic analysis’). That way you are only thinking about “one” backward step at a time, instead of an “unknown” number of steps forward from a starting structure you are not sure of. This is the way I presented the approaches below. You should also know the mechanism for every reaction below. I can write these pages until I am blue in the face, but they can’t help you learn, unless you do the work of trying them out. My job is to give you an opportunity to learn, and your job is to take advantage of that opportunity. These schemes were made quickly, so be on the lookout for mistakes. (I hope not too many.)
Nucleophilic Substitution & Elimination Chemistry 10
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1. Synthesis of RBr compounds - Free radical substitution at sp3 C-H and free radical addition to alkenes (anti-Markovnikov addition). Making these represents our most common starting points.
BrBr
Br
1o RX 1o RX 1o RX
These are our target molecules (TM).
BrBr
Br
allylic RXallylic RX allylic RX
H of each step is controlled by relative bond energies
Sample R-Br from R-H using Br2 / h - you have to make these
BrH3C Br
BrBr
Br
BrBr
methyl RX 1o RX 2o RX 3o RX
2o RX 1o benzylic RX 2o benzylic RX
Free radical substitution mechanism: (R-H + Br2 + light)
1. initiation 2a and 2b. propagation 3. termination.
H of each step is controlled by relative bond energiesFree radical addition mechanism: (alkene + HBr/ROOR + light)
1. initiation 2a and 2b. propagation 3. termination.
O
K
E2potassiumt-butoxide
free radical substitution2o RX
Br2 h
Br
propane
Br2H2O2 (cat.)
h
free radical addition
Br
1o RXwe need these
TMTM - 2TM - 1 allowed
starting material
alkene
Br2H2O2 (cat.)
h
free radical substitution
H3o RX
Br2 h
BrO
K
E2potassiumt-butoxide
free radical addition
Br
1o RXwe need these
2-methylpropanealkene
TM TM - 1 TM - 2 allowed starting material
(isobutane)
Br Br2H2O2 (cat.)
h
free radical addition
O
K
E2potassiumt-butoxide
TM TM - 1 TM - 2Br
free radical substitution
Br2 h
allowed starting material
ethylbenzene
allylic RBr compounds - (NBS is more likely reagent, but we only know Br2). You will need to make the starting alkene (E2 reactions)
Br
Br2 h
free radical substitution
1o allylic RX
O
K
E2potassiumt-butoxide
free radical substitution
H
3o RX
Br2 h
Br 2-methylpropane(isobutane)
TM TM - 1 TM - 2 allowed starting material
Nucleophilic Substitution & Elimination Chemistry 11
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Br2 h
free radical substitution
Br
1o allylic RX
O
K
E2potassiumt-butoxide
free radical substitution3o RX
Br2 hBr
propane
TM TM - 1 TM - 2allowed
starting material
Br Br2 h
free radical substitution
2o allylic RX
Br
potassiumt-butoxide
Br2 h
free radical substitution
E2
TM TM - 1 TM - 2
allowed starting material
cyclohexane
2. alcohol synthesis – starting from RX (later there will be many other approaches)
Sample alcohols - SN2 reactions using (R-X + HO ) at Me, 1o, 2o, allylic RX or SN1 reactions using (R-X + H2O) at 2o, 3o RX
OHH3C OHOH
OH
OH
OH OH
OH
OH
OH
OHOH
OH
These are our target molecules (TM).
SN2 SN2 SN2 SN2
SN2 SN2 SN2 SN2
SN1SN1
SN2 or SN1 SN2 or SN1
OH Na
OH
Br
alcohols - various approaches, SN2 at methyl and primary RX using NaOH and SN1 at secondary and tertiary RX using H2O
see above, from propene
1o alcohol SN2 > E2
Hydroxide and alkoxides are OK nucleophiles at methyl and 1o RX, but E2 > SN2 at 2o RX and only E2 at 3o RX.
TM TM - 1
1o RBr
OH Br Br2 h
free radical substitution
allowed starting structure
H2O
SN1 > E1
Generally, SN1 > E1 at 2o and 3o RXif we don't have to worry about rearrangements. No SN1/E1 at methyl and 1o RX.
TM
2o alcohol 1o RBr
TM - 1
Generally, SN1 > E1 at 2o and 3o RXif we don't have to worry about rearrangements. No SN1/E1 at methyl and 1o RX.
Br2 h
H2O
BrOH
SN1 > E1free radical substitution
allowed starting structure
TM
3o alcohol 3o RBr
TM - 1
SN2 mechanisms using aqueous hydroxide introduces a new alcohol functional group (R-OH)
BrH3C
nucleophile = ?electrophile = ?
SN2 OCH3
key bond
BrOHNa
H Na
Nucleophilic Substitution & Elimination Chemistry 12
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BrH2C
H3Cnucleophile = ?electrophile = ?
SN2 OBr
key bond
Na
OH
NaH
BrH2C
CH2H3Cnucleophile = ?electrophile = ?
SN2O
key bond
Br
Na
OH
NaH
SN1 mechanisms (if no rearrangement) using water introduces a new alcohol functional group (R-OH)
Br
H2O
SN1 > E1
H
O H
H
H
O
H
H
O H
H
H
O
H
water is a nucleophile water is a
base
SN1 > E1 at 2o and 3o RX and we don't have to worry about rearrangements here.
Br
H2O
SN1 > E1
O H
H
O
H
H
O H
H
O
H
water is a nucleophile
water is a base
3. ether synthesis - starting from RX (SN2 at Me and 1o RX with hydroxide, SN1 at 2o and 3o RX and ROH)
Sample ethers - SN2 reactions using (R-X + RO ) at Me, 1o, 2o, allylic RX or SN1 reactions using (R-X + ROH) at 2o, 3o RX There are many more possibilities.
OO O
O
(SN1 or SN2)(SN1 or SN2) SN2 SN2
TM
Otarget molecule SN1 > E1
Br2 h
free radical substitution
Br
OH
1. Na H
2.
SN2 > E2
acid / base Br
OHGenerally, SN1 > E1 at 2o and 3o RX. No SN1/E1at methyl and 1o RX.
ethers - various approaches, SN2 at methyl and primary RX using NaOR and SN1 at secondary and tertiary RX using ROH
BrNa OH
SN2
Br2 h
free radical substitution
HO
H
Br
TM - 1 TM - 2
allowed starting structure
allowed starting structure
TM - 1 TM - 2
Nucleophilic Substitution & Elimination Chemistry 13
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Na OH
O
1. Na H
2.
SN2 > E2
acid / base
HOPh Br
Br2 h
Ph = phenylBr Ph OHSN1 > E1
SN2
Ph Br
already made
already made
free radical substitutiontarget molecule
given
TM TM - 1
TM - 1 TM - 1
TM - 2
SN2 mechanisms using aqueous alkoxide introduces a new ether functional group (R-O-R’)
BrH3C
nucleophile = ?electrophile = ?
SN2 OCH3
key bond
BrOH3CNa
H3C Na
BrH2C
H3Cnucleophile = ?electrophile = ?
SN2 O
Br
key bond
NaOH3C
Na H3C
BrH2C
CH2H3Cnucleophile = ?electrophile = ?
SN2O
key bond
Br
Na
OH3C
NaH3C
SN1 mechanisms (if no rearrangement) using alcohol introduces a new ether functional group (R-O-R’)
Br
SN1 > E1
H
O H
CH3
H
O
H
CH3
O H
CH3
H
O
CH3
water is a nucleophile water is a
base
SN1 > E1 at 2o and 3o RX and we don't have to worry about rearrangements here.
H3CO
H
BrCH3OH
SN1 > E1
O H
CH3
O
H
CH3
O H
H
O
CH3
water is a nucleophile
water is a base
Nucleophilic Substitution & Elimination Chemistry 14
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4. ester synthesis (using the oxygen side and using the carbon enolate side, also ketone examples using an enolate)
Sample alcohols - SN2 reactions using (R-X + RCO2 ) at Me, 1o, 2o, allylic RX or SN1 reactions using (R-X + RCO2H) at 2o, 3o RX
These are our target molecules (TM) - using the oxygen side (carboxylates).
O
O
CH3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
SN2 SN2 SN2 SN2 SN1 SN2
SN1 SN2 SN1
SN2 SN1
SN2 SN2
SN2 SN2 SN2 SN1
esters - various approaches, SN2 at methyl, primary and secondary RX using RCO2Na. SN1 at secondary and tertiary RX using RCO2H but possible rearrangement.
O
O
O
OHtarget molecule
Br
1. Na OH
2.
SN2 > E2
acid / basealready made
O
OH
Br
SN1 > E1
Carboxylates are OK nucleophiles at methyl, 1o RX and 2o RX but only E2 at 3o RX.
given
given
O
O
Br
already made
TM
TM - 1
TM - 1TM - 1
TM
SN1 > E1
SN2 mechanism using carboxylate at RX center introduces a new ester functional group (RCO2R’)
BrH3C
nucleophile = ?electrophile = ?
SN2
key bond
Br
Na
NaO
O
O
O
CH3
BrH2C
H3Cnucleophile = ?electrophile = ?
SN2 O
Br
key bond
NaO
O
Na
O
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BrH2C
CH2H3Cnucleophile = ?electrophile = ?
SN2Br
NaO
key bondO
O
O
Na
Sample alcohols - SN2 reactions using (R-X + ketone enolate) at Me, 1o, 2o, allylic RX
These are our target molecules (TM) - using the carbon side (ketone enolates from only propanone for now).
O
SN2newbond
O
SN2newbond
O
SN2newbond
O
SN2newbond
O
SN2newbond
O
SN2newbond
O
SN2newbond
etc, etc, etc
O
SN2newbond
O
target molecule
key bond
HN
n-butyl lithiumacid / base
1.N
R R
Li
LDA(makes enolate)
Br2.
SN2 > E2
acid / base
O
diisopropylamine
via ester enolates
Enolates are OK nucleophiles at methyl, 1o RX and 2o RX but only E2 at 3o RX.
-78oC
TM
TM - 1
already made
allowed starting structure
SN2 mechanism using ester enolate at RX center makes a larger ester on the carbon side (RCO2R’)
BrH3C
nucleophile = ?electrophile = ?
SN2
H2C
Li
C
O
O
OC
CH2
O
CH3
(3C = 2C + 1C)
key bondLi(alkylation)
-78oC
R
RBr
BrH2C
H3C
Br
nucleophile = ?electrophile = ?
H2C
Li
C
O
OR
OC
CH2
O
H2C
(4C = 2C + 2C)
key bond
RCH3
LiSN2
(alkylation)
-78oC
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BrH2C
CH2H3Cnucleophile = ?electrophile = ?
BrLiO
CCH2
O
H2C
(5C = 2C + 3C)
key bond
RCH2
CH3
H2C
Li
C
O
OR
-78oC
SN2
(alkylation)
ketone enolates (good nucleophiles at epoxides, carbonyls and CH3X, 1oRX and 2oRX) bigger ketones
BrBrH3C
nucleophile = ?electrophile = ?
SN2
H2C
Li
C
O
H3C
H3CC
CH2
O
CH3
(4C = 3C + 1C)
key bondLi(alkylation)
-78oC
BrH2C
H3Cnucleophile = ?electrophile = ?
H2CC
O
H3C
Li
O key bond
LiBr
SN2
(alkylation)
-78oC
BrH2C
CH2H3Cnucleophile = ?electrophile = ?
H2CC
O
H3C
Li O key bond
(6C = 3C + 3C)
LiBr
SN2
(alkylation)
-78oC
5. azide and primary amine synthesis (azides can be made into primary amines via 1. LiAlH4 2. workup)
NN
N
NN
N
-2
azide anion
NH2H3C NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
NH2NH2
NH2
1. LiAlH4 (SN2 at nitrogen, N2 leaving group)2. workup (H3O+)
1o amines
azides
N3H3C N3
N3
N3
N3
N3
N3
N3
N3
N3 N3
N3
Sample azides - SN2 reactions using (R-X + N3 ) at Me, 1o, 2o, allylic RX, azides are converted into primary amines with 1. LiAlH4, 2. workup
These are our target molecules (TM).
No tertiary example becauseonly mechanismis SN2.
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Proposed mechanisms
RN
NN
H3Al H
RN
NN
H OH2H
2. workup
RN
H
H
lithiumaluminium
hydride alkyl azide nitrogen 1o amines
SN2 at nitrogen, N2 leaving group
Br
NN
N
NN
N
-2
2-azidopropane
SN2= N3
6. alkene synthesis (via one E2 reaction with RBr and t-BuOK, we will see other ways to make alkenes later)
Sample alkenes using E2 reactions: R-X + t-butoxide; alkenes can make allylic R-X compounds
Sample allylic bromides from alkenes (Br2 / h)
BrBr
Br
alkenes
Br
Br
1. Na OHacid / base
already made
inexpensive base is OK because RX is tertiary
O OHK already made
K Hacid / base
OK
already made
Br
already made
E2 > SN2 (need strong, bulky base to favor E2 at 1o RX)
E2
Use steric bulk and/or extreme basicity to drive E2 > SN2.
Br
already made
OK
already made
E2
Use steric bulk and/or extreme basicity to drive E2 > SN2.
relative alkene stabilities = tetrasub. > trisub. > trans-disub > cis-disub gem-disub > monosub > unsub.
allowed starting structure
TM
TM
TM
TM - 1
TM - 1
TM - 1
7. alkyne synthesis (via two E2 reactions with RBr2 and NaNR2, two times)
Sample alkynes using double E2 reactions of 1. RBr2 + NaNR2 2. workup
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Make starting alkynes using two leaving groups and very basic NR2
Na sodium amide(very strong base)
Br Br
Br
Brand
Br2 h
free radical substitution
(2 equivalents)(2 equivalents)
NR2
E2 twice
1.
2. workup
Use steric bulk and/or extreme basicity to drive E2 > SN2.
Br2 h
free radical substitution
(2 equivalents)Br Br
Na sodium amide(very strong base)
(2 equivalents)
NR2
E2 twice
1.
2. workup
Br2 h
free radical substitution
(2 equivalents)
Br Br
Na sodium amide(very strong base)
(2 equivalents)
NR2
E2 twice
1.
2. workup
Sample alkynes using SN2 reactions of 1. terminal alkyne + NaNR2 2. SN2 only at methyl or primary R-X (can do twice with ethyne)
(1 equivalent)
Na sodium amide(very strong base)
1.
2. BrH3C
acid / base
SN2 > E2
NR2newbond
(1 equivalent)
Na sodium amide(very strong base)
1.
2.
acid / base
SN2 > E2Br
NR2
Terminal acetylides are OK nucleophiles at methyl and 1o RX, but E2 > SN2 at 2o RX and only E2 at 3o RX.
newbond
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Possible steps in mechanism (E2 twice then 2. acid/base or 2. RX electrophile)
BrBr
HN
R R
Na
Br
H
H
NR R
H
NR R
Na
Na2. workup
H
H2C
R
X
H2C
R
HO
H
H
2.
a
b
a
b
SN2
1. RNH Na RNH2
1 equivalent
NaBr
2.
(4C = 2C + 2C)terminal alkyne
SN2
Br
2.
Na
1. RNH Na RNH2
1 equivalent
(5C = 3C + 2C)internal alkyne
SN2
1. RNH Na RNH2
1 equivalent
NaBr
2.
(6C = 3C + 3C)terminal alkyne
SN2
Br
2.
Na
1. RNH Na RNH2
1 equivalent
(5C = 3C + 2C)
internal alkyne
(zipper reaction)
1. excess NaNRH2. workup (neutralize)
SN2acid/base
like tautomers
Nucleophilic Substitution & Elimination Chemistry 20
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1. RNH Na RNH2
1 equivalent
Na
2.
2.
Na
(6C = 4C + 2C)terminal alkyne
1. RNH Na RNH2
1 equivalent
(6C = 3C + 3C)
internal alkyne
(zipper reaction)
1. excess NaNRH2. workup (neutralize)
Br
Br
like tautomers
SN2
SN2
acid/base
acid/base
terminal acetylides (SN2 only at methyl RX and 1o RX) larger alkynes
BrH3CCCH3C
Na SN2CCH3C CH3
nucleophile = ?electrophile = ?
Na
Br
BrH2CCCH3C
Na SN2CCH3C CH2
H3C CH3nucleophile = ?electrophile = ?
Na
Br
BrH2CCCH3C
Na SN2CCH3C CH2
CH2H2CH3C CH3nucleophile = ?
electrophile = ?
Na
Br
8. nitrile synthesis (via SN2 reaction at Me, 1o, 2o RX)
CN
CN
CN
H3CC
NCN
CN
Sample nitriles using SN2 reactions of cyanide + methyl, primary or secondary R-X
CN
CN
CN
nitriles
CN
BrSN2 > E2
Na
NC
already made
allowedCyanides are OK nucleophiles at methyl, 1o RX and 2o RX but only E2 at 3o RX.
Nucleophilic Substitution & Elimination Chemistry 21
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CN
SN2 > E2
Na
NC
Br
already made
allowed
cyanide nitriles
BrH3CNa SN2
CN CH3
nucleophile = ?electrophile = ?
Na
Br
CN
BrH2C
Na SN2CN CH2
H3C CH3nucleophile = ?electrophile = ?
Na
Br
CN
BrH2CNa SN2
CN CH2
CH2H2CH3C CH3nucleophile = ?
electrophile = ?
Na
Br
CN
9. thiols (via SN2 reaction with HS-- at Me, 1o, 2o RX) and sulfides synthesis (via SN2 reaction with RS-- at Me, 1o, 2o RX)
Sample thiols using SN2 reactions of HS + methyl, primary, secondary, allylic, benzylic R-X
SHH3CSH
SH SHSH
SHSH
SH
SH
SHSH
SH
Sample sulifides using SN2 reactions of RS + methyl, primary or secondary R-X (many possibilities)
SS
SS
thiols and sulfides
SN2 > E2
SBr
already made
Na SH
SH
thiol(pKa 8)
1. Na OHacid / base
Br2.
sulfideSN2 > E2
Sulfides are OK nucleophiles at methyl, 1o RX and 2o RX but only E2 at 3o RX.
Nucleophilic Substitution & Elimination Chemistry 22
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Possible mechanisms
BrH3C
nucleophile = ?electrophile = ?
SN2 SCH3
key bond
BrSHNa
H Na
BrH2C
H3Cnucleophile = ?electrophile = ?
SN2 S
key bond
NaNaH
Br
SH
BrH2C
CH2H3Cnucleophile = ?electrophile = ?
SN2S
key bond
Na
NaH Br
SH
BrH3C
nucleophile = ?electrophile = ?
SN2 SCH3
key bondNa
H3C NaBr
SH3C
BrH2C
H3Cnucleophile = ?electrophile = ?
SN2 S
key bond
NaNa H3C
Br
SH3C
BrH2C
CH2H3Cnucleophile = ?electrophile = ?
SN2S
key bond
Na
NaH3C Br
SH3C
10. introducing nucleophilic hydride or deuteride into organic molecules (via SN2 reaction) Sample deuterium added using SN2 reactions of LiAlD4 or NaBD4 + methyl, primary, secondary, allylic, benzylic R-X
DH3CD
D
D
D
DD
D
D
D D
D
Nucleophilic Substitution & Elimination Chemistry 23
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lithium aluminium hydride = LAH = (Li AlH4) and sodium borohydride (NaBH4) are both nucleophilic hydride. For now we will consider them to be equivalent reagents.
Br
AlD
D
D
D
BH
H
H
H
NaLiD
AlH
H
H
H
Li
SN2
lithium aluminium hydride (LiAlH4) and sodium borohydride (NaBH4) = nucleophilic hydride (using “deuteride” shows where the “hydrogen” goes)
BrH3C
nucleophile = ?electrophile = ?
SN2 DCH3
key bondLi
AlD
D
D
D
Li Br
BrH2C
H3Cnucleophile = ?electrophile = ?
SN2Li H
AlD
D
D
DLi
ethane
Br
key bond
BrH2C
CH2H3Cnucleophile = ?electrophile = ?
SN2H
key bond
propane
AlH
H
H
HLi Li Br
Mechanisms Worksheet
You need to be able to write your own mechanism from starting structures. I suggest you should practice using the nucleophiles from the list with the various RX compounds listed above. Writing mechanisms for each possibility would give you more than enough practice to learn the mechanism. Common mistakes include lone pairs, formal charge, curved arrows, correct Lewis structures, correct products predicted. This stuff takes practice – AND – correcting your mistakes. I have set up the following worksheet to give you templates to fill in so that you can use them multiple times by copying the basic framework and then filling in the details. You can do this IF YOU DO THE WORK!
Nucleophilic Substitution & Elimination Chemistry 24
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SN2 then E2 examples first, followed by SN1 and E1 reactions
Example 1 - CH3-X (deuterium = D and tritium = T are isotopes of hydrogen that can be distinguished from H) The only possible choice at methyl is SN2. There is no C-H for E2 reactions, and methyl R+ is too high energy for solution chemistry, so no SN1/R1.
C Br
T
HD
Nu
B
choose from
our list
?
OR H
Examples you might consider:
R
O
OH
OH H
only SN2
weak nucleophile/bases = no reaction - in our course
these are SN1 and E1 conditions (weak)
S-bromodeuteriotritiomethane
strong = anything with negative charge,and neutral sulfur or nitrogen
Easier methyl example - CH3-X
C Br
H
HH
Nu
B
only SN2 (with strongnucleophiles)
CNu
H
HH
bromomethane
Nu B=
strong = anything with negative charge,and neutral sulfur or nitrogenWe cannot see inversion of configuration,
but we assume it occurs if the kinetics is bimolecular.
choose from
our list
choose from above,
Harder methyl example - CHDT-X
C Br
T
HD
Nu
B
only SN2 (with strongnucleophiles)
CNu
T
HD
SR
S-bromodeuteriotritiomethane
Nu B=
strong = anything with negative charge,and neutral sulfur or nitrogen
We can see inversion of configuration, because there is a chiral center and the kinetics is bimolecular.
CbH
HH
Ca Br
HH
Ca
Cb
H
Br
HH
HH
bromoethane
Example 2 - primary RCH2-X (deuterium = D and tritium = T are isotopes of hydrogen that can be distinguished from H) SN2 is the main reaction unless the strong electron pair donor is bulky and basic, then E2 is the main reaction (only potassium t-butoxide in our course).
Nu
B
NuB
Easiest primary example - CH3-X
choose from
our list
a = E2
b = SN2
a
a = E2b = SN2
b
bromoethane
a b
Cb
CaNuCa
Cb
Nu
HH
Cb
Ca
H
H
H
H
verticalview
horizontalview
CC
H
H
H
Ha = E2
a = E2b = SN2 b = SN2H
H
H
H
HH
H H
Nucleophilic Substitution & Elimination Chemistry 25
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CbH
CH3D
Ca Br
DH
Ca
Cb
H
Br
HD
DH3C
(1S,2S)- 1-bromo-1,2-dideuteriopropane
?
(1S,2R)- 1-bromo-1,2-dideuteriopropane
Nu
B
Nu
B
?
Harder primary example - RCH2-X
choose from
our list
choose from
our list
CH
CH3D
C Br
DH
(1S,2S)- 1,2-dideuterio-1-bromopropane
Example 2 - primary RX
Nu
CH
CH3D
C Br
DH
(1S,2S)- 1,2-dideuterio-1-bromopropane
B
SN2 > E2C
CNu
DH
H
CH3
D
SN2 > E2
(unless t-butoxide) C
C
D
D
H3C
H
E-alkene
C
C
CH3
D
H
HZ-alkene
E2
H or D can be anti to Ca-Br
Nu B=
strong = anything with negative charge,and neutral sulfur or nitrogen
CH
TD
C Br
DH
(1S,2S)-1,2-dideuterio-1-bromoethane
Example 3 - primary RX
Nu
CH
TD
C Br
DH
(1S,2S)-1-bromo-1,2-dideuterio-1-tritioethane
B
SN2 > E2C
CNu
DH
H
T
D
SN2 > E2
(unless t-butoxide) C
C
D
D
T
H
E-alkene(if H is anti)
C
C
T
D
H
H
E2
H or D can be anti to Ca-Br
Nu B=
strong = anything with negative charge,and neutral sulfur or nitrogen
(1R,2S)-1,2-dideuterio-1-nucleophile-ethane
C
C
H
D
D
H
SN2 mechanism
E2 mechanism
Z-alkene(if D is anti)
E-alkene(if T is anti)
CD
TH
C Br
HD
(1R,2R)-1-bromo-1,2-dideuterio-1-tritioethane
B
Nu C
CNu
HD
D
T
H C
C
T
H
D
D
E-alkene(if H is anti)
C
C
H
H
T
D
E2
C
C
D
H
H
DZ-alkene
(if D is anti)E-alkene
(if T is anti)(1S,2R)
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CH
TD
C Br
HD
(1R,2S)-1-bromo-1,2-dideuterio-1-tritioethane
B
Nu C
CNu
HD
H
T
D C
C
D
H
T
D
Z-alkene(if H is anti)
C
C
T
H
H
D
E2
C
C
H
H
D
DE-alkene
(if D is anti)Z-alkene
(if T is anti)(1S,2S)
CD
TH
C Br
DH
(1S,2R)-1-bromo-1,2-dideuterio-1-tritioethane
B
Nu C
CNu
DH
D
T
H C
C
D
D
T
H
E-alkene(if H is anti)
C
C
T
D
H
H
E2
C
C
H
D
D
HZ-alkene
(if D is anti)E-alkene
(if T is anti)(1R,2R)
H3CC
CH2
Br
H H
other primary RX to consider.
H3CC
CH2
Br
H3C CH3
Br
Br
Br
Mechanism predictions with weak nucleophile/bases:
OR H
R
O
OH
OH H ?
No SN1/E1 is possible at primary RX in solution chemistry. The primary R+ is too high in energy.
look at C - fully substitutedno SN2 or E2 at 1o neopentyl RX,E2 is possible at 2o neopentyl RX
benzylic = fast SN2
CH
DCH3
C Br
C
HC
C
D
Br
CH
HH3C
H
CH2CH3CH3
H
CH3
CH2CH3
(2S,3R,4S)-2-deuterio-4-methyl-3-bromohexane
Example 4 - secondary RX (deuterium is an isotope of hydrogen that can be distinguished from H)
(2S,3S,4S)-2-deuterio-4-methyl-3-bromohexane
Nu
B choose from above
?
Nu
B choose from above
?
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(2R,3R,4S)-2-deuterio-3-bromo-4-methylhexane
NuSN2 and E2depends on basicity of donor
C
CNu
C
HH
H
H
HD
CH3less basic = SN2 > E2 at secondary RX
Some examples
OH Na
OR Na
R
O
O
Na
O KCH
DCH3
C Br
C
HH
CH3
CH2CH3
BSN2 and E2depends on basicity of donor
C
C
CH3
D
C
H
2Z-alkene 2E-alkene 3Z-alkene
C
C
H
C
CH3
D
H
Rstill R
CH
DCH3
C Br
C
HH
CH3
CH2CH3
(2R,3R,4S)-2-deuterio-3-bromo-4-methylhexane
H3C
CH2CH3H CH3
CH2CH3still S
C
C
H
H3C
C
H H CH3
CH2CH3still S
E2
SN2
more basic = E2 > SN2 at secondary RX
HCC
NC
BSN2 and E2depends on basicity of donor
C
C
CH3
D
CH3
H
2Z-alkene
C
C
H
H3C
CH3
H
2E-alkene 1-butene, neither E or Z
H2C
H
C
CH3
D
H
R
still R
(2S,3R)-3-deuterio-2-bromobutane
CH
DCH3
C Br
C
HH
H
H
SN2 and E2depends on basicity of donor
C
CNu
C
HH
H
H
HD
CH3
more basic = E2 > SN2Some examples
OH Na
OR Na
R
O
O
Na
OKSN2
Nu
CH
DCH3
C Br
C
HH
H
H
(2S,3R)-3-deuterio-2-bromobutane
2Rless basic = SN2 > E2
H3CC
CC
H H
other secondary RX to consider.
H3CC
CCH3
H3C CH3
Br
Mechanism predictions with:
OR H
R
O
OH
OH H ?
Br H
HH
H
Br HBr H
Br
Br
Br
Br
Usually SN1 > E1 (except ROH + H2SO4/.)
2o neopentyl allylic
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(2R,3R,4S)-2-deuterio-4-methyl-3-bromohexane
Example 5 - tertiary RX (deuterium is an isotope of hydrogen that can be distinguished)
(2S,3S,4S)-2-deuterio-4-methyl-3-bromohexane
Nu
B ?
Nu
B?
CH
DCH3
C Br
C
CH2
H
CH3
CH2CH3
H C
C
D
Br
C
CH2
HH3C
H
CH2CH3CH3
H
choose from
our list
choose from
our list
only E2 possible at 3o RX and strong base-nucleophile, need Cb-H though.
Some examples
OH Na
OR Na R
O
O
Na
OKNu No SN2 reaction
at 3o RX, backside is too sterically hindered
(2S,3R,4S)-2-deuterio-4-methyl-3-bromohexane
CH
DCH3
C Br
C
CH2
H
CH3
CH2CH3
H
E2 reaction at 3o RX with strong base-nucleophile
(2R,3R,4S)-2-deuterio-4-methyl-3-bromohexane
B
2Z-alkene(with D)
2E-alkene(without D) 1-butene, neither E or Z
C
C
H3C
C
CH3
D
H
Rstill R
H3C
H2C CH3
3Z-alkene from "S"
H2CC
C
C
CH3
H
D
H2C
CH3
still R
still SS
H CH3
CH
DCH3
C Br
C
CH2
H
CH3
CH2CH3
H
(3E-alkene if "R")
C
C
H
H3C
H3C
C
H2C
CH3
H CH3
still S
C
C
CH3
D
H3C
C
H2C
CH3
H CH3
still Sonly first mechanismis shown
Usually SN1 > E1 (except ROH + H2SO4/D.)
other tertiary RX to consider.
H3CC
C
H2C
H3C CH3
Mechanism predictions with:
OR H
R
O
OH
OH H ?
Br Br CH3
Br
Br H
CH3
Br
Br Br Br
Nucleophilic Substitution & Elimination Chemistry 29
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Example 5 - cyclohexane structures to consider (X must be axial to react by SN2 and E2) (X can be axial or equatorial to react by SN1 and E1). Essential details can be filled in on the following templates.
cyclohexanewithout branches
cyclohexanewith a branch
Mechanism predictions with:
OR H
R
O
OH
OH H
Many substitution patterns are possible.
XX X
X
X X X
X
X
a b c d e
fg
h ij
Some examples
OH Na OR Na R
O
O
Na
O K
X
weaknucleophiles
strong nucleophile/bases + other anions shown above
Nucleophilic Substitution & Elimination Chemistry 30
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Simple Examples – general patterns (this is as easy as it gets, more complicated examples follow)
BrH3CBr
Br
Br
Br
OH Na
OHH3C
Br
OH
OH
No Reaction(neopentyl)
nucleophile / base
only SN2 SN2 > E2 E2 > SN2 only E2 only E2
No SN2 Reaction(neopentyl)
BrH3CBr
Br
Br
Br
NaOR
OH3C
Br
O
OR
nucleophile / base
only SN2 SN2 > E2 E2 > SN2 only E2 only E2
R
R
No Reaction(neopentyl)
No SN2 Reaction(neopentyl)
BrH3CBr
Br
Br
Br
O
O
Na
Br
O
O
nucleophile / base
only SN2 SN2 > E2 only E2 only E2
O
O
O
O
SN2 > E2No Reaction(neopentyl)
No SN2 Reaction(neopentyl)
Nucleophilic Substitution & Elimination Chemistry 31
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BrH3CBr
Br
Br
Br
O K
Br
O
nucleophile / base
only SN2only E2
only E2
O
E2 > SN2 only E2 No Reaction(neopentyl)
No SN2 Reaction(neopentyl
and t-butoxide)
BrH3CBr
Br
Br
Br
OH H
Br
nucleophile / base
No Reaction(1o RX)
SN1 > E1 SN1 > E1SN1 > E1
with rearrangement(main product?)
OH
R R
R& S
OH
OHOH
R& S
No Reaction(1o neopentyl)No Reaction
(1o RX)
Nucleophilic Substitution & Elimination Chemistry 32
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BrH3CBr
Br
Br
Br
OR H
Br
nucleophile / base
SN1 > E1 SN1 > E1SN1 > E1
OR
R R
R& S
OR
OROR
R& S
No Reaction(1o RX)
No Reaction(1o RX)
No Reaction(1o neopentyl)
with rearrangement(main product?)
BrH3CBr
Br
Br
Br
R
O
OH
Br
nucleophile / base
SN1 > E1 SN1 > E1SN1 > E1
with rearrangement
O
R R
R& S
O
OO
R& S
O O
O
O
No Reaction(1o RX)
No Reaction(1o RX)
No Reaction(1o neopentyl)
Nucleophilic Substitution & Elimination Chemistry 33
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SN1 / E1 possibilities –extra complications at Cβ positions, 2o RX, rearrangements NOT considered (H2O,ROH,RCO2H)
OR HR
O
OOH H
Examples of weak nucleophile/bases in our course
a b
c
H
water alcohols carboxylic acids
E1 product from left C carbon atom
H3CC
CC
H2C
CH3
H H
H
H
Br
H
H3CC
CC
H2C
CH3
H H HH
H
Redrawn
(achiral)
(achiral)
CCH
H2C
H
H3CH
CH2
CH3
H2O
CCH
C
H
CH2H
CH3H
H3CH
H2O
same first step for SN1/E1
add nuclephile (top/bottom) = SN1
lose -H (top/bottom) = E1
rearrangement to similar or more stable carbocation (R+)(start all over)
"H" parallel to empty 2p orbital on top
"H" parallel to empty 2p orbital on bottom
C C
H3C H
H CH2
H2C
CH3
C C
H H
H3C CH2
H2C
CH3
2E-alkene
2Z-alkene
H2O
CH2C
H
C
H
H3C
CH2H
CH3
CCH2
H
C
H3C
"H" parallel to empty 2p orbital on top
"H" parallel to empty 2p orbital on bottom 3Z-alkene
3E-alkene
OH2
H
H
OH2
C
C CH2
H2C
H
H
CH3
H3C
C
C H
H2C
H2C
HH3C
CH3
OH2
CH2C
H
H2CH3C
CH2
CH3
OH2
H2O
a
b
SN1 product (a. add from top and b. add from bottom)
CCH2 H2C
H
O
HH
H3C H2C
CH3
C
H2C
H H2C
O
HH
H3CCH2
CH3
a
b
OH2
OH2
CCH2 C
H2
H
O
H
H3C H2C
CH3
C
H2C
H H2C
O
H
H3CCH2
CH3
(achiral)
(3S)
enantiomers
acid/base proton transfer
acid/base proton transfer
E1 product from right C carbon atom
H2C
H3C
(3R)
(3R)
carbocation choices
Nucleophilic Substitution & Elimination Chemistry 34
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SN1 / E1 possibilities –extra complications at Cβ positions, 2o RX, rearrangements NOT considered, with deuterium (makes it a little harder)
OR HR
O
OOH H
Examples of weak nucleophile/bases
a b
c
H
water alcohols carboxylic acids
E1 product from left C carbon atom
H3CC
CC
H2C
CH3
D H
H
D
Br
H
H3CC
CC
H2C
CH3
D H DH
H
Redrawn
(2S,3R,4S) (2S,4S)
(2S,4S)
CCH
C
D
H
H3CH
CH2D
CH3
H2O
CCH
C
H
CH2D
CH3D
H3CH
H2O
same first step for SN1/E1
add nuclephile (top/bottom) = SN1
lose -H (top/bottom) = E1
CCH
C
H
H
DH3C
CH2D
CH3
H2O
CCH
C
H
CH2D
CH3H
DH3C
H2O
"D" parallel to empty 2p orbital on top
"D" parallel to empty 2p orbital on bottom
"H" parallel to empty 2p orbital on top
"H" parallel to empty 2p orbital on bottom
C C
H3C H
H CHD
H2C
CH3
C C
H H
H3C CHD
H2C
CH3
C C
D H
H3C CHD
H2C
CH3
C C
H3C H
D CHD
H2C
CH3
4S,2E-alkene without "D"
4S,2Z-alkene without "D"
4S,2Z-alkene with "D"
4S,2E-alkene with "D"
H2O
(2S,4S)
(2S,4S)
(2S,4S)
(2S,4S)
(4S)
(4S)
(4S)
(4S)
rearrangement to similar or more stable carbocation (R+)(start all over)
carbocation choices
Nucleophilic Substitution & Elimination Chemistry 35
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Redrawn from above (2S,4S)
CCH
C
D
H
H3CH
CH2D
CH3
CCH
CD
H3CH
"D" parallel to empty 2p orbital on top
"D" parallel to empty 2p orbital on bottom
"H" parallel to empty 2p orbital on top
"H" parallel to empty 2p orbital on bottom
2S,3E-alkene without "D"
2S,3Z-alkene without "D"
2S,3Z-alkene with "D"
2S,3E-alkene with "D"
OH2
H
DH2C
OH2
CCH
C
D
D
H3CH
HCH2
CCH
CD
H3CH
OH2
D
H2C
H
OH2
H3C
H3C
CH3
C
CH2C
HDC
D
H
CH3
H3C
C
C D
CDH
H2C
HH3C
C
CH2C
CDH
H
H
CH3
H3C
CH3
C
C H
CDH
H2C
HH3C
CH3
OH2
CCH
C
D
H
H3CH
CH2D
CH3
OH2
H2O
a
b
SN1 product (a. add from top and b. add from bottom)
CCDH HDC
H
O
HH
H3C H2C
CH3
C
DHC
HDHC
O
HH
H3CCH2
CH3
a
b
OH2
OH2
CCDH HDC
H
O
H
H3C H2C
CH3
C
DHC
HDHC
O
H
H3CCH2
CH3
(2S,4S) (2S,3R,4S)
(2S,3S,4S)
diastereomers
acid/base proton transfer
acid/base proton transfer
E1 product from right C carbon atom
(2S,4S)(2S)
(2S)
(2S)
(2S,4S)
(2S,4S)
(2S,4S)
(2S)
Nucleophilic Substitution & Elimination Chemistry 36
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SN1 / E1 possibilities –extra complications at Cβ positions of 2o RX, rearrangement to more stable 3o R+ considered
E1 product from left C carbon atom (without rearrangement)
H3CC
CC
H2C
CH3
H H
H
CH3
Br
H
H3CC
CC
H2C
CH3
H H CH3H
H
Redrawn
(4S)
(achiral)
CCH
C
H
H3CH
H2O
CCH
CH
H3CH
H2O
same first step for SN1/E1
add nuclephile (top/bottom) = SN1
lose -H (top/bottom) = E1
"H" parallel to empty 2p orbital on top
"H" parallel to empty 2p orbital on bottom
C C
H3C H
H C
H2C
CH3
C C
H H
H3C C
H2C
CH3
4S,2E-alkene
4S,2Z-alkene
H2O
CH2C
H
C
H
H3C
CH2H3C
CH3
CCH2
H
C
H3C
"H" parallel to empty 2p orbital on top
"H" parallel to empty 2p orbital on bottom 3Z-alkene
3E-alkene
OH2
H
CH3
OH2
C
C CH2
CH2
H3C
H
CH3
H3C
C
C CH3
H2C
H2C
HH3C
CH3
OH2
CH2C
H
CH3C
OH2
H2O
a
b
SN1 product (a. add from top and b. add from bottom), (without rearrangement)
CCH2 C
H
O
HH
H3C H2C
CH3
C
H2C
H
C
O
HH
H3C
a
b
OH2
OH2
CCH2 C
H
O
H
H3C H2C
CH3
C
H2C
H
C
O
H
H3C
(3S,4S)
diastereomers
acid/base proton transfer
acid/base proton transfer
E1 product from right C carbon atom (without rearrangement)
H2C
H3C
(3R,4S)
(3R,4S)
H2C
CH3
CH3H CH3H
H2C
CH3
CH3H CH3
H
H2C
CH3
H CH3 CH3H2C
CH3
CH3H
H H
H
H2C
CH3
CH3
CH3
(4S)
(4S)
(4S)
(4S)
(4S)
diastereomers
diastereomers
3R stereochemistry is lost
(3R,4S)
(3S,4S)
rearrangement to similar or more stable carbocation (R+)(start all over)
carbocation choices
Nucleophilic Substitution & Elimination Chemistry 37
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After rearrangement to 3o carbocation (R+) – We will skip rearrangements in Chem 314
E1 products from left C carbon atom (top and bottom, after rearrangement)
Redrawn (achiral)
H2O
CC
CH3
H2C
HH3C
2E-alkene2Z-alkene
3Z-alkene3E-alkene
OH2
C
C CH2
H2C
H3C
H
CH3
H3CC
CH2C
H
H3C
CH2
OH2
H2O
a
b
SN1 product (a. add from top and b. add from bottom), (after rearrangement)
C
O
HH
C
O
HH
a
b
OH2
OH2
(achiral) acid/base proton transfer
E1 product from right C carbon atom (top and bottom, after rearrangement)
(3R)
diastereomers
CH2C
H
C
H
H3C
CH2H3C
CH3
(4S)
initial 2o carbocation rearranges via hydride shift to a 3o carbocation
C
C
H3C
H
CH2
H3CH
C
CH3
4S stereochemistry is lost in new carbocation
add nuclephile (top/bottom) = SN1
lose -H (top/bottom) = E1
rearrangement to similar or more stable carbocation (R+)(none is possible here)
R+ reaction possibilities start all over again with new carbocation
H
H
C
C
H3C
H
CH2
H3CH
C
CH3
H
H
C
C
H3C
H
CH2
H3CH
C
CH3
H
H
"H" parallel to empty 2p orbital on top and bottom of right C position
CH2
H3C
CC
HH2C
CH3H3C
CH2
H3C
diastereomers
C
C
H3C
H
CH2
H3CH
C
CH3
H
H
H2C
CH3
CH2
H3C
CH2
H3C
CH2
CH3CH2H3C
H2C
H3C
acid/base proton transfer
C
O
H
CH2
CH3CH2H3C
H2C
H3C
C
O
H
H2C
CH3
CH2
H3C
CH2
H3C
(3S)
enantiomers
CH3
H3C
CH2
C
CH3
H2C
H2C 1-alkene(does not have E/Z stereochemistry)
OH2
E1 product from methyl C carbon atom (top and bottom, after rearrangement, only one product from the methyl)
C
C
H2C
H
CH2
H3CH
CH2
CH3CH2
H3C
H
(3R)
(3S)
"H" parallel to empty 2p orbital on top and bottom of right C position
"H" parallel to empty 2p orbital on top and bottom of right C position
Nucleophilic Substitution & Elimination Chemistry 38
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Homework problems: The number of each type of product (SN1, E1, SN2, E2) is listed after a reaction arrow for each starting structure (assuming I analyzed the possibilities accurately in my head, while sitting at the computer). See if you can generate those products using a valid mechanism for each one.
Br H
H3C H
OH
O
OH
HO
H
SN1 E1 SN2 E2
O
O
O
HO
2 41 3
1 3
1 3
a.
2 5b.
2 4a.
2 5b.
2 4a.
2 5b.b. after rearrangement
a. initial carbocation
Br H
H3C H
Br H
H3C H
OH
O
OH
SN1 E1 SN2 E2
O
O
O
HO
2 61 3
1 3
1 3
a.
2 5b.
2 6a.
2 5b.
2 6a.
2 5b.b. after rearrangement
a. initial carbocation
Br H
H3C H
HO
H
D H D H
HO
H
2 3
chair 1 chair 2
SN1
XX X
a.
b.
SN2 E2
1 1
E1
1 1
1
SN1 SN2 E2
1 2
E1
2 2
SN1 SN2 E2
0 1
E1
5 6SN1
XX X
SN2 E2
1 2
E1
2 2
4
SN1 SN2 E2
1 2
E1
2 2
SN1 SN2 E2
1 2
E1
2 2
8 9
SN1
XX
SN2 E2
1 2
E1
2 2
7
SN1 SN2 E2
0 3
E1
2 3
SN1 SN2 E2
0 1
E1
2 1
1 2
Only consider carbocation rearrangements that immediately go to a more stable carbocation (not equally stable carbocations = too many possibilities)
a.
b.2 2
1 2
X
a.
b.c.
d.
consider any 3o R+ possibilityand consider stereoisomers
4 51 21 2
HO Na
condition 1 condition 2
Nucleophilic Substitution & Elimination Chemistry 39
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C
C
C
Br
CH
Hb
Ha H
H HH H
C
C
Ha
Br
CH
H3CHb H
H
Rotation of C-C1 brings Ha or Hb anti to C-Br, which allows SN2 and two different E2 possibilities: Ha (Z) and Hb (E). Since C2 is a simple methyl, there is no C2 substituent to inhibit either of these reactions.
C
C
Hb
Br
CH
Ha
H3C H
H
When methyl on C1 is anti to C-Br, no SN2 is possible and no E2 is possible from C1.
SN2 possibleE2 from C1 (2Z- butene)E2 from C2 (1-butene)
SN2 possibleE2 from C1 (2E- butene)E2 from C2 (1-butene)
No SN2 possible and noE2 from C1, but E2 from C2 (1-butene) is possible.
E2 possible here
Use these ideas to understand cyclohexane reactivity.
H H
H
H
H HBr
H
H
H
H
H
HH
H
H
HH
BrH
H
H
HH
No SN2 is possible (1,3 diaxial positions block approach of nucleophile), and no E2 is possible because ring carbons are anti.
No SN2 or E2 when "X" is in equatorial position.
SN2 possible if C is not tertiary and there is no anti C "R" group.
E2 possible with anti C-H.
Both SN2 and E2 are possible in this conformation with leaving group in axial position.
H H
H
H
H HBr
H
C
H
H
H
HH
H
H
HH
BrH
H
H3C
HH
No SN2 or E2 when "X" is in equatorial position.
No SN2 possible if there is an anti C "R" group.
E2 possible with anti C-H.
Only E2 is possible in this conformation. Leaving group is in axial position.
H
H
H
full rotation atC-C is possible in chain
only partial rotation is possible in ring
only partial rotation is possible in ring
H H H
equatorial leaving group
axial leaving group
No SN2 is possible (1,3 diaxial positions block approach of nucleophile), and no E2 is possible because ring carbons are anti.
No E2 possible, no anti C-H.
full rotation atC-C is possible in chain
alkene stabilities tetrasubstituted > trisubstituted > trans-disubstituted > gem-disubstituted cis-disubstituted > monosubstituted
Nucleophilic Substitution & Elimination Chemistry 40
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Examples - group A
C
H3C
H3C
H3C
H
H
CCH3H3C
H
H
severe steric repulsion
19,999
Keq »t-butyl substituent locks in chair conformation with equatorial t-butyl
X X
XX
XX
X
1. Is SN2 possible? Requires an open approach at C and C.2. Is E2 possible? Requires anti C-H.3. How many possible products are there?4. What is the relationship among the starting structures?5. What is the relationship among the products?6. Are any of the starting structures chiral?7. Are any of the product structures chiral?
X X
X X
1 2
3
4
5
6
7
8
9
10
11
Cyclohexane structures have two chair conformations possible.
X = Cl Br I OTs
H3C
1. Which conformation is reactive?2. Is SN2 possible? Requires an open approach at C and C.3. Is E2 possible? Requires anti C-H.4. How many possible products are there?5. What is the relationship among the starting structures?6. What is the relationship among the products?7. Are any of the starting structures chiral?8. Are any of the product structures chiral?
Examples - group B
1
TsO OTs
OTsTsO
TsO OTs
OTs
TsO OTsTsO OTs2
3
4
5
6
7
8
9
10
11
chair 1 chair 2
Nucleophilic Substitution & Elimination Chemistry 41
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strong base/nucleophile conditions (E+ = electrophile, Nu: = nucleophile)
n-butyl lithium (powerful nucleophile at epoxides and carbonyls (C=O), and the “most powerful base” at other times)
BrH3Cnucleophile = ?electrophile = ?
H3C
H2C
CH2
H2C
LiShould be SN2, but does not work well. Too many side reactions. Another approach is necessary,using cuprates (R2Cu Li ).
BrH2C
H3Cnucleophile = ?electrophile = ?
H3C
H2C
CH2
H2C
Li
BrH2C
CH2H3Cnucleophile = ?electrophile = ?
H3C
H2C
CH2
H2C
Li
Should be SN2, but does not work well. Too many side reactions. Another approach is necessary,using cuprates (R2Cu Li ).
Should be SN2, but does not work well. Too many side reactions. Another approach is necessary,using cuprates (R2Cu Li ).