Chapter 7a Lecture Slides PDF

Chapter 7 Alkyl Halides: Nucleophilic Substitution and
Elimination Reactions 1˚ halide
Hello
3˚ halide
Chapter 7 Alkyl Halides: Nucleophilic Substitution and
Elimination Reactions
Topics:
I. Introduction to Substitution and Elimination Reactions
II. Nomenclature and Uses of Alkyl Halides
III. SN2 Reactions
IV. Nucleophilic Strength and Solvent Effects in SN2 Reactions
V. Hello
SN2 Reactions in Biological Systems-Methylation
VI. Introduction to E2 Reactions
VII. Nomenclature and Stability of Alkenes
VIII. Regiochemical and Stereochemical Outcomes for E2 Reactions
IX. Unimolecular Reactions (SN1 and E1)
X. Kinetic Isotope Effects in Elimination Reactions
XI. Predicting Products: Substitution vs. Elimination
XII. Substitution and Elimination Reactions with Other Substrates
XIII. Synthesis Strategies
XIV. Building your “Toolbox” of Reactions
2
• Substitution and Elimination reaction are two of the

most common reactions in organic chemistry!
• Alkyl halides undergo substitution and elimination rxns
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Alkyl halide Aryl halide Vinyl halide
– Which structure represents an alkyl halide?

• Alkyl Halides can undergo a substitution reaction when reacted

with a nucleophile.
Hello
• Alkyl Halides can undergo an elimination reaction when reacted

with a base.
-‐ What do nucleophiles and bases have in common?
They both have at least one lone pair of electrons
• When the reagent can act as a nucleophile or a base:

• Elimination and substitution will be competing
reaction pathways
Hello
• A substrate is a chemical species of particular interest

(because we are studying it).
• In the example above, which compound is the substrate?
• In this case it is the alkyl halide.
Two main reasons why alkyl halides undergo substitution and
elimination reactions:
1. The halogen is electron-‐withdrawing, creating a partial positive
charge on the alpha carbon, making it susceptible to nucleophilic
attack. Hello
Nuc:
2. The halogen acts as a leaving group, and for a substrate to
undergo a substitution/elimination reaction, it must possess a good
leaving group.
• Good leaving groups are conjugate bases of an acid with
a pKa <0. This is because the conjugate base is stabilized.
• Unstabilized conjugate bases make poor leaving groups, they
are too high in energy.
Good leaving groups are the conjugate bases of strong acids.
Stabilized
Hello
conjugate
bases
Tosyl-OH
TsOH
Unstabilized
conjugate
bases
Alkyl halides: Compounds where an sp3 carbon group
(alkyl) is bonded to a halide (F, Cl, Br, or I)
• They are widely synthesized by us to serve a variety
of purposes such as…
– Hello
Insecticides (DDT, etc.)
– Dyes (tyrian purple, etc.)
– Drugs (anticancer, antidepressants, antimicrobial, etc.)
– Food additives (Splenda, etc.)
– Many more
• The structure of the molecule determines its function
• Halides appear in a wide variety of natural products.
Marine species and plants use these compounds as
“chemical warfare agents in order to protect themselves.
Cl
Cl Cl Cl Cl
Cl Cl PCB (polychlorinated biphenyls) Cl Cl
DDT (pesXcide) -‐ coolants, insulaXng fluids,

Hello N NH F F
R NO2 F
HO OH N
O
Bronopol
anX-‐microbial agent Cl
in baby-‐wipes Chlorpheniramine (R)-‐FluoxeXne

HO (Prozac)
OH
Cl HO
O
HO O O
Cl
OH
Cl
Sucralose or Splenda (hundreds of Xmes sweeter than sugar)

• Recall the steps we use to name a molecule

1. Identify and name the parent chain
2. Identify the name of the substituents
Hello
3. Assign a locant (number) to each substituents
4. Assemble the name alphabetically
• The halide group is the key substituent we will name and
locate.
• Halogens are named the following way:
• fluoro-‐, chloro-‐, bromo-‐, iodo-‐ prefix is listed first
followed by the rest of the name
• For each of these examples, convince yourself that they are
numbered in the most appropriate way.
Hello
• Give reasonable names for the following molecules
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2-‐bromo-‐2-‐iodo-‐3-‐methylbutane 2,3-‐dichloro-‐4-‐isopropyl-‐5-‐methylhexane
Assign a systematic name for each of the following compounds:
F
Br Br
Br
Cl
Cl
Hello
a. b. c. d.
Cl
Cl
Br Cl
Cl
e. f. g. h.
Answers:
F
Br Br
Br
Cl
Cl
a. Hello
b. c. d.
4,4-‐dibromo-‐1-‐ 1-‐bromo-‐1-‐ (R)-‐4-‐chloro-‐4-‐ 5-‐fluoro-‐2,2-‐
chloroheptane methylcyclohexane ethyloctane dimethylhexane
Cl
Cl
Br Cl
Cl
e. f. g. h.
3-‐bromo-‐3-‐ (2R,3R)-‐3-‐tert-‐butyl-‐2-‐ (2R 4S)-‐2-‐chloro-‐4-‐ 2,2-‐dichloro-‐3,3-‐
isopropyl-‐2-‐ chloro-‐1,1-‐ ethyl-‐8-‐methylnonane diethyl-‐4-‐
methylnonane dimethylcyclobutane methylpentane
• Some simple molecules are also recognized by their

common names.
– the alkyl group is named
as the substituent, and
Hello
the halide is treated as
the parent name

Systematic Name Common Name
Cl Cl
Methylene chloride is a
Cl Cl
commonly used organic
Dihalo alkane alkyl dihalide
solvent
Dichloromethane Methylene Chloride
(DCM)
methylene = a CH2 group
• Greek letters are often used to label the carbons of the
alkyl group attached to the halide
– The alpha carbon is connected to

the substituent we are focused on.
Hello
– We then count away, in all directions using beta and

gamma
– There can be as many as three beta positions

• The amount of branching at the alpha carbon affects the
reaction mechanism. There are three types of alkyl halides
Hello
– Primary alkyl halides only have 1 β position.

– Secondary alkyl halides have 2 β postions
– Tertiary alkyl halides have 3 β positions
• Some alkyl halides are used as insecticides. For the

insecticides below…
– Label each halide as either primary, secondary, or tertiary
– For the circled atoms, label all of the alpha, beta, gamma, and
delta carbons.Hello
Primary Secondary
• Organic halides are also useful to organic chemists as

synthetic precursors (building blocks to make more
complex molecules)
Hello Cl t-BuOK
NaOH An alkyl halide
an alkene
NaCN
OH
NaOCH3
NaSH CN
an alcohol CH3CO2Na
a nitrile
OCH3
O
an ether SH
an ester O
a thiol
III. SN2 Reactions
• A substitution reaction requires the loss of a leaving

group, and nucleophilic attack. There are two possible
mechanisms: (1) concerted, and (2) stepwise.
1. The concerted mHello

echanism involves breaking of the bond to the
leaving group and making of the bond to the nucleophile at the
same time (concerted = at the same time)
III. SN2 Reactions
2. The stepwise mechanism the leaving groups leaves first, to give
a carbocation intermediate, followed by nucleophilic attack
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III. SN2 Reactions
What do S, N, and 2 stand for in the SN2 name?
Hello
1 2
• How might you write a rate law for this reaction?

Rate = k [1]n[2]m
• How would you design a laboratory experiment to confirm this

rate law? Keep the concentraYon of one reactant the same,
and vary the other. Observe how the rate changes.
S = subsXtuXon, N = nucleophilic, 2 = bimolecular (second order reacXon)

III. SN2 Reactions
The following substitution reaction exhibits second-‐order
kinetics, and is therefore presumed to occur via an SN2 process.
I + NaOH OH + NaI
a. What happens to Hello

the rate if the concentration of 1-‐iodopropane
is tripled and the concentration of sodium hydroxide remains the
same?
b. What happens to the rate if the concentration of 1-‐iodopropane
remains the same and the concentration of sodium hydoxide is
doubled?
c. What happens to the rate if the concentration of 1-‐iodopropane
is doubled and the concentration of sodium hydroxide is tripled?
III. SN2 Reactions
Answers:
I + NaOH OH + NaI
a. What happens to the rate if the concentration of 1-‐iodopropane
is tripled and the concentration
Hello of sodium hydroxide remains the
same?
3x faster
b. What happens to the rate if the concentration of 1-‐iodopropane
remains the same and the concentration of sodium hydoxide is
doubled?
2x faster
c. What happens to the rate if the concentration of 1-‐iodopropane
is doubled and the concentration of sodium hydroxide is tripled?
2 x 3 = 6x faster
III. SN2 Reactions
• How does the observed stereochemistry in the
following reaction support an SN2 mechanism?
Hello
III. SN2 Reactions
• The transition state for the following reaction, explains why SN2
reactions proceed with inversion of configuration
Transition state symbol
(double dagger)
Hello
H Me
HS Br
Et
Back-‐side attack: The requirement that the nucleophile can only attack
from the back side (directly opposite, 180°, of the leaving group)
Inversion of Configuration: The stereocenter is inverted do to the fact
that the nucleophile attacks from the back-‐side. (see transition state
above)
III. SN2 Reactions
When (R)-‐2-‐bromobutane is treated with sodium hydroxide, a
mixture of products is obtained. An SN2 process is responsible for
generating one of the minor products, while the major product is
generated via an elimination process, as will be discussed later in
this chapter. Draw the SN2 product that is obtained when (R)-‐2-‐
Hello
bromobutane reacts with a hydroxide ion.
III. SN2 Reactions
When (R)-‐2-‐bromobutane is treated with sodium hydroxide, a
mixture of products is obtained. An SN2 process is responsible for
generating one of the minor products, while the major product is
generated via an elimination process, as will be discussed later in
this chapter. Draw the SN2 product that is obtained when (R)-‐2-‐
Hello
bromobutane reacts with a hydroxide ion.
Br
1 + NaOH ?
3 2
OH
(R)-‐2-‐bromobutane
Make it easy for yourself and

always have the H in the back! (S)-‐2-‐butanol
Inversion of Stereochemistry
due to the back-‐side attack
III. SN2 Reactions
Draw the product for each of the following SN2 reactions.
a. (S)-‐2-‐Chloropentane and NaSH

Hello
b. (R)-‐3-‐Iodohexane and sodium chloride
c. (R)-‐2-‐Bromohexane and sodium cyanide
d. 1-‐Bromoheptane and sodium hydroxide
III. SN2 Reactions
Answers:
Cl SH
a. + NaSH
Hello
b. + NaCl
I Cl
Br CN
c. + NaCN
Br OH
d. + NaOH
III. SN2 Reactions
A common method for confirming the proposed structure and
stereochemistry of a natural product is to synthesize the proposed
structure and then compare its properties with those of the
natural product. Draw curved arrows for both steps shown below
Hello
Br Br
H
O KO O O
H
H H
H
1 2 3
III. SN2 Reactions
Answers:
Br Br
Hello H
O KO O O
H
H H
H
1 2 3
III. SN2 Reactions
Mechanism of an SN2 Reaction (MO Theory)
• The nucleophile attacks from the back-‐side
– Electron density repels the attacking nucleophile from the
front-‐side (presence of bonded pair of electrons)
– The nucleophile must approach the back-‐side to allow
Hello
electrons to flow from the HOMO of the nucleophile to the
LUMO of the electrophile. (LUMO is the anti-‐bonding orbital)
– Proper orbital overlap cannot occur with front-‐side attack
because there is a node on the front-‐side of the LUMO
we compare the relative rates presented in Table 7.2, the following trends emerg
III. SN2 Reactions
e of an SN2 reaction is most sensitive to the number of substituents at the α p
bromide
Rates oisf pover onevhundred
rimary timesvs more
s secondary reactive
tertiary alkyl than ethyl bromide (a prima
halides
which is over one hundred times more reactive than isopropyl bromide (a se
• Less
lide). Noticesterically
that t-butyl hindered
bromidee(a lectrophiles
tertiary alkylreact halide)mis
ore readily towa
unreactive
bservations
under indicate
SN2 cthat SN2 reactions
onditions. are most
Tertiary effective
halides fortoo
are methyl halides and
hindered
lides, and SN2 reactions cannot be performed with tertiary alkyl halides.
to react via SN2 Hello
mechanism.
Reactivity toward SN2
Most
Unreactive
reactive
H3C X
X X X
Methyl 1° 2° 3°
• To 7.2
TABLE
rationalize this trend, examine the
EFFECT OF SUBSTITUENTS ON THE RATES OF SN2 REACTIONS
reaction coordinate diagram.
⊝
⊝
R Br R + Br
acetone
III. SN2 Reactions
• Alkyl groups branching from the α and β carbons hinder the
backside attack of the nucleophile, resulting in a slower rate of
reaction.
Hello
III. SN2 Reactions
To rationalize this trend, we must examine the energy diagram
• What feature of the diagram is relevant to rationalize the rate
of reaction?
• What feature is relevant to rationalize the thermodynamics of
the reaction? Hello
III. SN2 Reactions
• Which reaction will have the fastest rate of reaction?
• WHY? H H 3C H 3C
X X X
Nuc: H Nuc: H Nuc: H
H H H 3C
Hello
• 3° substrates react too slowly to measure. Other reactions

are possible, and will happen more quickly.
III. SN2 Reactions
As a class, lets draw the transition state of the following
reaction:
NaSH
Cl SH + NaCl
Hello
III. SN2 Reactions
Answer: Back-‐side attack! As the HS− come in, the Cl− leaves.
NaSH
Cl SH + NaCl
Hello
CH3
SH Cl
H H
III. SN2 Reactions
Draw the transition state for each of the following SN2 reactions:
Br NaOH OH
a. + NaBr
O
Hello
b.
O
O
I +
I
O
c. Cl
NaOH
OH + NaCl
Br SH
d. NaSH
+ NaBr
III. SN2 Reactions
a. c.
Hello HO Cl
HO Br
H H
H H
Br
b. O I d. H
O H H SH
III. SN2 Reactions
The total synthesis of the marine natural product aldingenin C in
the laboratory utilized an intramolecular SN2-‐type reaction which
utilized a poor leaving group. However, in this case the reaction
was favorable do the the relief of ring strain (opening of a 3-‐
membered ring). The relief of ring strain can be a powerful driving
force in reactions! DHello
raw the transition state for this reaction and
identify the leaving group.
O O
O
O
O
O
III. SN2 Reactions
Answer: Drawing these structures in 3D often works best!
Hello O
O
IV. Nucleophilic Strength and Solvent Effects in SN2
Reactions
• What are the factors that contribute to the strength of
a nucleophile? Polarizability and Charge
• A strong nucleophile
Hello i s n eeded for a n S N2 rxn
• We need to be able to recognize a given nucleophile as

being strong or weak
Reactions
Commonly nucleophiles used in substitution reactions:
Hello
• You should be able to determine if a nucleophile is strong or weak.
• In general, anions are strong nucleophiles
• If there is no charge, it tends to be a weaker nucleophile
• Polarizable atoms are good nucleophiles
• Polarizable = ability to unevenly distribute its electron density do to an
external influence. (More electrons are pulled toward the electrophile)
• Large atoms like S, Cl, Br, and I
• The solvent affects nucleophilicity
Reactions
• Need a polar aprotic solvent for SN2 rxns
Hello
• Protic solvents engage in H-‐bonding, and stabilize anionic species

(such as good nucleophiles).
• Hydrogen bonds are very very good at this!
• Aprotic solvents stabilize both cations and anions (but they do not
stabilize anions as well due to steric constraints)
Reactions
• How do these factors play into the strength of a nucleophile in protic
versus aprotic solvent?
• Nucleophiles are less stable,

thus more reactive Hello
in aprotic
solvent.
• The activation energy will be

lower and the reaction faster
Aprotic solvents are

best for SN2 reactions
Reactions
Hello
Nucleophiles are more reactive in aprotic solvents

Reactions
For each pair of reactions, which one will exhibit a faster rate?
Explain.
Cl NaOH/H2O OH
a. i. + Cl
Hello
NaOH/DMSO
ii. Cl OH + Cl
b. i. Br NaI / EtOH I +
Br
ii. Br NaCl / EtOH Cl +

Br
Reactions
Answers:
Cl NaOH/H2O OH
a. i. + Cl
NaOH/DMSO
ii. Cl
Hello OH + Cl
ii. is fastest since the DMSO (an operatic solvnet) does NOT stabilize the nucleophile
as well as H2O does (a protic solvent).
b. i. Br NaI / EtOH I +
Br
ii. Br NaCl / EtOH Cl +

Br
i. is fastest since I− is a more polarizable and therefore a better nucleophile!
Cl− is not as polarizable so it will not react as quickly therefore ii. reacts more slowly.
V. SN2 Reactions in Biological Systems—Methylation
Alkylation: The transfer of an alkyl group to a nucleophile

Methylation: The transfer of a methyl group to a nucleophile.
H3C
Hello
I
Nuc Nuc CH3 + I
SN2
• In lab, methyl iodide is regularly used. It is a liquid at room
temperature which is easy to handle and I− is an excellent leaving
group due to its polarizability and ability to stabilize a negative
charge.
• Halides are common leaving groups for laboratory use, but are not
common substrates in biological SN2 rxns.
Good
Good
Hello leaving
leaving group
group
Laboratory
methylaYng agent Biological methylaYng agent
• Both of these compounds are good methylating reagents: a good
nucleophile will attack the CH3 via an SN2 mechanism.
O
triphosphate O P O
O
very complex
leaving group O leaving group O
H 3N
O P O O O P O
NH2
O NH2 O
N
O P O N N + O P O
O N
O S
O SN2 Me N O
N
H 3N
O
N
Hello
N O O P O
O
S OH OH
OH OH
S-Adenosylmethionine (SAM)
Me Adenosine triphosphate (ATP) OH
Methionine
HO NH2
Sulfur is a great -H+
nucleophile HO
Noradrenaline
OH
H
HO N
Me
HO
Adrenaline
• When an alkyl halide is treated with a strong base, it can undergo beta
elimination (1,2-‐elimination) to form an alkene:
Hello
• A strong base will react in a concerted mechanism, called an E2 elimination.
• E2 elimination is concerted. The base removes a β-‐proton, causing

the loss of the leaving group and the formation of the C=C bond.
So, concerted elimination is bimolecular and follows second-‐order
kinetics:
Hello
• In what ways is E2 elimination similar to SN2 substitution? What are
the differences?
Similar: SXll second order

Akack happens 180° from the leaving group
Concerted (all happens at once)
Leaving group sXll leaves
• E2 elimination is concerted. The base removes a β-‐proton, causing

the loss of the leaving group and the formation of the C=C bond.
So, concerted elimination is bimolecular and follows second-‐order
kinetics:
Hello
• In what ways is E2 elimination similar to SN2 substitution? What are
the differences?
Different: An alkene is formed

Akack happens at the β posiXon to abstract a hydrogen
Base is required; has to be strong enough to yank off a hydrogen
Which reaction will occur??
• Consider a reagent such as NaOH, which is a strong nucleophile

(good for SN2 reactions) and a strong base (good for E2 rxns)…
Hello
… when the substrate is sterically hindered, E2 elimination will occur.
The following reaction exhibits a second-‐order rate equation:
Cl NaOH
a. What happens to the rate if the concentration of

chlorocyclopentane Hello is tripled and the concentration of sodium
hydroxide remains the same?
b. What happens to the rate if the concentration of

chlorocyclopentane remains the same and the concentration of
sodium hydoxide is doubled?
c. What happens to the rate if the concentration of

chlorocyclopentane is doubled and the concentration of sodium
hydroxide is tripled?
Answers:
Cl NaOH
a. What happens to the rate if the concentration of

chlorocyclopentane Hello is tripled and the concentration of sodium
hydroxide remains the same?
3x faster
b. What happens to the rate if the concentration of

chlorocyclopentane remains the same and the concentration of
sodium hydoxide is doubled?
2x faster
c. What happens to the rate if the concentration of
chlorocyclopentane is doubled and the concentration of sodium
hydroxide is tripled? 2 x 3 = 6x faster
Learning to Name Alkenes!
• Alkenes are given IUPAC names using the same

procedure to name alkanes, with minor modifications
1. Identify the parent chain, which includes the C=C double bond
Hello
2. Identify and Name the substituents
3. Assign a locant (and prefix if necessary) to each substituent.
Give the C=C double bond the lowest number possible
4. List the numbered substituents before the parent name in
alphabetical order. Ignore prefixes (except iso) when ordering
alphabetically
5. The C=C double bond locant is placed either just before the
parent name or just before the -‐ene suffix
1. -‐ane was used for alkanes, -‐ene is used for alkenes
1. Identify the parent chain, which should include the C=C double
bond
• The name of the parent chain should end in -‐ene rather than –ane
Hello
• The parent chain should include the C=C double bond
• If the double bond is on the first carbon, we don't need to specify it.
2. Identify and Name the substituents

3. Assign a locant (and prefix if necessary) to each substituent. Give
the C=C double bond the lowest number possible
Hello
– The locant of the double bond is a single number, and is the
number indicating where the double bond starts. The alkene
above is located at the “2” carbon.
4. List the numbered substituents before the parent name in

alphabetical order. Ignore prefixes (except iso) when ordering
alphabetically
5. The C=C double bond locant is placed either just before the
parent name or jHello
ust before the -‐ene suffix
Note: This alkene has the E configuration, which must be indicated in
the name, in parentheses: (E)-‐5,5,6-‐trimethylhept-‐2-‐ene
Recall how to assign E or Z to alkene stereoisomers…
• First, prioritize the groups attached to the C=C double bond
based on atomic number
Hello
• If the top priority groups are cis to each other, it is the
Z isomer
• If the top priority

Hello groups a re t rans to each o ther, i t i s the
E isomer
Provide a systematic name for each of the following compounds:
a. b. c.
Hello
d. e. f.
g. h.
Answers: instead of -‐ane use -‐ene and make sure the double bond gets
the lowest number possible. It is the highest priority group. Finally,
don't forget E and Z to show the geometry of the double bond.
7
2 4 6 1 2 5 6
1 3 5
1
a. b. 3 4 c. 2
3
4
5
(E)-‐3-‐methyl-‐3-‐hexene (E)-‐3-‐ethyl-‐4-‐methyl-‐2-‐pentene
Hello 2,3,5-‐trimethyl-‐2-‐heptene
1
4 5 2
1
d. 2 3 6 7 e. 3 5 f.
4 6 2
7 5 4 3 1
3-‐ethyl-‐2-‐methyl-‐2-‐heptene 4-‐tert-‐butyl-‐1-‐heptene
3-‐isopropyl-‐2,4-‐dimethylpentene
1 2 3
4 5 1 2
3 4
g. 6 7 h. 5 6
8
(E)-‐4,5-‐diethyl-‐2,2,7-‐trimethyl-‐4-‐octene (E)-‐3-‐ethyl-‐2,2,4,5,5-‐pentamethyl-‐3-‐hexene
Classify each of the following alkenes as monosubstituted,
disubstituted, trisubstituted or tetrasubstituted
a. b. c.
Hello
d. e.
Answers:
a. b. c.
Hello
trisubsYtuted disubsYtuted trisubsYtuted
d. e.
trisubsYtuted monosubsYtuted
Common Names for some Alkenes!
Hello
Ethylene Propylene Styrene
IUPAC Recognized substituents (like we did with isopropyl)
Methylene Vinyl Allyl

Which alkene is more stable?
Hello
cis-‐2-‐butene trans-‐2-‐butene
• Because of steric strain, cis isomers are generally less stable than
trans
Hello
• The difference in stability can be quantified by

comparing the heats of combustion
Hello
• Think about how the heats of combustion of the cis and
trans isomers reveal their relative stability…
Hello
• Alkyl groups stabilize the C=C pi bond via hyperconjugation.
Hello
More alkyl groups = more stable alkene

Arrange each set of isomeric alkenes in order of stability
a.
Hello
b.
c.
Answers: Most stable = tetrasubstituted, then tri, then di.
least stable = mono substituted, look out for ring strain!
No ring strain with 5-‐

a. membered rings or larger
Hello
most stable least stable intermediate stability
(tetrasubsYtuted) (disubsYtuted) (trisubsYtuted)
b.
intermediate stability most stable least stable
(disubsYtuted) (trisubsYtuted) (monosubsYtuted)
c.
most stable even though least stable even though
it is monosubsXtuted it is disubsXtuted
(no ring strain) (severe ring strain)
• In cyclic alkenes with less than 7 carbons in the ring, only cis
alkenes are stable. WHY? Too much ring strain!
Hello
• So we do not need to indicate if the alkene is cis or trans unless the
ring contains 8 carbons or more.
• When applied to bridged bicycloakenes, this rule is called

Bredt’s rule
• Apply Bredt’s rule to the compounds below
Hello
• The bridgehead carbon cannot have a trans pi bond unless one of
the rings has at least 8 carbons (otherwise the geometry of the
bridgehead prevents parallel overlap of the p-‐orbitals)
• Try building a handheld model of each compound shown above,
and see, first-‐hand, the relative geometric strain of each
• Don’t take my word for it, you have to see it!
VIII. Regiochemical and Stereochemical Outcomes for E2
Reactions
Alkenes: Thermodynamic vs the Kinetic Product
• It is common for a substrate to have more than one β-‐carbon that
can be deprotonated by a strong base, and so E2 elimination
results in more than one alkene product.
Hello
Zaitsev product Hofmann product
• When ethoxide is used as the strong base, 2-‐methyl-‐2-‐

bromobutane gives two E2 products (shown above), with the more
stable alkene (the Zaitsev product) produced as the major product,
and the less substituted alkene (the Hofmann product) is the minor
product.
Reactions
• E2 elimination is a regioselective:
Hello
Zaitsev product
• When constitutional isomers are formed as the products of a

reaction, with one of them as the major product, the reaction is
regioselective
• The regioselectivity of an E2 reaction can be controlled by carefully
choosing the strong base used.
Reactions
• Experimental data indicates that a bulky, sterically hindered base
will favor the formation of the Hofmann product, but an
unhindered base (like ethoxide) will favor the Zaitsev product:
Hello
Provide a rational for the observed results.

Reactions
• Why does a sterically hindered base favor the Hofmann product?

Since the base is so big, the other hydrogen is too sterically hindered
• Sterically hindered bases (also called non-‐nucleophilic bases) are

useful in many reactions
Hello
Reactions
Predict the major and minor products of the following E2
reaction.
NaOMe
Hello
Cl
Answers: First determine where the beta hydrogens are. Second,
a small base will react with the most thermodynamically stable
intermediate which will give the most thermodynamically stable
product. A bulky base will react with H H
H H
whatever hydrogen is the most accessible H H
(easiest to grab) and often gives the least H H

H
thermodynamically Hello stable product. H Cl

H
These hydrogens are idenYcal!
These are more hindered but “locked into This methyl group is freely spinning
conformaYon” due to the thermodynamic due to a low energy barrier of rotation.
Its more likely to not be in the proper
stability of the equatorial methyl group conformation for elimination, but it is
easily accessible to a large base
β
β
NaOMe
Cl
β Major product Minor product
(a small base was used) (Would be favored if a
large base was used)
Reactions
Predict the major and minor products for each of the following
E2 reactions.
Cl
a. NaOEt
Hello
Cl
b. t-BuOK
I
NaOEt
c.
Reactions
Answers: Smaller bases allow for the most thermodynamically
stable product. Larger bases grab onto the most accessible
hydrogen making the kinetic (often less stable product)
Cl
a.
NaOEt +
Hello
major minor
Cl
b. t-BuOK
+
minor major
I
NaOEt
c. +
major minor
Reactions
Predict the major and minor products for each of the following
E2 reactions.
d. I
t-BuOK
Hello
Br
NaOEt
e.
Br
t-BuOK
f.
Reactions
I
d. t-BuOK
+
Hello minor major
Br
NaOEt
e.
only product
Br
t-BuOK
f.
only product
Reactions
For each of the following reactions, identify whether you would
use ethoxide or t-‐butoxide to accomplish the desired
transformation.
Hello
a.
Cl
b.
Br
Reactions
HelloNaOEt
a.
Cl
t-‐BuOK
b.
Br
Reactions
• Consider the dehydrohalogenation(removal of XH) of 3-‐
bromopentane, where two stereoisomers are possible products:
Hello
Draw a Newman projection for each of these, rationalize

why one is preferred over the other!
Reactions
• Consider the dehydrohalogenation(removal of XH) of 3-‐
bromopentane, where two stereoisomers are possible products:
Hello
Use this energy diagram and

the Hammond postulate to
explain why the trans isomer is
formed stereoselectively
Trans is the thermodynamic & kinetic product

mple,
VIII.theRegiochemical
β position had two different protons:
and Stereochemical Outcomes for E2
Reactions Br
In such a case, both the cis and the trans isomers were produced, w
theNow
cis andlet’s
the trans isomers
consider a were
case produced,
where the with
β the trans isomer
position being only
contains favored.
one
• Consider dehydrohalogenation of the alkyl halide below:
case where the β position contains only one proton. For example, consider per-
forming an elimination reaction with the following substrate:
ion reaction with the following substrate:
There is Br
Ph only one β Ph Br
Me hydrogen
βthat can be Me α β
α
Ph = Ph =
removed
β
Hello β
H H H H
re are two β positions. One of these positions has no protons at all, and the other
• In this
You example,
m ight i there
magine t are
hat i two
t w β positions.
ould b e
e proton. In such a case, a mixture of stereoisomers is not obtained. In thisp One
ossible to f of these
orm b oth tpositions
he case,
E
and Z ahas
position
ne stereoisomeric lkene products,
only
product: one proton. but only Inthe
such E isomer
a case,is aformed
mixture of stereois
there will
Ph only
Br be one stereoisomeric
Ph H product: Ph
Me NaOEt
Ph Br Ph
H H MeMe Me
NaOEt H
this isomer is
only product Me
ssible stereoisomer not obtained? To understand H H answer to
the not formed
this question, we
gnment of Why
orbitalsis inthere only one
the transition state. product formed state,
In the transition in this
a π bondcase?is form-
bondWhyis comprised
is the other of overlapping
possiblep stereoisomer
orbitals. Therefore, notthe transition To
obtained? stateundersta
must
Reactions
• To rationalize the stereospecificity of the reaction, consider the
transition state for the reaction
• In the transition state, the C-‐H and C-‐Br bonds that are breaking
must be rotated into the same plane as the pi bond that is
forming Hello
• In other words, the β-‐hydrogen and the leaving group must be co-‐
planar.
Reactions
leophilic Substitution and
ides: Nucleophilic Elimination
Substitution and Reactions
Elimination Reactions
• There are two rotamers where the β-‐hydrogen and the leaving
atRecall that thesingle
the C−C C−C single
bond is bond
free toisrotate
free tobefore
rotate before the reaction
the reaction occurs.
occurs. If we Ifimagine
we imagin
rot
d,this
group
we bond,
see that
asee
wetherere that
care
oplanar:
there are two
two ways to ways to achieve
achieve a coplanar
a coplanar arrangement:
arrangement:
Ph Ph Br HBr Br
Br H
Me Me Rotate theRotate the C C bond
C C bond
Ph Ph
H Hello
H Me H
H H Me H
The first conformation is called anti-coplanar, while the second conformation is called syn-
conformation is called anti-coplanar, while the second conformation is called syn-copl
In this context, the terms anti and syn refer to the relative positions of the proton and th
ontext, the terms
• Since e aanti cand syn refertwo
to the relative positions ofthe
theNproton and the le
group, whichw can re seen
be omparing
more clearly with different
Newmanrotamers,
projections: ewman
hich can be seen more
projections clearly
are with
a good Newman
tool projections:
to compare them
Br H Br
Br Me Ph H Br
Me Ph t-Bu
t-Bu H Ph Me
t-Bu H
t-Bu H H Ph Me
H
H Anti-coplanar Syn-coplanar
(staggered)
Anti-coplanar (eclipsed)
Syn-coplanar
(staggered) (eclipsed)
When viewed in this way, we can see that the anti-coplanar conformation is staggered, whi
ewed in this
coplanar way, we canis see
conformation that the
eclipsed. anti-coplanar
Elimination conformation
via the syn-coplanarisconformation
staggered, while
wouldth
context, the terms antiMe
and syn refer to the relative
Rotate the positions
C C bond of the proton and the
VIII. Regiochemical and
which can be seen more clearly with
Stereochemical
Newman projections:
Outcomes
Ph for E2
H H Me H
Reactions
The first conformation is calledBranti-coplanar, whileH Br the second conformation is cal
The staggered rotamer, where the βto-‐hydrogen
In• this context, the terms anti and syn refer t-Bu
Me Ph and leaving group
the relative positions of the proto
group,are anti-‐coplanar (more
or anti-‐periplanar),
Ph is is tprojections:
he
Me only conformation
which can be seent-Bu H
clearly with Newman H
where elimination can
H occur. (electrons can properly flow into the
Anti-coplanar Syn-coplanar
anti bonding orbitals)
(staggered) Br (eclipsed) H Br
Me Ph
viewed in this way, we can Hello see that the
t-Bu
anti-coplanar
H
conformation
t-Bu isMestaggered, while
Ph
ar conformation is eclipsed. Elimination Hvia the syn-coplanar conformation H would in
on state of higher energy as a result of Anti-coplanar
the eclipsed geometry.Syn-coplanar
Therefore, elimination occu
(staggered) (eclipsed)
via the anti-coplanar conformation. In fact, in most cases, elimination is observed t
• via The
vely
When the
viewed product
in thisresulting
anti-coplanar from
conformation,
way, we can seetthat
he
which athe
nti-‐periplanar
leads rotamer
to one specific
anti-coplanar is formed
stereoisomeric
conformation prod
is stagge
coplanar conformationBr
is eclipsed. Elimination via the syn-coplanar conformation
Me Ph
transition stateMe of higher
Ph energy as
Elimination
a result Me
of the eclipsed
Ph
geometry. Therefore, elimin
rapidly viat-Bu the anti-coplanar
H
conformation.
t-Bu In fact,H in most cases, elimination is
exclusively via the H anti-coplanar conformation, which leads to one specific stereoiso
t-Bu H
Anti-coplanar
(staggered) Br Me Ph
Me Ph Me
Elimination Ph
e requirement for coplanarity is not entirely absolute.
t-Bu That is, small
H deviations from co
Reactions
• Evidence suggests that a strict 180° angle is not
necessary for E2 mechanisms.
• Similar angles (175–179°) are sufficient
• The term, anti-‐periplanar
Hello is generally used instead of
anti-‐coplanar to account for slight deviations from
coplanarity
• Although the E isomer is usually more stable because it
is less sterically hindered, the requirement for an anti-‐
periplanar transition state can often lead to the less
stable Z isomer
Reactions
Identify the major and minor products for the E2 reaction that
occurs when each of the following substrates is treated with a
strong base
Hello
a.
Cl
b.
Cl
Reactions
more stable, t-‐ less stable, t-‐butyl
Answer: In both cases, butyl and n-‐butyl and n-‐butyl groups
groups are anti
regiochemistry is irrelevant are Gauche
Cl Cl
because there is only one β H H
position that bears protons. H

H
H
H
Hello
a. +
Cl
major product minor product
Stereoselective, there are 2 protons to choose from
b. Cl
Cl
Stereospecific, there is only
one β proton available, so
Make sure you either draw your H
H only one product can form
Newman Projections or rotate the C-‐C
bonds until the Cl and the H are anti.
Reactions
Identify the major and minor products for the E2 reaction that
occurs when each of the following substrates is treated with a
strong base
Cl Cl
Br
a. d. g.
Hello
Cl Cl
b. e. h.
Br
Cl
Br
c. f.
Reactions
Answers: Draw all transition states where the H and the halogen are anti.
Determine which is most stable (less steric Gauche interactions), then
draw the product. Drawing Newman projections is very helpful here!
Br C 6H 5
H Br
Ha Hb
Hello Ha Hb
Hb
a. major product
C 6H 5
Br t-Bu
Br Ha Hb
H
Ha Hb
Ha
minor product
C 6H 5
b. Br H Br
Br
C 6H 5
t-Bu
t-Bu
rotate C-Cbond C 6H 5
H 3C H
H 3C H
H
only product
Reactions
C 6H 5
Br H Br
c. H CH3
Hello
Cl
H Cl
d. H
C 6H 5
Cl
Cl H
e. Me H
C 6H 5
Reactions
Cl CH3
f. H Cl rotate C-Cbond Cl C 6H 5 H
Hello
H C
C H
H3
6 5
H 3C
H
H
C 6H 5
Cl
H Cl
H
g. Hb Ha Ha Hb
C 6H 5
Hb
major product
rotate C-Cbond
Cl C 6H 5
Ha Hb minor product
H Ha
H
Reactions
h. Cl
Hello Cl H Ha
Ha Hb
C 6H 5
rotate C-Cbond major product

Hb
C 6H 5 Cl
Ha Hb
H
minor product
Reactions
• For the following substrate, the β-‐carbon has TWO β-‐hydrogens

• There are two different rotamers where a β-‐hydrogen is anti-‐
periplanar to the leaving group, and so two stereoisomers will be
formed.
Hello
• In this case, the reaction will be stereoselective, but not

stereospecific. (depends on the stereochemistry of the transition
state, but multiple products are possible)
• E2 elimination will be stereospecific only when both the α and β
carbons are stereocenters (only one product can be formed)
Br
e cis andReactions
the trans isomers were produced, with the trans isomer being favored.
se where the β position contains only one proton. For example, consider per-
nStereoselective: A single ssubstrate:
reaction with the following ubstrate can product two potential products.
Ph Br
Me α β Ph =
β
H H
areStereospecific:
two β positions.OOne ne sof these positions
Hello
tereoisomer can has no fprotons
only at pall,
orm one and the If other
roduct. you flip
proton. In such ya ou
the chirality, case, a mixture
will of stereoisomers
get a different is not
product. obtained. In this case,
stereoisomeric product:
Ph Br Ph H Ph
Me NaOEt
H H Me Me H
this isomer is
only product
ble stereoisomer not obtained? To understand the answer to thisnot formed we
question,
ment of orbitals inMethe transition
Br state. In the transition state,
Ph a π bond
t-Bu is form-
nd is comprisedPhof overlapping p orbitals.NaOEtTherefore, the transition state must
of p orbitals that are

H positioned
H
t-Bu such that they can overlap Me with each
H other as
rder to achieve this kind of orbital overlap, the following four atoms must all
Reactions
• It is very important to understand the difference between the

terms stereospecific and stereoselective.
Hello
• In a stereospecific reaction, the substrate is stereoisomeric and

results in one stereoisomer as the product
• In a stereoselective reaction, the substrate can produce two
stereoisomers as products, where one is the major product.
CH3 H3C H CH3 H3C CH3 H3C H CH3
VIII. Regiochemical
9 5 3 and Stereochemical Outcomes
9 5 for3 E2
6 2 6 2
Reactions
8
7
4
O
8
7
4
Br 1 Br 1
CH3 O CH3 CH3 O
• Consider the dehydrohalogenation of a cyclohexane derivative,
Base Base
where the leaving group is attached to the ring
Compound 1 Compound 2
roblems 7.61, 7.62, 7.74

Hello
specificity of E2 Reactions on Substituted Cyclohexanes
vious section, we explored the requirement that an E2 reaction proceed via an a
• Given the a nti-‐periplanar requirement, E
mation. That requirement has special significance when dealing with substitute2 elimination can o nly
ll that occur when tcyclohexane
a substituted he leaving group
ring can is in
adopt the atwo
xial different
position.chair conformati
Cl
Cl
ir conformation, the leaving group occupies an E2

E2 elimination axial position. In the other chair con
elimination
can occur in this
group occupies an equatorial position. The requirement
chair conformation cannot occurfor an anti-periplanar co
hat an E2 reaction can only occur from the chair conformation in which the leaving
Reactions
• Which of the two molecules below will NOT be able to undergo
an E2 elimination reaction? WHY?
• It might be helpful to draw their chair structures and build a
model
Hello
Reactions
Rationalize the product(s) formed in the following two reactions
Hello
One of the alkyl halides undergoes E2 elimination much faster than
it’s diastereomer. Why is there a difference in their rxn rates?
Reactions
Answers: Only one anti β hydrogen is
H available so only one product
H can form. Also the t-‐butyl
group wants to be equatorial
Cl NOT axial. But in this case
axial is required for the
Hello reaction to occur
(E2 reaction is slow)
(E2 reaction is fast)
Cl
There are two anti β hydrogen’s available so two products
can form. Also the t-‐butyl group wants to be equatorial
NOT axial. In this case an equatorial t-‐Butyl is required for
the reaction to occur, so the most stable chair
H H
configuration is required for the reaction to occur.
Reactions
Predict the major and minor products for each of the following E2
reactions:
a. d.
NaOEt I NaOEt
Cl
Hello
Br
Br
b. e.
t-BuOK
NaOEt
Br
Br
t-BuOK
c. NaOEt
f.
Reactions
Answers: There are many ways to do these problems depending on how
you want to draw the intermediates. Small base = thermodynamic
product. Large base generally leads to the kinetic product
H Cl
NaOEt
a. rotate C-C bond

Hello
(Beta H and Cl anti)
H
two different
beta hydrogens
Cl to choose from
I gave two examples for H
how you can do this.
major minor
H
H Some people like this drawing better
you can clearly see that the H and Cl
are anti and the wedges are on one
C 6H 5 side of the double bond and the
Cl dashes aer on the other side.
Small base, can grab the hard to get hydrogen which will form the thermodynamic product.
Br Br
NaOEt
b. H
H
two different
beta hydrogens
to choose from
minor major
Reactions
Br
c.
Br
NaOEt
Hello there are multiple beta

H hydrogens, but only
one of them is anti
only
product
I NaOEt + =
d.
minor major product 
(both are the same compound)
Reactions
e. Br Br
t-BuOK
Hello Me
two different anti
H beta hydrogens
H to choose from
minor major
Br Br
t-BuOK
f. H
there are multiple beta
hydrogens, but only
Me one of them is anti
only
product
Reactions
• There are many factors to consider in order to correctly predict
the product(s) of an E2 reaction and decide what the major
product will be.
Hello
– Will the substrate react stereospecifically? or will it be a
stereoselective E2 reaction?
– Will the substrate produce several regioisomeric alkenes? If
so, what will be the major product, given the steric hindrance
of the base that is used?
• The only way to master this material is to do lots of practice
problems.
End Quiz 7a

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Chapter 7 Alkyl Halides: Nucleophilic Substitution and

Elimination Reactions 1˚ halide

• Substitution and Elimination reaction are two of the

Alkyl halide Aryl halide Vinyl halide

– Which structure represents an alkyl halide?

• Alkyl Halides can undergo a substitution reaction when reacted

• Alkyl Halides can undergo an elimination reaction when reacted

• When the reagent can act as a nucleophile or a base:

• A substrate is a chemical species of particular interest

Cl Cl PCB (polychlorinated biphenyls) Cl Cl

DDT (pesXcide) -­‐ coolants, insulaXng ﬂuids,

in baby-­‐wipes Chlorpheniramine (R)-­‐FluoxeXne

Sucralose or Splenda (hundreds of Xmes sweeter than sugar)

• Recall the steps we use to name a molecule

• Give reasonable names for the following molecules

• Some simple molecules are also recognized by their

– The alpha carbon is connected to

– We then count away, in all directions using beta and

– There can be as many as three beta positions

– Primary alkyl halides only have 1 β position.

• Some alkyl halides are used as insecticides. For the

• Organic halides are also useful to organic chemists as

• A substitution reaction requires the loss of a leaving

1. The concerted mHello

• How might you write a rate law for this reaction?

• How would you design a laboratory experiment to confirm this

S = subsXtuXon, N = nucleophilic, 2 = bimolecular (second order reacXon)

a. What happens to Hello

Make it easy for yourself and

a. (S)-­‐2-­‐Chloropentane and NaSH

• 3° substrates react too slowly to measure. Other reactions

• We need to be able to recognize a given nucleophile as

• Need a polar aprotic solvent for SN2 rxns

• Protic solvents engage in H-­‐bonding, and stabilize anionic species

• Hydrogen bonds are very very good at this!

• Nucleophiles are less stable,

• The activation energy will be

Aprotic solvents are

Nucleophiles are more reactive in aprotic solvents

ii. Br NaCl / EtOH Cl +

ii. Br NaCl / EtOH Cl +

Alkylation: The transfer of an alkyl group to a nucleophile

Sulfur is a great -H+

• E2 elimination is concerted. The base removes a β-­‐proton, causing

Similar: SXll second order

• E2 elimination is concerted. The base removes a β-­‐proton, causing

Diﬀerent: An alkene is formed

• Consider a reagent such as NaOH, which is a strong nucleophile

a. What happens to the rate if the concentration of

b. What happens to the rate if the concentration of

c. What happens to the rate if the concentration of

a. What happens to the rate if the concentration of

b. What happens to the rate if the concentration of

• Alkenes are given IUPAC names using the same

• The parent chain should include the C=C double bond

2. Identify and Name the substituents

4. List the numbered substituents before the parent name in

Recall how to assign E or Z to alkene stereoisomers…

• If the top priority

IUPAC Recognized substituents (like we did with isopropyl)

Methylene Vinyl Allyl

• The difference in stability can be quantified by

DDT (pesXcide) -‐ coolants, insulaXng ﬂuids,

in baby-‐wipes Chlorpheniramine (R)-‐FluoxeXne

a. (S)-‐2-‐Chloropentane and NaSH

• Protic solvents engage in H-‐bonding, and stabilize anionic species

• E2 elimination is concerted. The base removes a β-‐proton, causing

• E2 elimination is concerted. The base removes a β-‐proton, causing

No ring strain with 5-‐

• When ethoxide is used as the strong base, 2-‐methyl-‐2-‐

• Sterically hindered bases (also called non-‐nucleophilic bases) are

• For the following substrate, the β-‐carbon has TWO β-‐hydrogens