Citation

1
Citation

• M. Jones, Jr. Organic chemistry must be read
  with a pencil in your hand

2
Question

• Draw all structural isomers of cis- and
  trans-1-isopropyl-2-methylcyclohexane assign R-
  and S-configurations. Which are enantiomers and
  which are diastereomers?

3
The solution
4
Which conformations predominate?
5
Substitution reactions
6
The arrow formalism
This is what you have always learned.
This is how you must write it from now on !

• Extremely important
• the arrows represent the flow of electrons !

7
Lewis acids and bases

• We have seen this before
• A compound with a lack of electrons is a Lewis
  acid
• A compound with an excess of electrons is a Lewis
  base
• The Lewis base reacts with the Lewis acid by
  donation of electrons into an empty orbital

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HOMO-LUMO

• The process involves reaction of the Highest
  Occupied Molecular Orbital (HOMO) of the Lewis
  base with the Lowest Unoccupied Molecular Orbital
  (LUMO) of the Lewis acid. This leads to an
  energetically favored situation.

9
New definition

• A species with an excess of electrons is also
  called a nucleophile
• A species with an electron deficiency is also
  called an electrophile

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Examples of substitution rxns
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The SN2 reaction

• The rate of this substitution reaction is
  proportional to the concentration of both the
  nucleophile (Nu) and the reactant (R-L).
  Therefore, it is called a nucleophilic
  bimolecular substitution SN2

12
Retention vs inversion

• Retention of configuration (or retention of
  stereochemistry) the configuration of the
  stereocenter does not change
• Inversion of configuration the stereochemistry
  of the stereocenter is inverted

13
Racemization

• In case the stereochemistry is lost, i.e. a
  mixture of both isomers is formed, we call this
  racemization

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SN2 inversion of configuration
leaving group
nucleophile

• One of the most important characteristics of the
  SN2 reaction is that it proceeds with inversion
  of the configuration at the stereocenter

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Inversion or not ?

• Have a close look at this SN2 reaction. Determine
  the configuration (R/S) of both stereocenters.
  What do you think? Did the reaction indeed
  proceed with inversion of configuration?

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Rationale for inversion

• The HOMO of the nucleophile overlaps with the
  LUMO of the electrophile this is the
  anti-bonding s-orbital of RL

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The retention mechanism

• In a potential retention mechanism, there would
  be poor overlap between the HOMO of the
  nucleophile and the LUMO of RL

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The next stage.

• The initial HOMO-LUMO overlap becomes bonding,
  while the bonding CI orbital becomes
  antibonding. In between, there is the transition
  state, which is symmetrical

19
Energy curve of the reaction

• The transition state has the highest energy the
  energy that is needed to pass this maximum is
  called the activation energy

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Influence of steric hindrance
R group CH2CHCH2 CH3 CH3CH2 CH3CH2CH2 (CH3)2CH (
CH3)3CCH2 (CH3)3C
Rxn rate 1.3 1 3.3 x 102 1.3 x 102 8.3 x
104 2.0 x 107 0

• The larger the R-groups, the lower the rate of
  the SN2 substitution

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SN2 rxns in cyclic compounds
Compound Cyclopropyl bromide Cyclobutyl
bromide Cyclopentyl bromide Cyclohexyl
bromide Isopropyl bromide
Rel rate lt 104 8 x 103 1.6 1 x 102 1.0
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SN2 in cyclohexanes is slow

• The SN2 reaction in cyclohexanes is relatively
  slow as a result of steric interactions between
  the axial hydrogens and the incoming nucleophile

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The nature of the nucleophile

• A base is similar to a nucleophile both possess
  an excess of electrons. However, a base needs to
  overlap with an 1s orbital (of H), whereas a
  nucleophile has to overlap with a 2p orbital

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In terms of energy

• The closer the HOMO and the LUMO are in energy,
  the larger the stabilization that results from
  overlap

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Nucleophiles
Species N?C HS I HO Br N3 NH3 NO2 Cl CH
3CO2 F CH3OH H2O
Species cyanide thiolate iodide hydroxide bromid
e azide ammonia nitrite chloride acetate fluoride
methanol water
Relative nucleophilicity 126,000 126,000 80,000
16,000 10,000 8,000 8,000 5,000 1,000 630 80 1 1
Excellent nucleophiles
Good nucleophiles
Fair nucleophiles
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Trends in nucleophilicity

• Nucleophilicity can be correlated to the presence
  of a negative charge, electronegativity of an
  atom, the basicity of an ion
• These are not rules, but trends

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Effect of the leaving group

• Rule of thumb the better the negative charge is
  stabilized, the better the leaving group

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HO vs H2O

• The hydroxide anion is a relatively poor leaving
  group. Protonation of the oxygen atom, however,
  will result in a much better leaving group, water.

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The result of protonation

• Reaction of a primary alcohol with a strong acid
  (HBr) that contains a good nucleophile (Br)
  leads to overall substitution via an SN2 mechanism

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Other excellent leaving groups

• A general method to convert alcohols into a good
  leaving group is conversion into a sulfonate
  group
• Why is the sulfonate such an excellent leaving
  group?

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Other examples

• Substitution can result in a charged product, or
  in the conversion of a charged starting material
  into a neutral product.

32
Influence of the solvent

• The transition state is a highly charged
  intermediate, which is more stabilized in a polar
  environment

33
The influence of the solvent

• This a general phenomenon for SN2 reactions

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Problems

• Make problems 6.36, 6.37, 6.39, 6.40 and 6.47

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Another type of substitution rxn

• We have already seen that SN2 substitution at the
  tert-butyl group does not take place
• But substitution is possible !

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The SN1 reaction
Rate k tert-butyl bromide

• The rate of this substitution reaction is only
  proportional to the concentration of the
  reactant. In other words, it is a nucleophilic,
  unimolecular, substitution SN1

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Energy diagram of the SN1 rxn

• The transition state for ionization (heterolytic
  cleavage) is the highest barrier (the slowest
  step) in this process.

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The first step is important

• Again, the rate of the reaction is independent of
  the concentration or quality of the nucleophile

39
Stereochemistry of the SN1 rxn

• The carbocation is planar therefore, SN1
  substitution will lead to complete loss of
  stereochemistry racemization

40
Examples

• In reality, there is usually no complete
  racemization as a result of ion pair formation

41
Ion pair formation

• The leaving group does not completely dissociate
  from the cation, but forms an ion pair so that
  the chirality is partially retained

42
Question

• Explain why the previous reaction proceeds via an
  SN1 type substitution

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Stability of carbocations
DHf (kcal/mol) 261.3 215.6 211 203 191 166
Cation CH3 CH3CH2 CH3CH2CH2 CH3CH2CH2CH2 (CH3
)2CH (CH3)3C
Type Primary Primary Primary Primary Secondary Te
rtiary

• The more substituted, the more stable the
  carbocation
• In other words tertiary carbocations are more
  stable than secondary carbocations, which are
  more stable than primary carbocations

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Influence on the rate

• The reaction rate is proportional to the
  stability of the cation tertiary substrates
  react faster than secondary and primary
  substrates in an SN1 substitution

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Effect of the nucleophile

• In the product-determining step, the best
  nucleophile will win

46
Influence of the leaving group

• Obviously, heterolytic cleavage and therefore
  the rate of the reaction is favored in the case
  of good leaving groups

47
Influence of the solvent

• Heterolytic cleavage is favored in a polar
  environment, where the charged intermediates can
  be stabilized.

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SN1 vs SN2 substitution

• Often, there is no clear border as to where the
  SN1 reaction ends and the SN2 process starts

49
SN1 vs SN2 substitution (II)
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Again, there is no clear border

• Note that in many cases, the mechanism is
  something in between the SN1 and SN2 reaction

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Problems

• Make problems 6.41, 6.48, 6.49, 6.50, 6.60