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3 Determination of Mechanism

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Title: 3 Determination of Mechanism


1
3 Determination of Mechanism
  • Philosophy of mechanistic studies
  • No reaction could be determined with 100
    certainty.
  • One can only disproof a hypothetical mechanism,
    not proof.
  • As the result, an approved, last mechanism is
    said to be reasonable, not correct.
  • More than one method would be needed to confirm,
    and their results must all be consistent.
  • Gather information from many experiments until
    enough to induce or extrapolate to a general
    conclusion.
  • Occams razor In the event that several
    hypotheses are found to fit the facts, the
    simplest one is given preference.

2
3. Determination of Mechanism
  • 3.1 Identification of products
  • 3.2 Determination of the presence of
    intermediates
  • 3.2.1 Isolation of intermediates
  • 3.2.2 Detection of intermediates
  • 3.2.3 Trapping of intermediates
  • 3.2.4 Addition of a suspected intermediate
  • 3.3 Study of catalysis
  • 3.3.1 General acid catalysis
  • 3.3.2 Specific acid catalysis
  • 3.4 Labeling study
  • 3.4.1 Group labeling
  • 3.4.2 Isotope labeling
  • 3.4.3 Crossover experiments

3.5 Isomeric selectivity study 3.5.1
Regiochemical evidences 3.5.2 Stereochemical
evidences 3.6 Kinetic studies 3.6.1 Measurement
of rate 3.6.2 Mechanistic information obtained
from kinetic studies 3.6.3 Rate law 3.7 Kinetic
isotope effects 3.7.1 Deuterium isotope
effects 3.7.2 Primary isotope effects 3.7.3
Secondary isotope effects 3.7.4 Solvent isotope
effects
3
3. Determination of Mechanism
  • 3.1 Identification of products
  • Mechanism must be compatible with its products
    including the by-product.
  • e.g. von Richter Rearrangement

At the first glance, the mechanism was though as
a simple nucleophilic substitution of NO2 by CN-
followed by the hydrolysis of CN- to CO2H
However,
4
Early proposed mechanism
But, from its product study, none of the NO2 or
NH3 gas was found, instead, the N2 gas was
detected.
5
The mechanism was then fixed as follow
6
3.2 Determination of the presence of intermediates
  • 3.2.1 Isolation of intermediates
  • Isolate the intermediate which can give the same
    products when subjected to the same reaction
    conditions at a rate no slower than the starting
    compound
  • e.g. Hofmann rearrangement
  • Neber rearrangement

7
3.2 Determination of the presence of intermediates
  • 3.2.2 Detection of an intermediate
  • In many cases, intermediate cannot be isolated
    but can be detected by IR, NMR, UV-Vis or other
    spectra.
  • Radical and triplet species can be detected by
    ESR and by Chemically Induced Dynamic Nuclear
    Polarization (CIDNP).
  • Radicals can also be detected by cis-trans
    isomerization of stilbene.

Caution Beware of non-intermediate species and
impurities which may give interference signals.
8
3.2 Determination of the presence of intermediates
  • 3.2.3 Trapping of an intermediate
  • In some cases, the suspected intermediate is
    known to be one that reacts in a given way with a
    certain compound.
  • Benzynes react with dienes in the Diels-Alder
    reaction

9
3.2 Determination of the presence of intermediates
  • Trapping an anion to determine if the elimination
    of alkenes is E2 or E1cb.

10
3.2 Determination of the presence of intermediates
  • Examples of free radical trapping agents are
    DPPH, oxygen (O2), triphenylmethylradical
    (Ph3C?), nitric oxide (NO), imine oxide, iodine,
    hydroquinone and dinitrobenzene.
  • A radical reaction may proceed slower in the
    presence of air if the free radical intermediate
    can be trapped by O2.

Imine Oxide
DPPH
11
3.2 Determination of the presence of intermediates
  • Kinetic requirement of intermediate trapping

- The intermediate B can be efficiently trapped
by X? when k2? ? k2. - The detection of D does
not always guarantee the formation of B
intermediate as A may directly react with X? to
form D.
12
3.2 Determination of the presence of intermediates
  • 3.2.4 Addition of a suspected intermediate
  • Perform a reaction by using a suspected
    intermediate obtained by other means can be used
    for a negative evidence.
  • e.g. von Ritcher reaction

13
3. Determination of Mechanism
  • 3.3 Study of catalysis
  • Mechanism must be compatible with its catalysts ,
    initiator and inhibitors.
  • Utilization of catalytic amount of peroxide, AIBN
    and iodine usually suggests a radical mechanism.
  • Kinetic study of acid-base catalyzed reaction can
    reveal the rate determination step (rds.) if it
    is involved with the proton transfer process
  • 3.3.1 General acid (or base) catalysis usually
    indicates that the proton transfer process is the
    rds.
  • 3.3.2 Specific acid (or base) catalysis usually
    indicates that the proton transfer process is not
    the rds.

14
3.3.1 General acid (or base) catalysis
  • In general acid catalysis all species capable of
    donating protons contribute to reaction rate
    acceleration.
  • The strongest acids (SH) are most effective (k1
    is the highest).
  • Reactions in which proton transfer is
    rate-determining exhibit general acid catalysis,
    for example diazonium coupling reactions.
  • When keeping the pH at a constant level but
    changing the buffer concentration a change in
    rate signals a general acid catalysis. (A
    constant rate is evidence for a specific acid
    catalyst.)

15
3.3.2 Specific acid (or base) catalysis
  • In specific acid catalysis taking place in
    solvent S , the reaction rate is proportional to
    the concentration of the protonated solvent
    molecules SH.
  • The acid catalyst itself (AH) only contributes to
    the rate acceleration by shifting the chemical
    equilibrium between solvent S and AH in favor of
    the SH species. S AH ? SH A-
  • For example, in an aqueous buffer solution the
    reaction rate for reactants R depends on the pH
    of the system but not on the concentrations of
    different acids.
  • This type of chemical kinetics is observed when
    reactant R1 in a fast equilibrium with its
    conjugate acid R1H which proceeds to react
    slowly with R2 to the reaction product for
    example in the acid catalyzed aldol reaction.

16
3.3 Study of catalysis
  • Diazonium coupling shows general base catalysis.
    Which step is the rds.?
  • Aldol reaction shows specific acid catalysis.
    Which step is the rds.?

17
3. Determination of Mechanism
  • 3.4 Labeling study
  • 3.4.1 Group labeling Easy to obtain starting
    materials but the group change may alter the
    mechanism.
  • 3.4.2 Isotope labeling Difficult to obtain the
    starting materials but no group alteration to
    affect the mechanism. (Isotopic scrambling can
    complicate the interpretation of the results.)
  • 3.4.3 Crossover experiments The experiments are
    closely related to either group or isotope
    labeling.

18
3.4.1 Group labeling
  • Is Claisen rearrangement a 1,3 or 3,3
    sigmatropic process?

19
3.4.2 Isotope labeling
  • D can be detected by NMR, IR and MS
  • 13C can be detected by 13C-NMR and MS
  • 14C can be traced by its radio activity
  • 15N can be detected by 15N-NMR
  • 18O can be detected by MS
  • e.g.

20
3.4.2 Isotope labeling
  • Does the hydrolysis of ester proceed through
    alkyl or acyl cleavage?

Labeled water is easier to find than the labeled
ester.
In these cases, the products can be easily
identified by MS.
21
Exercises
  • Do the following ethanolyses of ?-lactone involve
    alkyl or acyl cleavage?
  • Do the following hydrolyses of ?-lactone involve
    alkyl or acyl cleavage?

22
3.4.3 Crossover Experiments
  • Use for distinguishing between intra- and
    intermolecular reaction
  • Crossover products indicate intermolecular
    reaction.
  • The method requires identification of products in
    the mixture.
  • The method cannot distinguish between an
    intramolecular and solvent cage reactions.

No crossover product
23
3.4.3 Crossover Experiments
  • Is benzidine rearrangement an inter- or
    intramolecular process?

No crossover product indicates an intramolecular
rearrangement
24
3.4.3 Crossover Experiments
  • Is 1,2 rearrangement of alkyl lithium an inter-
    or intramolecular process?

Upon an addition of14C-labeled phenyl lithium
(Ph-Li), no 14C-labeled product was detected,
indicating no intermolecular process involved.
Upon an addition of14C-labeled benzyl lithium
(PhCH2-Li), the 14C-labeled product was
detected, indicating an intermolecular process.
This is called labeled fragment addition technique
25
3. Determination of Mechanism
  • 3.5 Isomeric selectivity study
  • Selectivity Non-statistical distribution of
    products
  • Specificity Correspondence between isomeric
    ratios of starting materials and products
  • Level of isomeric selectivity chemoselectivity ?
    regioselectivity ? diastereoselectivity ?
    enantioselectivity
  • 3.5.1 Regiochemical study
  • 3.5.2 Stereochemical study

26
3.5.1 Regiochemical evidences
  • HX addition on alkenes
  • Regioselectivity suggests radical mechanism.
  • Solvent polarity has no effect on the reaction
    rate supporting the radical mechanism.
  • Regioselectivity suggests cationic mechanism.
  • Polar solvents increase the reaction rate
    supporting the polar mechanism.

27
3.5.1 Regiochemical evidences
  • Aromatic substitution by strong basic nucleophiles

Possible mechanisms SNAr or benzyne
28
3.5.1 Regiochemical evidences
  • The benzyne mechanism was supported by
    regiochemical evidences obtained from group and
    isotope lebeling

11 ratio
29
3.5.1 Stereochemical evidences
  • SN2 reaction
  • The reaction is stereospecific with 100
    inversion indicating that the reaction is
    concerted and the nucleophile attacks from the
    back side of the leaving group.
  • The proposed transition state is a trigonal
    bipyramid.

and
30
3.5.1 Stereochemical evidences
  • Neighboring group participation (NGP)

The reaction is not stereospecific but
diastereoselective. Both diastereomers give the
same major product. The results suggest a common
intermediate for all diastereomers.
The stereochemistry is controlled by the
intermediate not by the starting material.
Which one is the major product?
31
3.5.1 Stereochemical evidences
  • Neighboring group participation (NGP)

Each reaction involves NGP in which an
intermediate with 2 reactive sites is formed.
32
3.5.1 Stereochemical evidences
  • Addition

Anti addition in which a bromonium ion was
proposed as an intermediate.
33
3.5.1 Stereochemical evidences
  • Photorearrangement of spirofuran

Possible mechanisms pericyclic or biradical
Stereospecific product
Racemic product
?
34
3. Determination of Mechanism
  • 3.6 Kinetic studies
  • 3.6.1 Measurements of rate
  • 3.6.2 Mechanistic information obtained from
    kinetic studies
  • 3.6.3 Rate law

35
3.6.2 Measurement of rate
  • Real Time Analysis by Periodic or Continuous
    Spectral Readings
  • Quenching and Analyzing
  • Removal of Aliquots at Intervals



(Rate Expression)
k rate constant kobs rate constant
directly obtained experimentally molecularity
number of molecules come together in a single step
N stoichiometric number nA order of
reaction for reactant A ?ni order of overall
reaction
36
3.6.2 Measurement of rate
Zeroth order
First order
37
3.6.2 Measurement of rate
  • Second order

Use pseudo first order B0gtgtA0 B constant
B0 Treat like first order
38
3.6.3 Mechanistic information obtained from
kinetic studies
  • Order of reaction can give information about
    which molecules take part in rate determining
    step and the previous steps.
  • Changes in rate constants upon structural and
    condition changes can give much information about
    mechanisms. (Linear free energy relationships)
  • From transition state theory, rate constants
    measured at various temperature can lead to
    important energetic parameters.

39
3.6.3 Rate law
  • First order Rate kA (rds. is unimolecular
    process)
  • Second order Rate kA2 or Rate kAB
  • Order is for the whole reaction while
    molecularity is the order for each step.
  • Rate law depends on the rate-determining step.
  • The first step is the rate-determining step
  • Rate kAB

40
3.6.1 Rate Law
  • The first step is a rapid equilibrium
  • Rate -dA/dt k1AB - k-1I
  • dI/dt k1AB - k-1I - k2IB
    k1AB - (k-1 k2B)I
  • Steady state assumption dI/dt 0 
  • I k1AB/(k-1 k2B)
  • Therefore
  • Rate k1AB - k1k-1AB/(k-1 k2B)
  • Rate k1k2AB2/(k-1 k2B)
  • For rapid equilibrium in the first step k-1I
    k2IB or k-1 k2B
  • Thus Rate K1k2AB2

41
Exercise
  • Using the steady state assumption, derive a rate
    expression for the following reaction if (a) the
    first step is a rate determining step, (b) the
    first step is a fast equilibrium.
  • Rate -dA/dt k1A - k-1B
  • dB/dt k1A - k-1B - k2B
  • Steady state assumption dB/dt 0
  • B k1A/(k-1 k2)
  • Rate k1A - k-1k1A/(k-1 k2)
  • Rate k1k2A /(k-1 k2)
  • k-1 ltlt k2 Rate k1A
  • k2 ltlt k-1 Rate Kk2A

42
Exercise
  • Condensations

a)
Rate kCH2(COOEt)2 CH2O OH-
The reaction between the enolate and formaldehyde
is the rds.
b)
Rate kCH3CHO OH-
The formation of the enolate is the rds.
Write a reasonable mechanism and specify the rds.
of each reaction.
43
3.7 Kinetic Isotope effects
  • 3.7.1 Deuterium isotope effects (kH/kD) is the
    ratio between the rate of reaction of the
    protonic substrate and that of the corresponding
    deutero substrate.
  • A normal isotope effect has kH/kD gt 1 indicating
    that the reaction of the protonic substrate is
    faster than the reaction of the corresponding
    deutero substrate.
  • An inverse isotope effect has kH/kD lt 1
    indicating that the reaction of the protonic
    substrate is slower than the reaction of the
    corresponding deutero substrate.
  • 3.7.2 Primary isotope effect is observed in the
    reaction that its rate determining step involves
    the breaking of the bond connecting to the
    isotopic H.
  • The primary isotope effects usually have 2
    kH/kD 7.

44
3.7.2 Primary isotope effects
  • Origin of the primary isotope effects

45
3.7.2 Primary isotope effects
  • Alcohol oxidation

Gives kH/kD 6.9 The transition state proposed
for the rds. is as follow
46
Exercise
  • Write a reasonable mechanism and specify the rate
    determining step for the following reaction which
    shows kH/kD ? 7

47
3.7 Kinetic Isotope effects
  • 3.7.3 Secondary isotope effect is observed in
    the reaction that its rate determining step does
    not involve the breaking of any bond connecting
    to the isotopic H.
  • ?-secondary isotope effect usually has kH/kD in
    the range 0.7-1.5. It is the result of the
    greater vibration amplitude of C-H bond comparing
    to C-D bond.
  • A normal ?-secondary isotope effect (kH/kD gt 1)
    generally suggests a rehybridization of the
    carbon connecting to the isotopic H from sp3 to
    sp2 in the rate determining step.
  • An inverse ?-secondary isotope effect (kH/kD lt 1)
    generally suggests a rehybridization of the
    carbon connecting to the isotopic H from sp2 to
    sp3 in the rate determining step.
  • ?-secondary isotope effect has kH/kD gt 1. It is
    mainly attributed to hyperconjugation.

48
3.7.3 Secondary isotope effect
  • Solvolysis of cyclopentyl tosylate
  • normal
  • Addition on aldehyde

sp3C-H sp2C-H (kH/kD 1.17)
sp2C-H sp3C-H (kH/kD 0.833)
inverse
49
Summary of primary and secondary kinetic isotope
effects
50
3.7 Kinetic Isotope effects
  • 3.7.4 Solvent isotope effects
  • Generally observed when a protic solvent e.g. D2O
    or ROD is used.
  • kH/kD lt 1 when the reaction involves a rapid
    equilibrium protonation because the acidity of
    D3O is greater than H3O (specific acid
    catalysis can be used for confirmation)
  • kH/kD gt 1 when proton transfer is the rate
    determining step (general acid catalysis can be
    used for confirmation)
  • Secondary solvent isotope effect can interfere
    the interpretation. Solvent isotope effect is
    thus used only as a supporting evidence.

51
Exercise
  • Write a reasonable mechanism for hydration of
    styrene and predict which step is the rate
    determining step. Suggest 3 experiments and the
    expected results that can support the proposed
    mechanism and rate determining step.
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