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3 Determination of MechanismPhilosophy 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.• Occam’s razor: In the event that several hypotheses are found to fit the facts, the simplest one is given preference.
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3. Determination of Mechanism3.1 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 study3.4.1 Group labeling
3.4.2 Isotope labeling
3.4.3 Crossover experiments
3.5 Isomeric selectivity study3.5.1 Regiochemical evidences3.5.2 Stereochemical evidences
3.6 Kinetic studies3.6.1 Measurement of rate3.6.2 Mechanistic information
obtained from kinetic studies
3.6.3 Rate law
3.7 Kinetic isotope effects3.7.1 Deuterium isotope effects
3.7.2 Primary isotope effects3.7.3 Secondary isotope effects3.7.4 Solvent isotope effects
3. Determination of Mechanism3.1 Identification of products
Mechanism must be compatible with its products including the by-product.
e.g. von Richter Rearrangement
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NO2
Br Br
COO-
CN-
NO2
CN-
COO- 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,
Early proposed mechanism
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But, from its product study, none of the NO2 or NH3 gas
was found, instead, the N2 gas was detected.
Br
NOO
CN-
Br
NO O
CN
Br
N O
NHH
O
Br
N O
NH
O
Br
NH
ON
O
Br
COOH
H2O
-H+
H2O
-NO2, -NH3
The mechanism was then fixed as follow:
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Br
O
NH2NO
Br
N N
O
Br
COOH
H2O
-N2
Br
NOO
CN-
Br
NO O
CN
Br
N O
NHH
O
Br
N O
NH
O
Br
NH
ON
O
Br
COOH
H2O
-H+
H2O
-NO2, -NH3
-H2O
3.2 Determination of the presence of
intermediates3.2.1 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
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CH3CH2 C NH2
O
CH3CH2 N C ONaOH, Br2
H2OCH3CH2NH2
RH2C C R'
N OTs
RHC C R'
O
EtO- RHC C R'
NNH2
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.
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Caution: Beware of non-intermediate species and impurities which may give interference signals.
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
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Br
F
O
OLi
(trap)
benzyne
•Trapping an anion to determine if the elimination of alkenes is E2 or E1cb.
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3.2 Determination of the presence of intermediates
ClHC CCl2 ClC CCl
ClC CCl2
OH-
E1cbE2
D2O
(trap)ClC CCl2
D
• 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.
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3.2 Determination of the presence of intermediates
O2N
NO2
O2N
Ph2NN PhHC NO
DPPH Imine Oxide
•Kinetic requirement of intermediate trapping
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k2[x]k1 BA C
k2'[x']
D
k'[x']?
3.2 Determination of the presence of intermediates
- The intermediate B can be efficiently trapped by Xwhen 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.
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:
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CO2H
CO2H
von Ritchercondition
von Ritchercondition
NO2
CN
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.
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3.3.1 General acid (or base) catalysis
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• 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.)
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.
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• Diazonium coupling shows general base catalysis. Which step is the rds.?
• Aldol reaction shows specific acid catalysis. Which step is the rds.?
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3.3 Study of catalysis
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.
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3. Determination of Mechanism
3.4.1 Group labeling
•Is Claisen rearrangement a [1,3] or [3,3] sigmatropic process?
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O OH
O OHPh
Ph
O OH
Ph Ph
• 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.
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RCOO- + BrCN RCN* *
3.4.2 Isotope labeling
N C Br
R C O-
O
N
C O
C Br
O-
R C
N C O
R R C
N C
OO
Oisolatedintermediate
R
C
N
O
C
O
+
•Does the hydrolysis of ester proceed through “alkyl” or “acyl” cleavage?
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3.4.2 Isotope labeling
R O
O
R' H218O R 18OH
O+ R'OH
R 18O
O
R' H2O R OH
O+ R'18OH
Labeled water is easier to find than the labeled ester.
In these cases, the products can be easily identified by MS.
Exercises• Do the following ethanolyses of -lactone involve “alkyl” or
“acyl” cleavage?
• Do the following hydrolyses of -lactone involve “alkyl” or “acyl” cleavage?
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OO
EtOH
H+ or OH- HO OEtO
OO
EtOH
neutralEtO OH
O
OO
H218O
H+ or OH- HO OH18O
OO
H218O
neutralH18O OH
O
3.4.3 Crossover Experiments• Use for distinguishing between intra- and intermolecular reaction
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A B AB
A' B' A'B'
+ +
A B AB
A' B' A'B'
+ +
+
+
A'B
AB'
+
crossoverproducts
• 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
• Is benzidine rearrangement an inter- or intramolecular process?
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3.4.3 Crossover Experiments
HN
HN
H2N NH2
HN
HN
H2N NH2
OR ORRO OR
HN
HN
OR' OR'
H2N NH2
R'O OR'
No crossover product indicates an intramolecular rearrangement
• Is 1,2 rearrangement of alkyl lithium an inter- or intramolecular process?
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3.4.3 Crossover Experiments
PhH2CCH2Li
PhPh
LiCH2
PhPh
CH2Ph
Upon an addition of14C-labeled benzyl lithium (Ph*CH2
-Li+), the 14C-labeled product was detected, indicating an intermolecular process.
This is called labeled fragment addition technique
PhCH2Li
PhPh
LiCH2
PhPh
Ph
Upon an addition of14C-labeled phenyl lithium (Ph*-
Li+), no 14C-labeled product was detected, indicating no intermolecular process involved.
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 study25
3. Determination of Mechanism
3.5.1 Regiochemical evidences
•HX addition on alkenes
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+ HBrBr
+ HBrBrH2O2
• Regioselectivity suggests cationic mechanism.
• Polar solvents increase the reaction rate supporting the polar mechanism.
• Regioselectivity suggests radical mechanism.
• Solvent polarity has no effect on the reaction rate supporting the radical mechanism.
• Aromatic substitution by strong basic nucleophiles
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3.5.1 Regiochemical evidences
Cl NH2
NaNH2
Possible mechanisms: SNAr or benzyne
Cl NH2NH2
-
Cl NH2
(NH2-)
NH2--HCl
-Cl-
1:1 ratio
• The benzyne mechanism was supported by regiochemical evidences obtained from group and isotope lebeling
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3.5.1 Regiochemical evidences
Cl NH2 NH214C label
+NH2
-
OMe
Cl
+ NH2-
SNAr
benzyne
OMe
NH2
OMe
NH2
•SN2 reaction
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3.5.1 Stereochemical evidences
OTs OAc
KOAc
OTs OAc
KOAc
and
• 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.
Ph
H CH3
OTsAcO
The stereochemistry is controlled by the intermediate not by the starting material.
•Neighboring group participation (NGP)
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3.5.1 Stereochemical evidences
HO Cl Cl
+HCl
Ph
The reaction is not stereospecific but diastereoselective. Both diastereomers give the same major product. The results suggest a common intermediate for all diastereomers.
Which one is the major product?
•Neighboring group participation (NGP)
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Ph
OTs
Ph
OAc
KOAconly product
Ph
OTs
Ph
OAc
KOAc+ enantiomer
3.5.1 Stereochemical evidences
enantiotopic
homotopic
C2
Each reaction involves NGP in which an intermediate with 2 reactive sites is formed.
•Addition
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Br2
BrBr
3.5.1 Stereochemical evidences
Anti addition in which a bromonium ion was proposed as an intermediate.
Br
•Photorearrangement of spirofuran
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3.5.1 Stereochemical evidences
OCOOMe
COOMe
OH
h
Possible mechanisms: pericyclic or biradical
OCOOMe
COOMe
OH
COOMe
O H
[1,3]sigmatropic
homo [1,5]
sigmatropic
COOMe
OH
COOMe
O
biradical
recombination
radical
Stereospecific product
Racemic product
3.6 Kinetic studies
3.6.1 Measurements of rate
3.6.2 Mechanistic information obtained from kinetic studies
3.6.3Rate law
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3. Determination of Mechanism
3.6.2 Measurement of rate• Real Time Analysis by Periodic or Continuous Spectral
Readings• Quenching and Analyzing• Removal of Aliquots at Intervals
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A + B P
dt
Pd
NRate
p
][1
dt
Ad
N A
][1
dt
Bd
N B
][1
BA nn BAkRate ][][
N = stoichiometric numbernA = order of reaction for reactant
Ani = order of overall reaction
k = rate constantkobs = rate constant directly obtained
experimentallymolecularity = number of molecules come together in a single step
(Rate Expression)
36t
slope = -k0
A0
[A]
[B]
3.6.2 Measurement of rate
Zeroth order
BAk0
0
][k
dt
Ad tkAA 00
First orderBA
k1
][][
1 Akdt
Ad
tkeAA 10
tkAA 10lnln
t
ln A
ln A0
slope = -k1
•Second order
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3.6.2 Measurement of rate
P2Ak2
22 ][2
][Ak
dt
Ad
tkAA 2
0
2][
1
][
1
A + B Pk2
]][[][
2 BAkdt
Ad
Use pseudo first order: B0>>A0
[B] constant = B0
Treat like first order
])[(][
02 ABkdt
Ad
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.
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kr = A e-Ea/RT ; A = kT eS /R ; Ea = H + RT h
3.6.3 Rate law • First order: Rate = k[A] (rds. is unimolecular process)• Second order: Rate = k[A]2 or Rate = k[A][B]• 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 = k[A][B]39
A + B Islow
I + Bfast
C
3.6.1 Rate Law– The first step is a rapid equilibrium:
Rate = -d[A]/dt = k1[A][B] - k-1[I]
d[I]/dt = k1[A][B] - k-1[I] - k2[I][B] = k1[A][B] - (k-1 + k2[B])[I]
Steady state assumption: d[I]/dt = 0
[I] = k1[A][B]/(k-1 + k2[B])
Therefore
Rate = k1[A][B] - k1k-1[A][B]/(k-1 + k2[B])
Rate = k1k2[A][B]2/(k-1 + k2[B])
For rapid equilibrium in the first step k-1[I] » k2[I][B] or k-1 » k2[B]
Thus Rate = K1k2[A][B]240
A + B Ik1
I + B C
k-1
k2
• 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.
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BAk1
k-1
Ck2
Exercise
Rate = -d[A]/dt = k1[A] - k-1[B]d[B]/dt = k1[A] - k-1[B] - k2[B]
Steady state assumption d[B]/dt = 0[B] = k1[A]/(k-1 + k2)
Rate = k1[A] - k-1k1[A]/(k-1 + k2)Rate = k1k2[A ]/(k-1 + k2)a)k-1 << k2: Rate ~ k1[A] b)k2 << k-1: Rate ~ Kk2[A]
•Condensations
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Exercise
OH-
CH2(COOEt)2 + CH2O HOCH2CH(COOEt)2
Rate = k[CH2(COOEt)2] [CH2O] [OH-]
Write a reasonable mechanism and specify the rds. of each reaction.
OH-
2CH3CHO CH3CH(OH)CH2CHO
a)
b)
Rate = k[CH3CHO] [OH-]
The reaction between the enolate and formaldehyde is the rds.
The formation of the enolate is the rds.
3.7 Kinetic Isotope effects3.7.1 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 > 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 < 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. 43
3.7.2 Primary isotope effects
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•Origin of the primary isotope effects
k
E4
10
ABA
BAAB m
mm
mm
HD EE 00
kH/kD < 7 (early T.S)
kH/kD < 7 (late T.S)
maximum kH/kD ~ 7
R H X
R H X
R H X
R DR H
•Alcohol oxidation
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3.7.2 Primary isotope effects
R
R
OH
H (D)+ H2CrO4
R
RO
Gives kH/kD = 6.9
The transition state proposed for the rds. is as follow
R
R
O
H
CrO3H
base
Exercise• Write a reasonable mechanism and specify the rate
determining step for the following reaction which shows kH/kD 7
46
CH3CCH3 + Br2
OH+
CH3CCH2Br
O
3.7 Kinetic Isotope effects3.7.3 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 > 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 < 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 > 1. It is mainly
attributed to hyperconjugation.47
3.7.3 Secondary isotope effect
•Solvolysis of cyclopentyl tosylate
normal•Addition on aldehyde
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OTs
H (D)H (D)
sp3C-H sp2C-H (kH/kD = 1.17)
Ph H (D)
O CN-
Ph H (D)
O
CN
sp2C-H sp3C-H (kH/kD = 0.833)
inverse
Summary of primary and secondary kinetic isotope effects
49
(CH3)3CD + X (CH3)3C. + DBr primary
(CH3)2CDX (CH3)2CD+ + X- -secondary (normal)
(CD3)2CH+ + X- -secondary(CD3)2CHX
(CH3)2C=CD2 + H+ (CH3)2CCD2H -secondary (inverse)+
3.7 Kinetic Isotope effects3.7.4Solvent isotope effects
Generally observed when a protic solvent e.g. D2O or ROD is used.
• kH/kD < 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 > 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.
50
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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