Chapter 2: Key Concepts in Catalysis Reaction Coordinate

OC VI (HS 2015) Bode Research Group http://www.bode.ethz.
ch/
Chapter 2: Key concepts in catalysis
1 Reaction coordinate
- Free energy, enthalpy and entropy are thermodynamic phenomena.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Boger’s Modern Organic Synthesis C.2
2 Transition state theory

2.1 Energy of activation
- Energy, enthalpy and entropy of activation are kinetic phenomena.

- 20 kcal/mol energy available at 25°C for free energy of activation (∆G‡).
- Increasing reaction temperature increases the rate of reaction but may decrease selectivity.
- R = the universal gas constant; kB = Boltzmann constant; and h = Planck's constant.
Boger’s Modern Organic Synthesis C.2
2.2 Rate determining step (rds)
- In a reaction involving more than one elementary step – that is where one or more intermediates are
formed – there is more than one energy barrier (more than one TS).
- The elementary step involving the highest energy barrier going to the TS is the rate-determining step (a).
- Note that the pathway involving the highest energy TS is not necessarily the rate-determining step (b & c).
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7
Page 1
OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/
2.3 Kinetic and thermodynamic control
- In a reversible reaction, the majority of the product will be the thermodynamic product.
- In an irreversible reaction, the majority of the product may be the kinetic product.
Trost JOC 1965, 30, 1341
3 Catalysis
3.1 Catalyst definition and energy diagram
Boger’s Modern Organic Synthesis C. 2
4 Enantioselective catalysis
- Enantiomeric ratio is directly proportional to the relative rates of formation of the enantiomeric products.
- Enantiomeric ratio is governed by differential activation parameters (∆∆G ‡, ∆∆H‡ and ∆∆S‡).
- R and S are chosen below arbitrarily.
Walsh and Kozlowski, Fundamentals of Asymmetric Catalysis, C.1

Some useful number to think about in enantioselective catalysis:
- ∆∆G‡ of 1.38 kcal/mol is needed to achieve 80% ee at room temp
- ∆∆G‡ of ~2.0 kcal/mol is needed to achieve 90% ee at room temp
- ∆∆G‡ of 1.80 kcal/mol is needed to achieve 98% ee at -78oC
Hartwig (Walsh) Organotransition Metal Chemistry, C.14
Page 2
4.1 Diastereomeric transition states
- Case 1: simple complex with a diastereomeric transition state
Shibasaki Adv. Synth. Catal 2004, 346, 1533
- Case 2: a more complicated TS involving a complex with multiple catalysts
Blackmond and Jacobsen JACS 2004, 126, 1360
4.2 Transition state stabilization
Hiersemann & Strassner JOC 2007, 72, 4001
4.3 Microscopic reversibility

- The conversion of the product back to the reactant has to proceed through the same pathway with the
forward reaction, encountering exactly the same intermediate(s) and transition state(s).
Blackmond ACIE 2009, 48, 2648
4.4 The Hammond postulate
- Activated complex (TS) most resembles the structure of adjacent reactant, intermediate, or product that is
closest in energy (thermodynamic factor).
- For example, in a highly exothermic reaction, the TS is closer in energy and in structure to the reactant than
the product (early transition state e.g. Grignard reagent addition to carbonyl compounds).
Page 3
H+ R R Nu-
R3COH C R3CNu
R E
E TS1
TS2 CH2R
The trans ition s tate s The ralative s tability of
re s e m ble the ge om e try carbocation:
R R of the carbocation CHR2 the TS be com e s m ore
C
inte rm e date , not the s table as the re action
R re actant nor the product. be com e s le s s e ndothe rm ic.
R3COH CR3
R3CNu
reaction coordinate reaction coordinate
Hammond JACS 1955, 77, 334
4.5 The CurtinHammett Principle
- In multistep reactions, there may exist an equilibrium between two diastereomeric intermediates.
- The overall enantioselectivity is determined by the difference in the relative heights of the turnover-limiting
barrier (∆∆G‡).
- From the graph below, I1 is more stable than I2 (from ∆∆G). But formation of I2 is more favorable because of
the lower relative activation energy (∆∆G ‡).
I1 gradually reverses back to the starting material (SM) then to I2 (SM, I1 and I2 are in equilibrium).
Halpern Science 1982, 217, 401
4.6 Catalyst turnover
- Catalyst productivity: Turn Over Number (TON) = mol product/mol catalyst

- Catalyst reactivity: Turn Over Frequency (TOF) = (mol product/mol catalyst)/hour = TON/hour (unit of h -1)
- For example, hydrogenation should have TON > 1000 for high value product and >50,000 for large-scale.
- For hydrogenation, TOF > 500 h-1 for small scale and TOF>10,000 h-1 for large scale
Blaser Appl. Catal. A 2001, 221, 119
Page 4
4.7 Catalyst resting state
Stoltz ACIE 2009, 48, 6840
4.8 Product inhibition

- Product inhibition occurs when the product binds better to the catalyst than the starting material. This is a
common problem in the catalysis of the Claisen reaction.
Yamamoto JACS 1990, 112, 316
4.9 Background rate

- The starting materials may react to form the product without the aid of the catalyst. If the background rate of
reaction is comparable to or faster than the catalyzed reaction, lower selectivity is obtained. (The background
reaction is normally unfavorable and has to be avoided).
Evans JACS 1999, 121, 7582
5 Modes of binding
5.1 Single point binding
10 mol% (R)-BINOL
O OH
10 mol% TiCl2(Oi-Pr)
+ Me TiL*
Me H CF3 CF3
O
Me H
CF3
OH 98% syn
L* =
OH 96% ee H
Mikami Tetrahedron 1996, 52, 85

Page 5
5.2 Multiple points binding (tends to give higher selectivity because of a highly organized TS)
Hiersemann ACIE 2001, 40, 4700
6 Types of catalysis
6.1 BrØnsted acid catalysis
NMe2
NMe2 NMe2
NMe2
B
H
2 mol% B-H
O N
Toluene, 1 d N O HN O
H Ar t-BuO H C H
O N t-BuO2C H 2 2 B t-BuO2C
t-BuO2C H Ar Ar
H Ar N H N
N
N
N N N
N
B-H = 9-anthryl
O Ar = 4-FC6H4, 74% yield, 97% ee

O
P 4-PhC6H4, 71% yield, 97% ee
O OH
4-MeOC6H4, 62% yield, 97% ee
9-anthryl
9-anthryl
Terada JACS 2005, 127, 9360
6.2 Lewis acid-base catalysis
Walsh and Kozlowski, Fundamentals of Asymmetric Catalysis, C.2
Denmark JACS 1999, 121, 4982
Page 6
6.3 Transition metal catalysis
Trost Acc. Chem. Res 1996, 29, 355
6.4 Organocatalysis
Barbas JACS 2000, 122, 2395
6.5 Hydrogen bonding catalysis
Ph NH HN CN
HN N O
Ph HN
O OH H
2 mol% Ph NH
O O H N
H CN
HCN H
H N O
toluene, -20 oC H
97% conv., 97% ee
Inoue JOC 1990, 55, 181
6.6 Ion-pair catalysis

Phase Transfer Catalysis (PTC) – (convenient for process chemists because of the ease of product isolation)
O’Donnell Acc. Chem. Res. 2004, 37, 506
7 Modes of activation
7.1 Electrophile activation
Fu Acc. Chem. Res. 2000, 33, 412

Page 7
7.2 Nucleophile activation
Ph
Ph Ph
N
O NO2 TMSO H Ph N
+ 10- 20 mol% TMSO Yield %ee
H R1 R2 syn:anti
Hexanes (%) (syn)
R1 R2 1- 48 h R1
Me Ph 85 94:6 99
activate d nucle ophile
Me n-Bu 52 84:16 99
Me Cy 56 96:4 99
Ph Et Ph 66 93:7 99
O R2 Ph N R2 O i-Pr Ph 72 93:7 99
NO2 TMSO N
H O
R1 R1
Hayashi ACIE 2005, 44, 4212

8 Ligand effect on catalysis
8.1 Ligand decelerated reaction
- A chiral reagent adds more quickly than the ligated adduct (faster background reaction).
- For example, ligand decelerated catalysis is a common problem in asymmetric catalytic Grignard addition.
This is usually overcome by using chiral reagents in stoichiometric fashion.
Cram JACS 1981, 103, 4585
8.2 Ligand accelerated catalysis

- This is a case where there is almost no background rate (the two starting materials do not react at 0 oC).
- The binding of Et2Zn to the ligand DAIB increases the Lewis acidity of the central Zn and accelerates the
reaction rate. The product enantiomeric outcome is governed by the catalyzed pathway.
Noyori JACS 1986, 108, 6071
Page 8
8.3 Non-linear effect - (product enantiopurity does not correlate with catalyst enantiopurity)
Me Me Me Me
N R N R
Zn Me Zn Me
HO Ph PhCHO
O O O O hom odim e r form ation
R H Zn Zn
Me Me is re ve rs ible
R = Et R N R N
cat %e e = 15 Me Me Me Me
product %e e = 95 Kho mo
Me Me Me Me
Me Me
N N
NMe2 R2Zn R Zn
Zn R
OH
Me O O
+ enantiomer Me Me
Khe te ro
DAIB
Me Me
% ee N
product R
Zn Me he te rodim e r is
O O "trappe d" and s low to
Zn re e nte r the catalytic cycle
Me
R N
Me Me
non-linear effect
linear effect
% ee of catalyst
Noyori JACS 1989, 111, 4028
8.4 Autocatalysis – the product formed in the reaction acts as the catalyst
- The Soai reaction
Soai Nature 1995, 378, 767 & Review: Soai Top. Curr. Chem. 2008, 284, 1
8.5 The Horeau principle

- A sequential multistep process on two (or more) prochiral centers on the same molecule that leads to a
high enantiomeric excess at the expense of diastereomeric ratio by means of statistical amplification.
Review: Glueck Catal. Sci. Technol. 2011, 1, 1099

2nd order amplification
x2 OH OH
Ph
Ph (S ) (S ) eep = xn-(1-x)n
OH O Ph Ph xn+(1-x)n
O 3
N B
Ph (S ) 3 Ph x(1-x)
O O OH OH Amplification:
OMe x A large part of minor
(S ) (R )
x(1-x)
Ph 3 Ph BH3.DMS OH O Ph 3 Ph enantiomer formed in
THF m es o the first step is diverted
Ph (R) 3 Ph into the meso compound
Condition: (1-x)2 OH OH and suppresses the
1-x (R ) (R ) formation of the product's
- A s ingle catalys t perform s all re actions
- no chiral re cognition from the pre vious s te p Ph 3 Ph minor enantiomer.
- no rate diffe re nce am ong the is om e rs on the s am e s tep 17.2 dr
94.3% ee
Kagan JACS 2003, 125, 7490
Page 9
Sherburn Angew. Chem. Int. Ed. 2013, 52, 8333
Higher order amplification
Sharpless Science 1993, 259, 64

9 Kinetic analysis
9.1 Rate law
- Rate order may be integral (0, 1, 2, etc) or partial (2/3, 1/2, etc).
- A complex rate law is not uncommon in catalytic systems with multiple substrates.
Reaction order Differential form Integral form

Zero-Order d[P]/dt = k [A] = kt + [A]0
First Order d[P]/dt = k [A]1 ln[A] = kt + ln[A]0
Second-Order d[P]/dt = k [A]2 1/[A] = kt + 1/[A]0
Second-Order (two species) d[P]/dt = k[A][B] ln([A]0[B]/ [B]0[A]) = kt ([B]0-[A]0)
Complex d[P]/dt = k[A]m[B]n[C]p … solving differential equations
9.1.1 Initial rate kinetics

- In a complex reaction with multiple competing pathways, it’s possible to measure the rate by following the
reaction to the first 5-10% (ideally no more than 20%) of the reaction. This is done by measuring the
concentration of the starting material or the product and plot that against time.
Hartwig JACS 2008, 130, 5842
9.1.2 Pseudo rate order

- Used when one substrate is employed in large excess (usually >10 equiv).
- This greatly simplifies the rate law and rate constant determination.
d[P]/dt = k[A][B]
If [B] >> [A], then [B] remains approximately constant, and k'  k[B]
d[P]/dt = k’[A]

Page 10
9.1.3 Steady state kinetics
- Use to simplify the rate law in a reaction involving an intermediate that is approximated to be small in
concentration. Effectively the concentration of the intermediate is assumed to be constant.
Me Me
Me Me B
Me Me
k1 ROMP
P
rds k2
TiCp2 TiCp2
A TiCp2
d[P]/dt = k2[I][B]
Steady state approximation: d[I]/dt = k1[A] - k2[I][B] = 0  k2[I][B] = k1[A]
d[P]/dt = k1[A]
This explains the observed first order in the catalyst and zero order in substrate B.
Grubbs JACS 1986, 108, 733
9.1.4 Mechanistic studies

Analytical methods for mechanistic studies: NMR, UV-Vis, Calorimetry, IR, GC/MS, and HPLC.
Example 1: HPLC detection of nitrone intermediates. (for slow reactions)
Bode ACIE 2006, 45, 1248
Example 2: Reaction IR monitoring of the reaction of oxazolidinone A with nitrostyrene B to form C.
Seebach and Eschenmoser Helv. Chim. Acta 2007, 90, 425
9.1.5 Rate law determination

- “Power rate law” method. The rate orders are determined by measuring initial rates of each substrate over
a range of concentrations. The slope of the plot of ln[initial rate] vs. ln[concentration] affords the rate order.
Page 11
Denmark JACS 2009, 131, 11770 & JOC 2010, 75, 5558
- Reaction progress kinetics (RPK)
Alternative to the power rate law, which involves performing multiple reactions, reaction progress kinetics
“employs in situ measurements and simple manipulations to construct a series of graphical rate equations
that enable analysis of the reaction to be accomplished from a minimal number of experiments. Such an
analysis helps to describe the driving forces of a reaction and may be used to help distinguish between
different proposed mechanistic models.” Reaction calorimetry is often a method of choice for RPK.
Blackmond ACIE 2005, 44, 4302
10 Mechanism determination
One can not prove a mechanism, but rather disprove one.
10.1 Activation parameter analysis (Eyring analysis)

- Determination of activation energy, enthalpy, and entropy (∆G‡, ∆H‡, ∆S‡) based on the following
relationship: ln(k/T) = -(ΔH‡/RT) + (ΔS‡/R) + ln(kB/h) where R = the gas constant; kB = Boltzmann constant;
and h = Planck's constant
Sigman JACS 2004, 126, 9724
Page 12
10.2 Linear free energy relationship (LFER or Hammett analysis)
- Substitution effect can be quantitatively studied using Hammett plots – a plot of log[ksubstituted/kno substitution] vs
sigma () values, characteristic for each substitution group and pattern.
- The slope of this plot is the rho () value.
- Negative  means positive change built up (or decrease in negative charge) in the transition state of the
rate-limiting step of the reaction. Positive  means the opposite, and  = 0 means no substitution effect.
Bode ACIE 2011, 50, 1673
Other kind of LFERs correlate the rate of a reaction with steric parameters, pKa values, etc
Sigman PNAS 2011, 108, 2179
10.3 Labeling experiment

Kinetic Isotope Effect (KIE)
• Label tracking by analysis of the products (MS, 13C/17O-NMR, IR-spectroscopy, etc).
• Kinetic Isotope Effect (KIE): isotope distribution changes the reaction rate (k).
• Primary KIE: the X-D/X-H bond is broken in the rate determining step (primary KIE usually > 1.5).
• Secondary KIE: arises from the isotopic distribution remote from the bonds undergoing reaction.
• Normal Secondary KIE: kH/kD= 1.1-1.2 (the substituted carbon changes hybridization from sp3 to sp2)
• Inverse Secondary KIE: : kH/kD = 0.8-0.9 (the substituted carbon changes hybridization from sp2 to sp3)
Page 13
Angelis Tet. Lett. 2001, 42, 3753
10.4 Computational chemistry

- “The discovery of several computational principles and algorithms — together with the development of fast
computers — has resulted in enormous leaps in the accuracy and speed of computational methods, and it is
now feasible to model many synthetic reactions …. [Computational techniques] provide information about
known catalytic reactions that is not available from experiments alone … [and] have become an invaluable
tool for predicting the behaviour of catalysts and have earned their place as a standard tool for the design of
catalysts.”
- Common techniques are Density functional theory (DFT), Hartree–Fock (HF), and Molecular mechanics
(MM).
Houk Nature 2008, 455, 309
Houk JACS 1986, 108, 554
10.5 Intermediate trapping

- "Pentacoordinate species (ii) are proposed to be intermediates in the hydrolysis of RNA and DNA.
Compound i can cyclize to give ii, although ii was never seen at room temperature. However, upon
adding acetyl chloride to solution of i, both iii and iv are isolated."
- Intermediate may be a part of the catalytic cycle even if it cannot be isolated.
Ramirez JACS 1978, 100, 5391
10.6 Off-cycle intermediate

- The detection of an intermediate species in any catalytic cycle must be interpreted with care.
- Detectable intermediate may be stable but it may not be relevant for the resting state of the reaction.
Page 14
Me Me Me Me
Me Me H H
H H Me
Ph3P PPh3 S Ph3P S Ph3P Me
Rh Rh Rh
Cl PPh3 Cl PPh3 Cl PPh3
Ph3P Cl PPh3
Rh Rh Wilkins on's catalys t S
Ph3P Cl PPh3
This species has been detected. H2 H2
However, it's not in the actual H
H H Me Me
catalytic cycle.
S Ph3P H
Ph3P H Ph3P H Rh
Rh Me Me Cl PPh3
Rh
Cl PPh3 Cl PPh3
PPh3 S Me Me
Me Me
Halpern Science 1982, 217, 401

10.7 Cross-over experiment
- A cross-over experiment is used to determine if a reactant breaks apart to form intermediates that are
released before they recombine to give the product. It is usually used to determine if the reaction is intra- or
intermolecular.
Bode JACS 2011, 133, 14082
A Case Study: Claisen rearrangements

11
There are a number of excellent reviews in the subject of the Claisen
rearrangements. For examples: (a) Ito Chem. Soc. Rev. 1999, 28, 43. (b)
Hiersemann Eur. J. Org. Chem. 2002, 9, 1461. (c) Hiersemann and
Nubbemeyer The Claisen Rearrangment 2007, Wiley-VCH.
11.1 Types of Claisen rearrangements
Carreira and Kvaerno Classics in Stereoselective Synthesis, C.16.2
Page 15
11.2 Standard Claisen rearrangements: mechanistic and kinetics studies
- Based on the Hammond postulate, the high exothermicity of the aliphatic Claisen rearrangement implies an
early-transition state (resembling the reactant with more bond breaking character) based on the observation
of a secondary deuterium kinetic isotope effect. KIE data and the substitution effect data suggest a
concerted, pericyclic mechanism (though not perfectly synchronous).
Gajewski JACS 1979, 101, 2747 & 6693
Carpenter JACS 1981, 103, 6983

- Catalyzed vs. uncatalyzed Claisen reaction energy profiles
Hiersemann & Strassner JOC 2007, 72, 4001
11.3 Catalytic Claisen rearrangements

11.3.1 Chorismate mutase
- Chorismate mutase catalyzes the only known sigmatropic rearrangement (a Claisen rearrangement)
involved in primary metabolism. Rate accelerations on the order of 10 6 over background rate are observed.
The study of this enzyme and the development of small molecule mimetics has been an area of considerable
interest for the past 15–20 years.
Hilvert JACS 2003, 125, 3206
Page 16
11.3.2 Hydrogen-bonding catalysis
- Chiral hydrogen-bonding organic catalysts are an area of intense interest at the moment where
chiral phosphoric acids, thioureas, or diols are most widely used as the hydrogen bond donors.
- An example below demonstrates that dual, rather than mono, hydrogen-bond activation plays an important
role in rate acceleration in the catalytic Claisen rearrangements.
Ar
O O Cat. krel
N O
1.0 equiv cat. H none 1.0

N Cat. A 22.4
80 oC O H Ar
OMe OMe Cat. B 1.0
MeO Cat. C 1.6
bis - hydrogen bonding
CF3 CF3 CF3 CF3 CF3

O O O
C8H17O2C N N CO2C8H17 C8H17O2C N N CO2C8H17 C8H17O2C N
H H H
Me Me
Cat. A Cat. B Cat. C
Curran Tet. Lett. 1995, 36, 6647
Kozlowski Org. Lett. 2009, 11, 621
11.3.3 Lewis acid catalysis

- Extensive efforts on chiral and achiral Lewis acid catalyzed Claisen rearrangements have been reported,
but these tend to suffer from poor substrate scope and lack of catalyst turnover.
Majumdar Tetrahedron 2008, 64, 597
Sharma Synlett 2000, 5, 615
Hiersemann Org. Lett. 2000, 3, 149
Page 17
11.4 Catalytic enantioselective Claisen rearrangement
- Although the enzymatic Claisen rearrangement has long been known from biosynthesis, there have been
relatively few examples of a simple organic catalyst that provides significant rate accelerations and control of
enantioselectivity.
Hiersemann ACIE 2001, 40, 4700
Kozlowski JACS 2008, 130, 16162
Jacobsen JACS 2008,130, 9228 & JACS 2011, 133, 5062 (mechanism)
Jacobsen ACIE 2010, 49, 9753
Page 18
11.5 Enantioselective Claisen rearrangement by catalytic generation of a reactive intermediate
- Transition metal catalyzed enantioselective formal Claisen rearrangement via a metal-pi complex
Nelson JACS 2010, 132, 11875
- We have devised a catalytic Claisen reaction that overcomes the limitation of slow catalyst turnover by
considering an enantioselective variant of the Coates-Claisen reaction of enols and acetals of unsaturated
aldehydes that would give lactones as a means of catalyst turnover. A chiral NHC was used as the catalyst
for highly enantioselective Claisen rearrangments via the intermediacy of an α,β-unsaturated acyl azolium.
characte rize d by
O
NMR , UV-VIS
Me and HR MS HO
Me
O
O
N N
O O O D H‡ = +15.30 kcal/mol
N O
O Me
B Hc C OTBS DS‡ = – 25.50 cal/K.mol
O C1
H N k obs = – 3.41x10-4 s-1
10 mol% C2 Ar O
Ar rate = -k obs [B]1[A]0.5[C]-0.5
A N N Hd Ar OTBS
Mes
Bode JACS 2010, 132, 8810 & ACIE 2011, 50, 1673
- An aza-Claisen variant of the above reaction has also been achieved. Here, the key α,β-unsaturated acyl
azolium was catalytically generated via an oxidation of the Breslow intermediate instead of an internal redox
reaction.
Bode Org. Lett. 2011, 13, 5378
Page 19

Chapter 2: Key Concepts in Catalysis Reaction Coordinate

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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.

Chapter 2: Key concepts in catalysis

- Free energy, enthalpy and entropy are thermodynamic phenomena.

Boger’s Modern Organic Synthesis C.2

2 Transition state theory

- Energy, enthalpy and entropy of activation are kinetic phenomena.

Boger’s Modern Organic Synthesis C.2

2.2 Rate determining step (rds)

Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7

Trost JOC 1965, 30, 1341

Boger’s Modern Organic Synthesis C. 2

Walsh and Kozlowski, Fundamentals of Asymmetric Catalysis, C.1

Shibasaki Adv. Synth. Catal 2004, 346, 1533

- Case 2: a more complicated TS involving a complex with multiple catalysts

Blackmond and Jacobsen JACS 2004, 126, 1360

4.2 Transition state stabilization

Hiersemann & Strassner JOC 2007, 72, 4001

4.3 Microscopic reversibility

Blackmond ACIE 2009, 48, 2648

4.4 The Hammond postulate

Hammond JACS 1955, 77, 334

4.5 The CurtinHammett Principle

Halpern Science 1982, 217, 401

4.6 Catalyst turnover

- Catalyst productivity: Turn Over Number (TON) = mol product/mol catalyst

Blaser Appl. Catal. A 2001, 221, 119

Stoltz ACIE 2009, 48, 6840

4.8 Product inhibition

Yamamoto JACS 1990, 112, 316

4.9 Background rate

Evans JACS 1999, 121, 7582

5.1 Single point binding

Mikami Tetrahedron 1996, 52, 85

Hiersemann ACIE 2001, 40, 4700

O Ar = 4-FC6H4, 74% yield, 97% ee

Terada JACS 2005, 127, 9360

6.2 Lewis acid-base catalysis

Walsh and Kozlowski, Fundamentals of Asymmetric Catalysis, C.2

Denmark JACS 1999, 121, 4982

Trost Acc. Chem. Res 1996, 29, 355

Barbas JACS 2000, 122, 2395

6.5 Hydrogen bonding catalysis

Inoue JOC 1990, 55, 181

6.6 Ion-pair catalysis

O’Donnell Acc. Chem. Res. 2004, 37, 506

Fu Acc. Chem. Res. 2000, 33, 412

Hayashi ACIE 2005, 44, 4212

Cram JACS 1981, 103, 4585

8.2 Ligand accelerated catalysis

Noyori JACS 1986, 108, 6071

Noyori JACS 1989, 111, 4028

8.5 The Horeau principle

Review: Glueck Catal. Sci. Technol. 2011, 1, 1099

Kagan JACS 2003, 125, 7490

Sherburn Angew. Chem. Int. Ed. 2013, 52, 8333

Higher order amplification

Sharpless Science 1993, 259, 64

Reaction order Differential form Integral form

9.1.1 Initial rate kinetics

Hartwig JACS 2008, 130, 5842

9.1.2 Pseudo rate order

Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7