OC VI (HS 2015) Bode Research Group … · · 2016-11-10Hartwig (Walsh) Organotransition Metal...
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OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ Page 1 This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Chapter 2: Key concepts in catalysis 1 Reaction coordinate - Free energy, enthalpy and entropy are thermodynamic phenomena. 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; k B = 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
Transcript of OC VI (HS 2015) Bode Research Group … · · 2016-11-10Hartwig (Walsh) Organotransition Metal...
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Chapter 2: Key concepts in catalysis
1 Reaction coordinate
- Free energy, enthalpy and entropy are thermodynamic phenomena.
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
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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 2.60 kcal/mol is needed to achieve 98% ee at room temp
- ∆∆G‡ of 2.73 kcal/mol is needed to achieve 99% 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
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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).
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E
reaction coordinate
TS1
TS2
R3COHH+
CR
R R Nu-R3CNu
R3COH
CR
R R
R3CNu
The transition statesresemble the geometryof the carbocationintermedate, not the reactant nor the product.
E
reaction coordinate
CR3
CHR2
CH2RThe ralative stability of carbocation: the TS becomes morestable as the reaction becomes less endothermic.
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
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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
Me+
H CF3
O10 mol% (R)-BINOL10 mol% TiCl2(Oi-Pr)
CF3
OH
Me
98% syn96% ee
OHMe
H
CF3
TiL
L =OHOH
Mikami Tetrahedron 1996, 52, 85
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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
Toluene, 1 d
O
9-anthryl
9-anthryl
OP
OH
O
NO
H Ar
NMe2
2 mol% B-H
t-BuO2C H
NN
NO
H Ar
NMe2
t-BuO2C H
NN
B H
N
ArN
t-BuO2H2CH
N
O
NMe2
BH t-BuO2C
NN
Ar
HN O
NMe2
B-H =
Ar = 4-FC6H4, 74% yield, 97% ee 4-PhC6H4, 71% yield, 97% ee 4-MeOC6H4, 62% yield, 97% ee
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
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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
H
OHN
NHPh
O
O
NHN
2 mol%
HCNtoluene, -20 oC
CN
OH
97% conv., 97% ee
NH
N
O
OPh
H
Ph
H
OH
H
NHHN
CN
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
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7.2 Nucleophile activation
H
O
R1
+
R2
NO2
NH
PhPhTMSO10 20 mol%
Hexanes1 48 h
NPh
PhTMSO
R1
NPh
PhTMSO
R1
NO
O
R2
H
ONO2
R1
R2
activated nucleophileMeMeMeEti-Pr
Phn-BuCyPhPh
8552566672
94:684:1696:493:793:7
9999999999
R1 R2 Yield(%) syn:anti %ee
(syn)
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
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8.3 Non-linear effect - (product enantiopurity does not correlate with catalyst enantiopurity)
% ee of catalyst
% ee product
linear effectnon-linear effect
MeOH
NMe2
Me Me
DAIB
R2Zn
N
OZn
Me MeR
ZnR
Me
HO
R H
Ph
+ enantiomer
N
OZn
Me Me
R
Me
N
OZn
MeMe
R
MeKhetero
N
O
MeMe
Me
N
OZn
Me MeR
ZnR
MeN
O
MeMe
Me
heterodimer is"trapped" and slow to
reenter the catalytic cycle
Khomo
N
OZn
Me MeR
ZnR
MeN
O
MeMe
Me
homodimer formationis reversible
R = Etcat %ee = 15
product %ee = 95
PhCHO
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
O
Ph
OH
(S)(S)Ph
O
Ph
OH(S)(S)
Ph(S)(S)
Ph
OH
OH
(R)(R)Ph
O
Ph
OH(S)(S)
Ph(R)(R)
Ph
OH
OH(R)(R)
Ph(R)(R)
Ph
OH
Ph
ON B
O
OMe
Ph Ph
BH3.DMSTHF
x
1-x
x2
x(1-x)
x(1-x)
(1-x)2Condition:- A single catalyst performs all reactions- no chiral recognition from the previous step- no rate difference among the isomers on the same step
eep = xn-(1-x)n
xn+(1-x)n
meso3
3
3
3
3
3
Amplification:A large part of minor enantiomer formed inthe first step is diverted into the meso compoundand suppresses the formation of the product'sminor enantiomer.
17.2 dr94.3% ee
Kagan JACS 2003, 125, 7490
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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
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7 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]
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7
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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.
A
k1
k2
B
TiCp2
MeMe
TiCp2
MeMe
TiCp2
Me Me
Prds
ROMP
d[P]/dt = k2[I][B]
Steady state approximation: d[I]/dt = k1[A] - k2[I][B] = 0 Æ 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.
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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
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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 (V) values, characteristic for each substitution group and pattern. - The slope of this plot is the rho (U) value. - Negative U means positive change built up (or decrease in negative charge) in the transition state of the rate-limiting step of the reaction. Positive U means the opposite, and U = 0 means no substitution effect.
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.8
Bode ACIE 2011, 50, 1673 Other kind of LFERs correlate the rate of a reaction with steric parameters, pKa values, etc
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.8
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)
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7
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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.
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RhPh3P PPh3
Cl PPh3
H2
RhPh3P H
Cl PPh3
H
PPh3
RhPh3P S
Cl PPh3
H2
RhPh3P H
Cl PPh3
H
S
Me
Me
Me
Me RhPh3P H
Cl PPh3
H
MeMe Me
Me
RhPh3P
Cl PPh3
H
S
MeMe
Me HMeMe Me
MeMeH H
RhPh3P Cl
Ph3P ClRh
PPh3
PPh3
S
S
Wilkinson's catalyst
This species has been detected. However, it's not in the actual
catalytic cycle.
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
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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 106 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
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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.
NH
NH
O
CF3 CF3
C8H17O2C CO2C8H17 N N
O
CF3 CF3
C8H17O2C CO2C8H17Me Me
NH
O
CF3
C8H17O2C
O
OMe
1.0 equiv cat.
80 oC
O
OMe
Cat.noneCat. ACat. BCat. C
krel1.022.41.01.6
Cat. A Cat. B Cat. C
O
MeO
HN
NH
OAr
Ar
bis hydrogen bonding
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
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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
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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.
Ar
O
HO
OO
Ar
O
OTBS
H‡ = +15.30 kcal/mol S‡ = – 25.50 cal/K.molkobs = – 3.41x10-4 s-1
rate = -kobs [B]1[A]0.5[C]-0.510 mol%
NNN
O
MeMe
Me
N
N NC2
O
Mes
C1
O Hc
HdAr
characterized byNMR, UV-VIS and HRMS
O
HOO
OTBS
A
B C
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
