[PDF] Activity and selectivity of DMAP derivatives in acylation reactions PDF Larionov

31 mai 2011 · The reverse reaction, esterification of alcohols, is also well studied and widely used in methanol and methylamine acetylation with acetic anhydride at the electron-rich pyridines such as DMAP (4-dimethylaminopyridine,

Acetylation of alcohols and phenols with acetic anhydride has been carried out in pyridine) have unpleasant odour and are not so easy to remove, DMAP4 is

[PDF] Acetic Anhydride - Sigma-Aldrich

Pyridine may also react with acetic anhydride, however, forming N-acetyl- derivatives of alcohols, phenols, and amines for analysis by GC/ FID Acetylated

[PDF] Reactions of alcohols in acetic anhydride-mineral acid mixtures

Acetyl sulphate would be expected to be more acidic than sulphuric acid because Reactions of Alcohols with Acetic Anhydride and Inorganic Acids In acetylation To a solution of 3S-cholestanol (lg) in dry pyridine (15ml) was added acetic

[PDF] Acylation by acetyl tririuoroacetate and trifluoroacetic anhydride A

The mechanism of the effect of pyridine on the reactions B Reaction of hydroxy compounds with acetic anhydride ii) Acylation of Alcohols and Hienols

[PDF] Activity and selectivity of DMAP derivatives in acylation reactions

An Efficient Method for Acylation Reactions - ScienceDirectcom

1 4-(Dimethylamino)pyridine (DMAP) and 4- pyrrolidinopyridine efficient catalyst for acylation of alcohols using acetic anhydride/acetic acid We also report

Dissertation zur Erlangung des Doktorgrades

Activity and Selectivity of DMAP Derivatives in

Acylation Reactions: Experimental and Theoretical

Studies

von

Evgeny Larionov

aus

Leningrad, Russland

2011
Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29. Januar 1998 (in der Fassung der sechsten Änderungssatzung vom 16. August 2010) von Prof.

Dr. Hendrik Zipse betreut.

München,

Evgeny Larionov

Dissertation eingereicht am 19/04/2011

1. Gutachter: Prof. Dr. H. Zipse

2. Gutachter: Prof. Dr. H. Mayr

Mündliche Prüfung am 31/05/2011

This work was carried out from September 2007 to January 2011 under the supervision of The work for this thesis was encouraged and supported by a number of people to whom I would like to express my gratitude at this point. First of all, I would like to appreciate my supervisor Prof. Dr. Hendrik Zipse for giving me the opportunity to do my Ph. D. in his group and his guidance in the course of scientific research presented here. I thank him for all the constructive discussions, especially for the great degree of independence and freedom to explore. I would like to thank Prof. Dr. Herbert Mayr for acting as my Zweitgutachter" and assessing

this work. I would like to appreciate Hildegard Lipfert for all kind help for my stay in

Munich. I acknowledge AK Mayr for the possibility to carry out the low-temperature kinetic measurements in their thermostat. Furthermore, I would like to thank Johnny Hioe, Raman Tandon and Aliaksei Putau for careful and patient reading and correcting this thesis. My thanks to all the members of our research group: Dr. Ingmar Held, Dr. Yin Wei, Boris Borix" Maryasin, Florian Achrainer, Christoph Lindner, Dr. Valerio Wall-E" D"Elia, Dr. Sateesh DrNa" Patrudu, Johnny Alter" Hioe, Elija Slave" Wiedemann, Jowita Iwota" Humin, Florian Barth, Michael Miserok, Cong YeYe" Zhang, for their helps and lasting friendships, which have made my time in Germany a pleasant and worthwhile experience. I thank my F-Praktikum student Regina Bleichner for creating nice atmosphere in the lab. I would especially like to thank my great colleague Dr. Yinghao Liu who I spent the whole Ph. D. time with, for his interesting discussions and helpful suggestions. Additional thanks go to Russian mafia" Konstantin Troshin and Anna Antipova from AK Mayr, as well as Boris Maryasin, for helpful discussions, nice teatimes and hiking tours. Rechenzentrum München for providing some computation facilities. Most importantly I would like to thank my parents and Ksenia for their love, support, help and encouragement during these years. Thank you very much!

To my family

Parts of this Ph. D. Thesis have been published:

1. Larionov, E.; Zipse, H.; Organocatalysis: Acylation Catalysts. WIREs Computational

Molecular Science 2011, Early View (DOI: 10.1002/wcms.48).

2. Held, I.; Larionov, E.; Bozler, C.; Wagner, F.; Zipse, H.; The Catalytic Potential of 4-

Guanidinylpyridines in Acylation Reactions. Synthesis 2009, 2267-2277. i

1. General Introduction 1

1.1 Acylation reactions: mechanistic survey 1

1.2 Catalyzed acylation reactions 4

1.2.1 Acid catalysis 4

1.2.2 Base catalysis 6

1.2.3 Nucleophilic mechanism of DMAP-catalyzed acylation 8

1.2.4 Base catalysis mechanism of DMAP-catalyzed transesterification 11

1.3 Objectives 14

2. The Catalytic Potential of Substituted Pyridines in Acylation Reactions:

Theoretical Prediction and Experimental Validation 16

2.1 Introduction 16

2.2 Synthesis and catalytic activity of 3,4-diaminopyridines 20

2.2.1 Synthesis of 3,4-diaminopyridines 20

2.2.2 Catalytic activity of 3,4-diaminopyridines 24

2.3 Acetylation enthalpies (ground state model) 26

2.4 Activation enthalpies (transition state model) 31

2.4.1 Relative activation enthalpies 31

2.4.2 Conformational properties of the transition states 35

2.4.3 Influence of the solvation model 36

2.4.4 Discussion 41

2.5 Conclusions 42

3. Applications of the Relative Acylation Enthalpies 44

3.1 Photoswitchable pyridines 44

3.1.1 Introduction 44

3.1.2 Results and Discussion 47

3.1.3 Conclusions and Outlook 54

3.2 Relative acetylation enthalpies for paracyclophane derivatives 55

3.3 Relative isobutyrylation enthalpies for chiral 3,4-diaminopyridines 59

3.4 Relative acetylation enthalpies for ferrocenyl pyridines 63

4. (4-Aminopyridin-3-yl)-(thio)ureas as Acylation Catalysts 68

4.1 Introduction 68

4.2 Achiral (4-aminopyridin-3-yl)-(thio)ureas 70

4.2.1 Acetylation enthalpies of (4-aminopyridin-3-yl)-(thio)ureas 70

4.2.2 Synthesis and catalytic activity of (4-aminopyridin-3-yl)-(thio)ureas 74

4.2.3 Catalysts agregation studied by NMR and kinetic measurements 77

4.3 Chiral (4-aminopyridin-3-yl)-ureas 80

4.3.1 Synthesis of chiral catalysts, derived from (S)-amino acids 80

4.3.2 Derivatization of catalysts by Grignard reagent 81

4.3.3 Acetylation enthalpies and benchmark reaction kinetics 82

4.3.4 Introduction of a linker between the pyridine and urea moieties 85

4.3.5 Potential of (4-aminopyridin-3-yl)-ureas in the kinetic resolution of alcohols 87

4.4 Conclusions 90

5. Theoretical Prediction of Selectivity in KR of Secondary Alcohols 91

5.1 Introduction 91

5.2 Catalytic system with PPY 94

5.2.1 Determination of activation parameters for the PPY-catalyzed acylation reaction 94

5.2.2 Theoretical study of the catalytic cycle with PPY 96

5.3 Catalytic system with Spivey"s catalyst 103

5.3.1 The energy profile of the acylation catalyzed by catalyst 59a 103

5.3.2 Reaction barriers and conformational space of TSs 106

5.3.3 The selectivity rationalization: TS 67 for catalysts 59b, 59c and 59e 111

5.3.4 The selectivity prediction for catalysts 59d, 59f and 59g 114

5.3.5 Synthesis and selectivity measurements for catalysts 59d, 59f and 59g 116

5.3.6 Comparison with theoretical predictions 118

5.4 Estimating the stereoinductive potential of the pyridines 120

5.4.1 Chiral 3,4-diaminopyridine derivatives 120

5.4.2 Prochiral probe approach 121

5.4.3 Conformational analysis of transition states 123

5.5 Conclusions 130

6. Summary and general conclusions 131

iii

7. Experimental part 135

Chapter 2. Experimental details 136 Chapter 4. Experimental details 154 Chapter 5. Experimental details 180

8. Appendix (Computational details) 187

Chapter 2. Computational details 187 Chapter 3. Computational details 227 Chapter 4. Computational details 243 Chapter 5. Computational details 255

9. Kinetics of reactions in homogeneous solution: derivation of the kinetic law 283

References 295

Abbreviations 302

Curriculum Vitae 303

Chapter 1. General Introduction

Acyl-transfer reactions are among the most fundamental reactions in organic chemistry and biochemistry. Considering their importance in biochemical and synthetic processes, these reactions have been widely studied both in solution and in the gas phase.

1.1 Acylation reactions: mechanistic survey

Until now a large number of experimental and theoretical [1] studies on ester hydrolysis in aqueous solution have been carried out, resulting in a multitude of possible reaction mechanisms, which are described in many textbooks. [2] Several possible mechanisms of the base-catalyzed ester hydrolysis are shown in Figure 1.1. Early experimental results in aqueous solution showed that acyl-transfer reactions proceed via a stepwise mechanism B

AC2, which

includes tetrahedral intermediates (Figure 1.1a). [3a] Subsequent studies suggested that the reaction can also occur through a one-step, concerted mechanism (Figure 1.1c), when the substrate has a good leaving group. [3b] The two possible mechanisms for ester hydrolysis, B AC2 and BAL2 (Figure 1.1a,b), which were shown to compete in the gas phase hydrolysis of methyl formate, were studied computationally by Pliego et al. at high ab initio level MP4/6-

311+G(2df,2p)//MP2/6-31G(d).

[1g] The calculated distribution of reaction paths was in excellent agreement with experimental values (85% of B

AC2). The main challenge in

theoretical analysis of aqueous ester hydrolysis is the inclusion of water solvent effects by, for example, a cluster-continuum model [1c] or by explicit inclusion of all solvent molecules.[1f] Biochemically meaningful ester hydrolysis by enzymes was modeled by imidazole-catalyzed hydrolysis in several theoretical studies. [4] R O OR' + OH-R OR' OH O- R O

O-+ R'OHBAC2:

R O OR' + OH-R O OR' O R O

O-+ R'OHBAL2:

Concerted:

R O OR' + OH-R

R'OOHO

R O

O-+ R'OH

a b c Figure 1.1. Possible mechanisms of the base-catalyzed ester hydrolysis.

Chapter 1. General Introduction

2 The reverse reaction, esterification of alcohols, is also well studied and widely used in organic synthesis. [5] The general mechanisms are well known (Figure 1.2). The nucleophilic species undergoes addition to the carbonyl group, followed by elimination of the halide or carboxylate anion. Kinetic studies of the reaction of alcohols with acid chlorides in polar solvents in absence of basic catalysts generally reveal terms both first-order and second-order in alcohol. [5a,b] The first term is associated with the formation of a tetrahedral intermediate (Figure 1.2a), whose deprotonation is assisted by the solvent molecule (e.g., acetonitrile). [5a] Transition states in which the second alcohol molecule acts as a proton acceptor have been proposed for the second term (Figure 1.2b). The mechanism is concerted when anionic nucleophiles, such as phenoxides, reacted with carboxylic acid derivatives (Figure 1.2c). [5c-e] R O X + HXR X O O aR O

OR'+ R'OH

b c+ R'OH 2 R' H R O X + XR X O O R O

OR'+ R'OHR'

H + R'OH O H R' R O Y + YR Y OAr O R O

OAr+ ArO

X = RCOO-, Cl-

Y = RCOO-, Ar'O-

X = RCOO-, Cl-

Figure 1.2. Possible mechanisms of alcohol esterification. However, a surprisingly small number of theoretical studies on uncatalyzed alcohol and amine acylation reactions were carried out. Kruger [6a] has calculated activation energies for methanol and methylamine acetylation with acetic anhydride at the MP2/6-31+G(d,p) level of theory. The activation energy for amide formation was found to be much lower (37 kJ/mol) than that for the corresponding ester (71 kJ/mol) on this occasion. The latter proceeds through a six-membered ring transition state whose structure was found to be similar to that for the hydrolysis of acetic anhydride. It is worth noting that the leaving acetate serves as a base inquotesdbs_dbs20.pdfusesText_26

[PDF] [PDF] Activity and selectivity of DMAP derivatives in acylation reactions

[PDF] An efficient and simple procedure for acetylation of alcohols - NOPR

[PDF] Acetic Anhydride - Sigma-Aldrich

[PDF] Reactions of alcohols in acetic anhydride-mineral acid mixtures

[PDF] Acylation by acetyl tririuoroacetate and trifluoroacetic anhydride A

[PDF] Activity and selectivity of DMAP derivatives in acylation reactions

An Efficient Method for Acylation Reactions - ScienceDirectcom

Dissertation zur Erlangung des Doktorgrades

Activity and Selectivity of DMAP Derivatives in

Acylation Reactions: Experimental and Theoretical

Studies

Evgeny Larionov

Leningrad, Russland

Dr. Hendrik Zipse betreut.

München,

Evgeny Larionov

Dissertation eingereicht am 19/04/2011

1. Gutachter: Prof. Dr. H. Zipse

2. Gutachter: Prof. Dr. H. Mayr

Mündliche Prüfung am 31/05/2011

To my family

Parts of this Ph. D. Thesis have been published:

1. Larionov, E.; Zipse, H.; Organocatalysis: Acylation Catalysts. WIREs Computational

2. Held, I.; Larionov, E.; Bozler, C.; Wagner, F.; Zipse, H.; The Catalytic Potential of 4-

Table of contents

1. General Introduction 1

1.1 Acylation reactions: mechanistic survey 1

1.2 Catalyzed acylation reactions 4

1.2.1 Acid catalysis 4

1.2.2 Base catalysis 6

1.2.3 Nucleophilic mechanism of DMAP-catalyzed acylation 8

1.2.4 Base catalysis mechanism of DMAP-catalyzed transesterification 11

1.3 Objectives 14

2. The Catalytic Potential of Substituted Pyridines in Acylation Reactions:

2.1 Introduction 16

2.2 Synthesis and catalytic activity of 3,4-diaminopyridines 20

2.2.1 Synthesis of 3,4-diaminopyridines 20

2.2.2 Catalytic activity of 3,4-diaminopyridines 24

2.3 Acetylation enthalpies (ground state model) 26

2.4 Activation enthalpies (transition state model) 31

2.4.1 Relative activation enthalpies 31

2.4.2 Conformational properties of the transition states 35

2.4.3 Influence of the solvation model 36

2.4.4 Discussion 41

2.5 Conclusions 42

3. Applications of the Relative Acylation Enthalpies 44

3.1 Photoswitchable pyridines 44

3.1.1 Introduction 44

3.1.2 Results and Discussion 47

3.1.3 Conclusions and Outlook 54

3.2 Relative acetylation enthalpies for paracyclophane derivatives 55

3.3 Relative isobutyrylation enthalpies for chiral 3,4-diaminopyridines 59

3.4 Relative acetylation enthalpies for ferrocenyl pyridines 63

4. (4-Aminopyridin-3-yl)-(thio)ureas as Acylation Catalysts 68

4.1 Introduction 68

4.2 Achiral (4-aminopyridin-3-yl)-(thio)ureas 70

4.2.1 Acetylation enthalpies of (4-aminopyridin-3-yl)-(thio)ureas 70

4.2.2 Synthesis and catalytic activity of (4-aminopyridin-3-yl)-(thio)ureas 74

4.2.3 Catalysts agregation studied by NMR and kinetic measurements 77

4.3 Chiral (4-aminopyridin-3-yl)-ureas 80

4.3.1 Synthesis of chiral catalysts, derived from (S)-amino acids 80

4.3.2 Derivatization of catalysts by Grignard reagent 81

4.3.3 Acetylation enthalpies and benchmark reaction kinetics 82

4.3.4 Introduction of a linker between the pyridine and urea moieties 85

4.3.5 Potential of (4-aminopyridin-3-yl)-ureas in the kinetic resolution of alcohols 87

4.4 Conclusions 90

5. Theoretical Prediction of Selectivity in KR of Secondary Alcohols 91

5.1 Introduction 91

5.2 Catalytic system with PPY 94

5.2.1 Determination of activation parameters for the PPY-catalyzed acylation reaction 94

5.2.2 Theoretical study of the catalytic cycle with PPY 96

5.3 Catalytic system with Spivey"s catalyst 103

5.3.1 The energy profile of the acylation catalyzed by catalyst 59a 103

5.3.2 Reaction barriers and conformational space of TSs 106

5.3.3 The selectivity rationalization: TS 67 for catalysts 59b, 59c and 59e 111

5.3.4 The selectivity prediction for catalysts 59d, 59f and 59g 114

5.3.5 Synthesis and selectivity measurements for catalysts 59d, 59f and 59g 116

5.3.6 Comparison with theoretical predictions 118

5.4 Estimating the stereoinductive potential of the pyridines 120

5.4.1 Chiral 3,4-diaminopyridine derivatives 120