Activity and selectivity of DMAP derivatives in acylation reactions [Elektronische Ressource] : experimental and theoretical studies / von Evgeny Larionov

Evgeny Larionov

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2011
• Nombre de lectures: 50
• Langue: English
• Poids de l'ouvrage: 11 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München







Activity and Selectivity of DMAP Derivatives in
Acylation Reactions: Experimental and Theoretical
Studies












von
Evgeny Larionov
aus
Leningrad, Russland


2011 Erklärung

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.





Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.


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
Professor Dr. Hendrik Zipse at the Fakultät für Chemie und Pharmazie of the Ludwig-
Maximilians-Universität, München.








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.
I acknowledge Ludwig-Maximilians-Universität, München for financial support and Leibniz-
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.

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:
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

i 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

ii 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
iii Chapter 1. General Introduction


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
[1]
Until now a large number of experimental and theoretical studies on ester hydrolysis in
aqueous solution have been carried out, resulting in a multitude of possible reaction
[2]mechanisms, which are described in many textbooks. 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 2, which AC
[3a]includes tetrahedral intermediates (Figure 1.1a). Subsequent studies suggested that the
reaction can also occur through a one-step, concerted mechanism (Figure 1.1c), when the
[3b]
substrate has a good leaving group. The two possible mechanisms for ester hydrolysis,
B 2 and B 2 (Figure 1.1a,b), which were shown to compete in the gas