Automatic Verification of Small Molecule Structure with One Dimensional Proton Nuclear Magnetic Resonance Spectrum DOCTORAL THESIS FOR THE DEGREE OF A DOCTOR OF INFORMATICS AT THE FACULTY OF ECONOMICS, BUSINESS ADMINISTRATION AND INFORMATION TECHNOLOGY OF THE UNIVERSITY OF ZURICH by JIWEN LI from V.R. China Accepted on the recommendation of PROF. DR. A. BERNSTEIN PROF. DR. K. BALDRIDGE 2010 The Faculty of Economics, Business Administration and Information Technology of the University of Zurich herewith permits the publication of the aforementioned dissertation without expressing any opinion on the views contained therein. Zurich, April 14. 2010 The Vice Dean of the Academic Program in Informatics: Prof. Dr. H. C. Gall Contents Acknowledgements .................................................................................................................................... viii Abstract ........................................................................................................................................................ ix List of Figures ................................................................................................................................................ x List of Tables ............................................................................................................................................... xii Part I .............................................................................................................................................................. 1 Introduction, Background and the Proposal ................................................................................................. 1 Chapter 1 Motivation ................................................................................................................................ 3 1.1 Quantification ................................................................................................................................. 4 1.2 Compound Structure Verification ................................................................................................... 5 1.3 Applying NMR in Compound Library Management QC/QA ............................................................ 6 1.3.1 1H NMR versus 13C NMR ......................................................................................................... 6 1.3.2 1D 1H NMR versus 2D 1H NMR ............................................................................................... 6 1.3.3 Applying 1D 1H NMR for Structure Verification and Quantification ....................................... 8 1.3.4 Automating 1D 1H NMR Molecule Structure Verification ....................................................... 9 1.3.5 Expert Systems and their Applications .................................................................................. 10 1.3.6 Using Artificial Intelligence for Molecule Structure NMR Verification .................................. 11 1.4 Structure of the Thesis .................................................................................................................. 12 Chapter 2 Background ............................................................................................................................. 13 2.1 Human Structure Verification Procedure with 1D 1H NMR Spectrum ......................................... 13 2.1.1 1H 1D NMR Spectroscopy, NMR Sample and NMR Solvent .................................................. 13 2.1.2 Basic NMR/Chemical Concepts used in Molecule Structure 1D 1H NMR Verification. ......... 14 2.1.2.1 Chemical shift .................................................................................................................. 14 2.1.2.2 Integration ...................................................................................................................... 16 2.1.2.3 J-coupling ........................................................................................................................ 17 2.1.2.4 Coupling Constant and Connectivity ............................................................................... 19 2.1.2.5 Second-order Coupling ................................................................................................... 20 2.1.2.6 Magnetic Inequivalence .................................................................................................. 21 2.1.3 Human Process of Molecular Structure 1D 1H NMR Verification- an Example ..................... 22 iii iv ∙ Contents 2.1.3.1 Identifying Peak Clusters ................................................................................................. 23 2.1.3.2 Identifying Solvent .......................................................................................................... 24 2.1.3.3 Computing Proton Numbers of Peak Clusters ................................................................ 26 2.1.3.4 Verifying Consistency between the Molecular Structure and the Peak Clusters with Proton Number ........................................................................................................................... 29 2.1.3.5 Further Verifying the Consistency between Peak Clusters and Function Groups by Coupling Analysis ........................................................................................................................ 32 2.1.4 Summary of the Human Logic for 1D 1H NMR Molecular Structure Verification ................. 36 2.2 Current Automatic NMR Spectrum Molecule Structure Consistency Analysis System ................ 39 2.2.1 General System Architecture ................................................................................................. 41 2.2.1.1 Molecular Interpreter ..................................................................................................... 41 2.2.1.1.a Identifying Chemical Equivalent Functional Groups ............................................... 42 2.2.1.1.b Predicting Chemical Shift ......................................................................................... 42 2.2.1.1.c Predicting Number of Couplings and Coupling Constant ......................................... 43 2.2.1.1.d Count Total Number of Protons within a Molecule ................................................. 44 2.2.1.2 NMR Spectrum Interpreter ............................................................................................. 44 2.2.1.2.a Automatically Identifying Peaks in Spectrum .......................................................... 44 2.2.1.2.b Grouping Symmetric Peaks into Peak Clusters ........................................................ 45 2.2.1.2.c Estimating Multiplicities and Coupling Constants for Each Peak Cluster ................. 45 2.2.1.3 Consistency Analyzer ...................................................................................................... 45 2.2.2 Difference between Human Structure Verification Logic and Techniques used in the Structure Verification System ......................................................................................................... 47 2.2.2.1 Differences in Molecular Interpretation ......................................................................... 47 2.2.2.2 Differences in NMR Spectrum Interpreter ...................................................................... 48 2.2.2.3 Differences in Consistency Analysis ................................................................................ 50 2.3 NMR Structure Verification Technique beyond 1D 1H NMR Spectra ........................................... 51 2.4 Conclusion ..................................................................................................................................... 51 Chapter 3 The Proposal ........................................................................................................................... 52 3.1 Implementation Plans ................................................................................................................... 52 3.2 Possible Challenges ....................................................................................................................... 53 Part II ........................................................................................................................................................... 55 Automatic 1D 1H NMR Molecule Structure Verification Software Architecture, Methods and Evaluation ................................................................................................................................................... 55 Chapter 4 Automatic 1D 1H NMR Molecule Structure Verification Architecture and Methods ............ 57 Contents ∙ v 4.1 System Architecture ...................................................................................................................... 57 4.2 Molecular Interpreter ................................................................................................................... 59 4.3 NMR Spectrum Interpreter ........................................................................................................... 62 4.3.1 Peak Hypothesis Generator (Deconvolution Method + Derivative Method) ........................ 64 4.3.2 Peak Cluster Hypothesis Generation ..................................................................................... 65 4.3.3 Experimental Multiplet Hypothesis Interpreter .................................................................... 66 4.4 Consistency Analyzer - Searching Consistent