METHODS FOR THE SYNTHESES OF COMPOSITIONALLY DIVERSE DENDRIMERS USING CHEMOSELECTIVE ROUTES A Dissertation by MACKAY BAGLEY STEFFENSEN Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY August 2004 Major Subject: Chemistry METHODS FOR THE SYNTHESES OF COMPOSITIONALLY DIVERSE DENDRIMERS USING CHEMOSELECTIVE ROUTES A Dissertation by MACKAY BAGLEY STEFFENSEN Submitted to Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved as to style and content by: ___________________________ ___________________________ Eric E. Simanek Hagan Bayley (Chair of Committee) (Member) ___________________________ ___________________________ Kevin Burgess Richard M. Crooks (Member) (Member) ___________________________ Emile Schweikert (Department Head) August 2004 Major Subject: Chemistry iii ABSTRACT Methods for the Syntheses of Compositionally Diverse Dendrimers Using Chemoselective Routes. (August 2004) Mackay Bagley Steffensen, B.S., Southern Utah University Chair of Advisory Committee: Dr. Eric E. Simanek Dendrimers are a unique class of macromolecules that present perfect branching on a molecular scale. The pattern of branching at the atomic scale is compared to the branching of trees, from whence dendrimers get their name. Dendrimers have been attractive synthetic targets for the past twenty years. The methods and building blocks used in the synthesis of dendrimers vary, but molecules of this class of polymeric materials all possess symmetrical branching emanating from the core. At each branch point the number of groups increases exponentially. Efforts directed toward the synthesis of dendrimers presenting multiple functional groups at the surface and within the dendrimer structure are described. Methods are described which provide access to dendrimers in a one-pot per generation fashion, with triazines as the common moiety. Chemoselective routes utilize the temperature dependant substitution of cyanuric chloride to construct dendrimers, obviating the use of protected monomers or the need to manipulate functional groups during the synthesis. These methods are atom economical, as the only by-products are HCl and a base to scavenge it. The methods are efficient, with typical isolated yields of product in the middle to high ninety percent range, often on a multi-gram scale. Methods are described for conducting three separate reactions in a single pot. Specific emphasis is placed on structural control of the interior and surface groups of the dendrimers. The synthesis of a G3 dendrimer of layered composition is described. The use of a different difunctional linkage group for each generation of dendrimer growth produced a G3 dendrimer with layered composition without the use of protecting groups or functional group interconversions. A G3 dendrimer was synthesized presenting five different functionalities at the periphery on a 10 gram scale, resulting in approximately 70% overall yield. The peripheral iv groups are composed of orthogonal functionality, which can be independently and selectively unmasked or manipulated in the presence of the other functionality. The syntheses of dendrimers incorporating the short linker hydrazine produce materials with interesting physical properties as well as a low ratio of carbon to nitrogen. The use of dendrimers in the construction of novel macromolecular constructs is also described. v To: Mariam, McKade, MaKella, Madalyn, and Malayna: My Little M-Empire. vi ACKNOWLEDGMENTS I must thank my second family, the Simanek group, ranging back to the days of Kiran, Dan and Scott to the current members that have stuck it out with me for the last four years: Dr. Erick Acosta, Sergio Gonzalez, Megan McLean and Alona Umali. To the new recruits: Dr. Ting, Dr. Hollink, Carlos, Michael and Susan I bid farewell and bequeath all my clean glassware to you. May your reactions be quick and the products pure. I am indebted to Dr. Eric Simanek for allowing me the freedom to work in his group and explore my own ideas and most importantly to do what I love, mix chemicals. The advice, friendship and mentoring from Dr. Kevin Burgess is gladly acknowledged, and service on my committee is much appreciated. To Dr. Hagan Bayley much appreciation is extended for discussions throughout the years and for the future opportunity to continue to mix chemicals. For service on my committee and helpful suggestions I thank Dr. Richard Crooks. I am probably most indebted to two early teachers who expressed science in such a manner as to make it exciting, applicable and enjoyable. To my Father: those snakes you brought home during the summer and chemistry textbooks scattered throughout the house, as well as your love and enthusiasm for science, instilled within me a love for learning about and investigating the exquisite functioning of biological systems. I must thank Dr. Ty Redd who made the predictive power of organic chemistry come alive. I do not think the same way since I took your class. To my lovely wife Mariam, it has been an enjoyable journey. Nine years, four children and a Ph.D; none of it possible without you. Your continued support, encouragement, and understanding will never be forgotten and hopefully some day repaid. McKade, MaKella, Madalyn and Malayna: the hugs at the end of a hard day put chemistry into perspective. vii TABLE OF CONTENTS Page ABSTRACT .................................................................................................................. iii DEDICATION .............................................................................................................. v ACKNOWLEDGMENTS............................................................................................. vi TABLE OF CONTENTS .............................................................................................. vii LIST OF FIGURES....................................................................................................... x LIST OF SCHEMES ..................................................................................................... xi CHAPTER I INTRODUCTION .................................................................................. 1 1.1 From Polymers to Dendrimers...................................................... 1 1.2 Difficulties in the Emergence of Polymer Chemistry as a Science ......................................................................................... 2 1.2.1 Setbacks........................................................................ 3 1.2.2 Advances...................................................................... 4 1.2.3 The role of natural polymers in the development of polymer science ............................................................ 5 1.2.4 The role of analytical methods in advancing polymer chemistry as a science .................................... 6 1.2.5 Confusion abounds concerning the nature of proteins .. 9 1.3 Evolution of the Macromolecular Hypothesis .............................. 9 1.3.1 The doctrinaire of polymers: Hermann Staudinger ..... 10 1.3.2 An organic chemist for polymers: Wallace Carothers... 11 1.3.3 The academic community begins to accept polymers .. 11 1.4 The Rapid Evolution of Polymer Chemistry as a Science ............ 11 1.4.1 The movement of polymers from industry to academia ....................................................................... 11 1.4.2 Consensus on the structure of natural polymers ........... 12 1.4.3 The year of the polymer................................................ 13 1.4.4 Controlling the polymer................................................ 14 1.4.5 Polymer chemists' attempts at mimicking nature.......... 15 1.5 Polymers Are Not Just Straight Chain Molecules ........................ 18 1.5.1 Polymer chemistry begins to branch out ...................... 18 1.5.2 Dendrimer chemistry begins......................................... 19 1.6 The Discovery of Cyanuric Acid: The Start of Triazine Chemistry...................................................................................... 22 1.6.1 Melamine: The most widely used triazine................... 24 1.6.2 Cyanuric chloride: A versatile molecule ..................... 24 1.6.3 Triazine herbicides....................................................... 25 1.6.4 Triazine optical brighteners and tie-dyes...................... 26 viii CHAPTER Page 1.6.5 Triazine drugs............................................................... 27 1.6.5.1 Triazine drugs for parasites .............................. 28 1.6.5.2 Triazine drugs in cancer treatment ................... 29 1.6.6 Potential triazine containing drugs ............................... 33 1.6.6.1 Triazine drugs by combinatorial methods ........ 35 1.6.7 Triazine explosives and industrial applications............ 36 1.6.8 Academic exploration of triazines................................ 37 1.6.8.1 Triazines as condensing reagents...................... 37 1.6.8.2 Triazines in functional group manipulations .... 38 1.6.8.3 Triazines in molecular recognition, supramolecular, and materials chemistry ........ 38 1.7 Triazine Dendrimers...................................................................... 40 1.7.1 The 20th century............................................................ 40 1.7.2 The 21st century ............................................................ 43 1.7.3 Future possibilities.......................................................