Ortho substitution effects on the acidic and alkaline hydrolyses of formanilides

290 Pages·2016·2.72 MB·English

by  Salil Dileep Desai

University of Iowa
Iowa Research Online
Theses and Dissertations
Fall 2009
Ortho substitution effects on the acidic and alkaline
hydrolyses of formanilides
Salil Dileep Desai
University of Iowa
Copyright 2009 Salil Dileep Desai
This dissertation is available at Iowa Research Online: https://ir.uiowa.edu/etd/353
Recommended Citation
Desai, Salil Dileep. "Ortho substitution effects on the acidic and alkaline hydrolyses of formanilides." PhD (Doctor of Philosophy)
thesis, University of Iowa, 2009.
https://doi.org/10.17077/etd.sgud4mto.
Follow this and additional works at:https://ir.uiowa.edu/etd
Part of thePharmacy and Pharmaceutical Sciences Commons
ORTHO SUBSTITUTION EFFECTS ON THE ACIDIC AND ALKALINE
HYDROLYSES OF FORMANILIDES
by
Salil Dileep Desai
An Abstract
Of a thesis submitted in partial fulfillment
of the requirements for the Doctor of
Philosophy degree in Pharmacy
in the Graduate College of
The University of Iowa
1
December 2009
Thesis Supervisor: Associate Professor Lee E. Kirsch
1
ABSTRACT
The objectives of this project were to determine the reaction schemes of
formanilide and substituted formanilides in acidic and alkaline solutions, to quantiate the
kinetics of hydrolysis, to propose reaction mechanisms, and to assess the role of ortho
substitution in formanilide hydrolysis kinetics.
A set of thirty substituted formanilides were synthesized and characterized.
Hydrolysis of the formanilides was carried out under first order conditions in
hydrochloric acid (0.01-8 M, 40°C) and in hydroxide solutions (0.01-3 M, 25°C and
40°C). Hydrolysis kinetics were evaluated in terms of temperature (20°C- 60°C), solvent
composition(0-50 % dimethyl sulfoxide, dioxane, ethanol and acetone) and ionic strength
(0.1-1) effects. The degradation products were separated and identified using RP-HPLC,
and the alkaline and acidic reaction schemes were proposed.
For acidic hydrolysis of formanilides, the observed rate constants were
proportional to the hydronium concentrations. Modified Hammett plots constructed
using the second order rate constants for specific acid catalysis were linear. The ortho
effect was analyzed using the Fujita-Nishioka method. In alkaline solutions the observed
rate constants showed mixed first and second order dependences with respect to
hydroxide concentration. A complex degradation scheme was used to estimate individual
rate constants and to construct Hammett plots. Ortho effects were examined for the first
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order hydroxide concentration dependent pathway.
Arrhenius plots for substituted formanilides were linear in both acidic and
alkaline media. Ionic strength did not show any effect on the acidic and alkaline
hydrolysis rates. In both acidic and alkaline media the rate of hydrolysis decreased with
increase in organic solvent content.
Formanilide hydrolyzes in acidic solutions by specific acid catalysis and the
kinetic study results were consistent with A 2 mechanism. Ortho substitution led to
AC
2
reduction in rates. The ortho effect could be split in steric inhibition of resonance,
retardation due to steric bulk and through space interactions. In alkaline solutions a
complicated kinetic scheme was used to describe the multiple pathways of degradation.
The results from the kinetic studies could be explained using a modified B 2
AC
mechanism. The hydrolysis of meta and para substituted formanilides in alkaline
conditions did not show substituent effects however ortho substitution led to an decrease
in rate constants proportional to the steric bulk of the substituent.

Abstract Approved: ____________________________________
Thesis Supervisor
____________________________________
Title and Department
____________________________________
Date

2
ORTHO SUBSTITUTION EFFECTS ON THE ACIDIC AND ALKALINE
HYDROLYSES OF FORMANILIDES
by
Salil Dileep Desai
A thesis submitted in partial fulfillment
of the requirements for the Doctor of
Philosophy degree in Pharmacy
in the Graduate College of
The University of Iowa
1
December 2009
Thesis Supervisor: Associate Professor Lee E. Kirsch
Copyright by
SALIL DILEEP DESAI
2009
All Rights Reserved

2
Graduate College
The University of Iowa
Iowa City, Iowa
CERTIFICATE OF APPROVAL
_______________________
PH.D. THESIS
_______________
This is to certify that the Ph.D. thesis of
Salil Dileep Desai
has been approved by the Examining Committee
for the thesis requirement for the Doctor of Philosophy
degree in Pharmacy at the December 2009 graduation.
Thesis Committee: ___________________________________
Lee E. Kirsch, Thesis Supervisor
___________________________________
Douglas R. Flanagan
___________________________________
Maureen D. Donovan
___________________________________
Dale E. Wurster
___________________________________
Daniel M. Quinn
To
My parents, Leena and Dileep Desai

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ACKNOWLEDGMENTS
This achievement would not have been possible without the support and
encouragement of several people. I would like to express my appreciation and gratitude
to all of them.
First and foremost - to Dr. Lee Kirsch, my advisor and mentor, for his support and
guidance.
I would like to thank Dr. Wurster, Dr. Quinn, Dr. Flanagan, and Dr. Donovan for
serving on my thesis committee. A special thanks to Dr. Matheson for delaying his trip
to accommodate my comprehensive exam.
I could not have reached this milestone without the unwavering support of my
parents, Leena and Dileep Desai. My brother and his wife, Mihir and Deepali, who
checked on me regularly and kept me going through thick and thin. My late
grandparents, Indira and Vasudeo Desai, Muktabai and Maharudra Netravali who always
guided me to be my best. My extended family, especially my aunts - Sheela, Rekha, and
Jyoti who have always nudged me towards research and science.
Special thanks goes out to my former roommates Praveen, Mogili, Subhashish,
Ankur, and Bhavik, who have been my family away from home. My years at Iowa could
not have been memorable without my friends Vaibhavi, Mowyee, Sushmita, Neeraj,
Sriram and Himanshu. I would also like to thank my labmates Bhanu, Lida, Anjali, Lairi,
Madhu, Zong, Nui, Fon, and Jiang for all their support and help.

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TABLE OF CONTENTS
LIST OF TABLES ............................................................................................................. vi
LIST OF FIGURES ........................................................................................................... xi
CHAPTER I INTRODUCTION .........................................................................................1

Introduction .......................................................................................................1
Project Objectives .............................................................................................3
Formanilides as Model Compounds .................................................................7
Overview of Kinetic Techniques ......................................................................8
pH-Rate Profiles ......................................................................................11
Temperature Effects ................................................................................16
Ionic Strength Effects ..............................................................................18
Binary-Solvent Effects ............................................................................22
Buffer Catalysis .......................................................................................22
Structure-Reactivity Relationships ..........................................................23
Organization of the Thesis ..............................................................................29
CHAPTER II SYNTHESIS AND CHARACTERIZATION OF SUBSTITUTED
FORMANILIDES...........................................................................................31

Introduction .....................................................................................................31
Materials .........................................................................................................31
General Methods Used for Synthesis and Characterization ...........................34
Synthetic Methods ...................................................................................34
Azeotropic synthesis ........................................................................34
Acylation reaction ............................................................................35
Purification of Reaction Products ............................................................40
Identification, Purity Assessment and Characterization of Products ......41
Nuclear magnetic spectroscopy ........................................................43
Differential scanning calorimetry .....................................................44
Determination of pK .......................................................................46
a
Results.............................................................................................................48
CHAPTER III ORTHO SUBSTITUTION EFFECTS ON THE ACIDIC
HYDROLYSIS OF FORMANILIDES ..........................................................79

Introduction .....................................................................................................79
Materials .........................................................................................................79
Methods ..........................................................................................................80
Standard Protocols for Kinetic Analysis. ................................................80
Kinetic Studies .........................................................................................82
Determination of reaction schemes for all substrates. ......................82
Effect of pH on reaction kinetics ......................................................82
Effect of temperature on the stability of formanilides .....................83
Effect of ionic strength on the stability of formanilide. ...................83
Effect of binary solvents on the stability of formanilide ..................83
Results.............................................................................................................84
Determination of Reaction Schemes .......................................................84
Effect of pH ...........................................................................................122
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