• unlimited access with print and download
    $ 37 00
  • read full document, no print or download, expires after 72 hours
    $ 4 99
More info
Unlimited access including download and printing, plus availability for reading and annotating in your in your Udini library.
  • Access to this article in your Udini library for 72 hours from purchase.
  • The article will not be available for download or print.
  • Upgrade to the full version of this document at a reduced price.
  • Your trial access payment is credited when purchasing the full version.
Buy
Continue searching

Ortho substitution effects on the acidic and alkaline hydrolyses of formanilides

ProQuest Dissertations and Theses, 2009
Dissertation
Author: Salil Dileep Desai
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 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 AAC 2 mechanism. Ortho substitution led to 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 AC 2 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.

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 a .......................................................................46

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

v

Effect of Ionic Strength .........................................................................132

Binary Solvent System Studies .............................................................133

Effect of Temperature ............................................................................133

Discussion .....................................................................................................134

Conclusion ....................................................................................................154

CHAPTER IV ORTHO SUBSTITUTION EFFECTS ON THE ALKALINE HYDROLYSIS OF FORMANILIDES ........................................................169

Introduction ...................................................................................................169

Materials .......................................................................................................169

Methods ........................................................................................................170

Standard protocols for kinetic analysis. .................................................170

Kinetic Studies .......................................................................................172

Determination of reaction schemes for all substrates. ....................172

Effect of pH ....................................................................................172

Effect of Ionic Strength ..................................................................173

Binary-Solvent System Studies ......................................................173

Effect of Temperature ....................................................................173

Structure-Reactivity Relationship Studies .....................................173

Results...........................................................................................................174

Determination of reaction schemes .......................................................174

Effect of pH ...........................................................................................199

Effect of Ionic Strength .........................................................................208

Binary Solvent System Studies .............................................................208

Effect of Temperature ............................................................................208

Discussion .....................................................................................................209

Conclusion ....................................................................................................221

APPENDIX A ESTIMATION OF IONIZATION CONSTANTS ................................233

APPENDIX B DERIVATION OF RATE LAWS..........................................................248

APPENDIX C STATISTICAL INFORMATION ..........................................................252

Data used for the multiple linear regression analysis of the ortho effect in the acidic hydrolysis of formanilide .........................................................252

Output Information after Multiple Regression Analysis From JMP ® ..........254

REFERENCES ................................................................................................................258

vi

LIST OF TABLES Table II- 1: Representative structure for substituted formanilides and Hammett substituent constants (σ m , σ p ), electrophilic substituent constant (σ m + , σ p + ), enhanced substituent constants (σ p - ), and Taft steric substituent constant (E 0 s) values for selected substituent groups. ...............................32

Table II- 2: List of substituted formanilides either obtained or synthesized. Compounds commercially available are marked with X, and synthesized compounds are marked with √ ...............................................33

Table II- 3: Summary table for m-chloroformanilide ...................................................57

Table II- 4: Summary table for m-bromoformanilide ...................................................58

Table II- 5: Summary table for p-nitroformanilide .......................................................59

Table II- 6: Summary table for m-nitroformanilide ......................................................60

Table II- 7: Summary table for o-nitroformanilide .......................................................61

Table II- 8: Summary table for m-methoxyformanilide ...............................................62

Table II- 9: Summary table for o-methoxyformanilide ................................................63

Table II- 10: Summary table for p-hydroxyformanilide .................................................64

Table II- 11: Summary table for m-hydroxyformanilide ................................................65

Table II- 12: Summary table for o-hydroxyformanilide .................................................66

Table II- 13: Summary table for p-carboxyformanilide .................................................67

Table II- 14: Summary table for m-carboxyformanilide ................................................68

Table II- 15: Summary table for o-carboxyformanilide .................................................69

Table II- 16: Summary table for m-methylformanilide ..................................................70

Table II- 17: Summary table for p-ethylformanilide ......................................................71

Table II- 18: Summary table for m-ethylformanilide .....................................................72

Table II- 19: Summary table for o-ethylformanilide ......................................................73

Table II- 20: Summary table for p-isopropylformanilide ...............................................74

Table II- 21: Summary table for m-isopropylformanilide ..............................................75

Table II- 22: Summary table for o-isopropylformanilide ...............................................76

Table II- 23: Summary table for p-phenylformanilide ...................................................77

vii

Table II- 24: Summary table for o-phenylformanilide ...................................................78 Table III- 1: HPLC conditions for analysis of substituted formanilides and their reaction products. .......................................................................................85

Table III- 2: Experimental conditions and observed rate constants for the hydrolysis of formanilide in hydrochloric acid solutions at 40 °C. ...........88

Table III- 3: Experimental conditions and observed rate constants for the hydrolysis of p-methylformanilide in hydrochloric acid solutions. ...........89

Table III- 4: Experimental conditions and observed rate constants for the hydrolysis of m-methylformanilide in hydrochloric acid solutions. ..........90

Table III- 5: Experimental conditions and observed rate constants for the hydrolysis of o-methylformanilide in hydrochloric acid solutions. ...........91

Table III- 6: Experimental conditions and observed rate constants for the hydrolysis of p-chloroformanilide in hydrochloric acid solutions. ............92

Table III- 7: Experimental conditions and observed rate constants for the hydrolysis of m-chloroformanilide in hydrochloric acid solutions. ...........93

Table III- 8: Experimental conditions and observed rate constants for the hydrolysis of o-chloroformanilide in hydrochloric acid solutions. ............94

Table III- 9: Experimental conditions and observed rate constants for the hydrolysis of p-nitro formanilide in hydrochloric acid solutions. .............95

Table III- 10: Experimental conditions and observed rate constants for the hydrolysis of m-nitroformanilide in hydrochloric acid solutions. .............96

Table III- 11: Experimental conditions and observed rate constants for the hydrolysis of o-nitroformanilide in hydrochloric acid solutions. ..............97

Table III- 12: Experimental conditions and observed rate constants for the hydrolysis of p-bromoformanilide in hydrochloric acid solutions. ...........98

Table III- 13: Experimental conditions and observed rate constants for the hydrolysis of m-bromoformanilide in hydrochloric acid solutions............99

Table III- 14: Experimental conditions and observed rate constants for the hydrolysis of o-bromoformanilide in hydrochloric acid solutions. .........100

Table III- 15: Experimental conditions and observed rate constants for the hydrolysis of p-ethylformanilide in hydrochloric acid solutions. ............101

Table III- 16: Experimental conditions and observed rate constants for the hydrolysis of m-ethylformanilide in hydrochloric acid solutions. ...........102

Table III- 17: Experimental conditions and observed rate constants for the hydrolysis of o-ethylformanilide in hydrochloric acid solutions. ............103

viii

Table III- 18: Experimental conditions and observed rate constants for the hydrolysis of p-isopropylformanilide in hydrochloric acid solutions. .....104

Table III- 19: Experimental conditions and observed rate constants for the hydrolysis of m-isopropylformanilide in hydrochloric acid solutions. ....105

Table III- 20: Experimental conditions and observed rate constants for the hydrolysis of o-isopropylformanilide in hydrochloric acid solutions. .....106

Table III- 21: Experimental conditions and observed rate constants for the hydrolysis of p-methoxyformanilide in hydrochloric acid solutions. ......107

Table III- 22: Experimental conditions and observed rate constants for the hydrolysis of m-methoxyformanilide in hydrochloric acid solutions. .....108

Table III- 23: Experimental conditions and observed rate constants for the hydrolysis of o-methoxyformanilide in hydrochloric acid solutions. ......109

Table III- 24: Experimental conditions and observed rate constants for the hydrolysis of p-carboxyformanilide in hydrochloric acid solutions. .......110

Table III- 25: Experimental conditions and observed rate constants for the hydrolysis of m-carboxyformanilide in hydrochloric acid solutions. ......111

Table III- 26: Experimental conditions and observed rate constants for the hydrolysis of o-carboxyformanilide in hydrochloric acid solutions. .......112

Table III- 27: Experimental conditions and observed rate constants for the hydrolysis of p-hydroxyformanilide in hydrochloric acid solutions........113

Table III- 28: Experimental conditions and observed rate constants for the hydrolysis of m-hydroxyformanilide in hydrochloric acid solutions. ......114

Table III- 29: Experimental conditions and observed rate constants for the hydrolysis of o-hydroxyformanilide in hydrochloric acid solutions........115

Table III- 30: Experimental conditions and observed rate constants for the hydrolysis of p-phenylformanilide in hydrochloric acid solutions. .........116

Table III- 31: Experimental conditions and observed rate constants for the hydrolysis of o-phenylformanilide in hydrochloric acid solutions. .........117

Table III- 32: Experimental conditions and observed rate constants for the hydrolysis of formanilide in 0.010 M, and 1.00 M hydrochloric acid solutions at different temperatures. ..........................................................118

Table III- 33: Experimental conditions and observed rate constants for formanilide degradation in 0.010 M hydrochloric acid at 40 °C. ................................119

Table III- 34: Experimental conditions and observed rate constants for the hydrolysis of formanilide in 0.010 M hydrochloric acid solutions containing different amounts of organic solvents at 40 °C. .....................120

ix

Table III- 35: Second-order rate constants for acid catalyzed hydrolysis of substituted formanilides at 40 °C in the range of 0.01-1.0 M hydrochloric acid solutions. .....................................................................137

Table III- 36: Activation parameters for degradation of formanilide in 0.010 M HCl and 1.0 M HCl solutions. The ionic strength of 0.010 M hydrochloric acid solution was adjusted to 1.0 using potassium chloride. ...................................................................................................141

Table III- 37: Activation parameters for the hydrolysis of formanilides in 1.0 M hydrochloric acid. ....................................................................................142

Table III- 38: Substituent parameters used for correlation. ...........................................156 Table IV- 1: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of formanilide at 40 °C. ....................................................175

Table IV- 2: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of p-methylformanilide at 40 °C. ....................................176

Table IV- 3: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of o-methylformanilide at 40 °C. .....................................177

Table IV- 4: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of p-bromoformanilide at 40 °C. ......................................178

Table IV- 5: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of o-bromoformanilide at 40 °C. ......................................179

Table IV- 6: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of p-chloroformanilide at 40 °C. ......................................180

Table IV- 7: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of o-hydroxyformanilide at 25 °C. ...................................181

Table IV- 8: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of p- hydroxyformanilide at 25 °C. ..................................182

Table IV- 9: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of formanilide at 25 °C. ....................................................183

Table IV- 10: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of p-chloroformanilide at 25 °C. ......................................184

Table IV- 11: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of p-methoxyformanilide at 25 °C....................................185

Table IV- 12: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of p-methylformanilide at 25 °C. .....................................186

Table IV- 13: Sodium hydroxide concentrations and observed rate constants for the hydrolysis of m-nitroformanilide at 25 °C. ........................................187

x

Table IV- 14: Adjusted ionic strengths and observed rate constants for ionic strength studies for the hydrolysis of formanilide in 0.010 M sodium hydroxide solutions at 40 °C. ...................................................................188

Table IV- 15: Concentrations of organic solvents and observed rate constants for the hydrolysis of formanilide in 0.10 M sodium hydroxide solutions containing different amounts of organic solvents at 40 °C. .....................189

Table IV- 16: Reactions temperatures and observed rate constants for the hydrolysis of formanilide in 0.10 M sodium hydroxide solutions. ..........190

Table IV- 17: Observed rate constants for the hydrolysis of substituted formanilides in 0.10 M sodium hydroxide solutions at 40°C. .................191

Table IV- 18: Rate constants and ionization constants for the base catalyzed hydrolysis of formanilides at 25° C. ........................................................207

Table IV- 19: Activation parameters for degradation of formanilide in 0.10 M sodium hydroxide.....................................................................................213 Table A- 1: Potentiometric titration data for titration of a 40 mL aliquot of 5.0 mM p-hydroxyformanilide with 0.10 N sodium hydroxide with calculated G (modified titrant volume) used for determination of hydroxyl pK a . ...........................................................................................233

Table A- 2:. Absorbance values at 250 nm and 310 nm for 9.99×10-4 M o- carboxy formanilide in the pH range 1.56-6.95 .......................................236

Table A- 3: Absorbance values at 303 nm for 4.98×10 -5 M meta-carboxy formanilide in the pH range 1.53-6.91. ....................................................239

Table A- 4: Absorbance values at 282 nm for 4.99×10 -5 M p-carboxyformanilide in the pH range 1.60-6.95. .......................................................................242

Table A- 5: Absorbance values at 278 nm and 301 nm for 5.70×10 -5 M m- hydroxyformanilide in the pH range 7.03-11.61. ....................................244

Table A- 6: Absorbance values at 308 nm and 278 nm for 1.88×10 -4 M o- hydroxyformanilide in the pH range 7.07-11.75. Stock solutions were prepared in DMSO. .........................................................................246 Table C- 1: Data used in the analysis of the Fujita Nishioka Equation. .....................252

Table C- 2: Summary of Fit .........................................................................................255

Table C- 3: Analysis of Variance ................................................................................255

Table C- 4: Parameter Estimates.................................................................................256

Table C- 5: Effect Tests ..............................................................................................256

xi

LIST OF FIGURES Figure I- 1: A1 mechanism for the acidic hydrolysis of acetanilide. ..............................4

Figure I- 2: Acid catalyzed acyl cleavage bimolecular (A AC 2) mechanism for acidic hydrolysis of amides. .........................................................................5

Figure I- 3: Pathways for amide hydrolysis in alkaline solutions. .................................6

Figure I- 4: Scheme for alkaline hydrolysis of formoterol. ............................................6

Figure I- 5: Chemical structure of formanilide. ..............................................................9

Figure I- 6: Hammett plots for formanilide: (A) acid hydrolysis at very high acid concentrations (H A = -3.2); (B) acid hydrolysis at lower acid concentrations (H A = 0); (C) second-order ( k 3 ) alkaline hydrolysis of formanilide. The line in I-6 (A) is a linear regression line for the Hammett equation while the lines in I-6(B) and (C) are smooth lines not fit to the data. .......................................................................................10

Figure I-7: Fundamental curves into which most pH-rate profiles can be resolved. .....................................................................................................20

Figure I- 8: Examples for Arrhenius plot (A) and Eyring plot (B) for the hydrolysis of m-chloroformanilide in 1.0 M hydrochloric acid. ...............21

Figure I- 9: Types of Hammett plots showing (a) negative slope, (b) positive slope, (c) slope close to zero (d) slope changing concave upwards, and (e) slope changing concave downwards. .............................................30 Figure II- 1: Reaction scheme for the formation of formanilides from aniline and formic acid .................................................................................................37

Figure II- 2: Reaction scheme for the synthesis of formanilide from aniline using azeotropic synthesis. ..................................................................................37

Figure II- 3: Complete reaction assembly for synthesis of substituted formanilides by azeotropic synthesis. ........................................................38

Figure II- 4: Reaction scheme for acylation of amines by unsymmetrical acid anhydrides. .................................................................................................39

Figure II- 5: Formylation reaction for synthesis of formanilides. (A) Formation of acetic formic anhydride from acetic anhydride and formic acid and (B) Reaction of acetic formic anhydride with aniline to form formanilide. ................................................................................................39

Figure II- 6: Vacuum distillation apparatus used for the purification of formanilides. ..............................................................................................42

Figure II- 7: Representative DSC thermogram (A) and vant Hoff plot (B) for the determination of purity for formanilide using DSC. ..................................51

xii

Figure II- 8: Determination of pK a of p-hydroxyformanilide by potentiometric titration of a 40 mL aliquot of 5.0 mM p-hydroxyformanilide with 0.10 N sodium hydroxide at 25 °C. (A) Potentiometric titration curve (B) Gran's plot. G is modified term for volume of titrant at higher pH. Slope of plot gives the K a value of 2.66×10 -10 (pK a of 9.57) ...........................................................................................................52

Figure II- 9: Determination of the hydroxyl pK a of m-hydroxyformanilide. UV spectra of 5.70×10 -5 M meta-hydroxyl formanilide in the pH range 7.03-11.6 from 250 nm to 360 nm. At 278 nm highest absorbance is due to pH 7.03 and lowest absorbance is due to pH 11.6. .........................53

Figure II- 10: Non linear regression fits for absorbance values for 5.70×10 -5 M meta-hydroxy formanilide in the pH range 7.03-11.61. Solid squares represent experimental data. Solid lines generated using Equation II-3) (A) 278 nm (estimated K a =5.98×10 -10 ). (B) 301 nm (estimated K a =4.73 ×10 -10 ). The K a ’s were averaged and the average pK a reported was 9.27. .................................................................54

Figure II- 11: 1 H NMR spectrum of p-ethylformanilide in deuterated chloroform (CDCl 3 ) obtained on a 300 MHz NMR spectrometer. The colored boxes correspond to the protons in the compound.....................................55

Figure II- 12: 13 C NMR spectrum of p-ethylformanilide deuterated chloroform (CDCl 3 ) obtained on a 300 MHz NMR spectrometer. The colored boxes correspond to the carbons in the compound. ...................................56 Figure III- 1: Representative chromatogram of separation of reaction mixture of formanilide in 0.075 M hydrochloric acid using isocratic method with a C12 HydroRP Phenomenex 4μ 4.6×75 mm column using a mobile phase with 30:70 acetonitrile:water at a flow rate of 0.8 mL/min. ....................................................................................................123

Figure III- 2: Typical HPLC calibration curves for (A) formanilide and (B) aniline. ......................................................................................................124

Figure III- 3: Concentration-time profiles for hydrolysis of formanilide in 0.10- 0.025 M hydrochloric acid at 1.0 ionic strength and 60 °C. Solid circles (●) represent loss of formanilide, solid squares (■) represent appearance of aniline, and solid triangles (▲) represents mass balance for the reaction. The solid line is a first-order fit for formanilide loss and the broken lines are interpolations. ........................125

Figure III- 4: Concentration of formanilide versus time at pH 1.09 (♦), pH 1.21 (▲), pH 1.38 (■), and pH 1.68 (●) at 60 °C. ...........................................126

Figure III- 5: Selected UV spectra collected as a function of time for the hydrolysis of formanilide in 1.0 M hydrochloric acid solutions at 60°C. The spectrum with the highest absorbance value is that of the pure formanilide and the spectrum with the least absorbance values correspond to the reaction products. ........................................................127

xiii

Figure III- 6: Reaction scheme for degradation of substituted formanilides in hydrochloric acid solution........................................................................128

Figure III- 7: Concentration-time profile of hydrolysis of m-methoxy formanilide in 0.1 M hydrochloric acid at 1.0 ionic strength, and 40 °C. Solid circles (●) represent loss of formanilide; solid squares (■) represent appearance of aniline and solid triangles (▲) represent mass balance for the reaction. The solid lines are fitted using Scheme II-2 and estimates in Table III-22. The broken line is an interpolation. ................129

Figure III- 8: pH-rate profile for formanilide hydrolysis at 40 °C in hydrochloric acid solutions. ..........................................................................................135

Figure III- 9: Pseudo-first-order rate constant (k′, hr -1 ) versus hydrochloric acid concentration in the pH region of 0.07 to 1.99. The slope gives a specific acid catalytic rate constant (k H ) of 7.39 M -1 hr -1 . .......................136

Figure III- 10: Plot of log of the rate constants (k) against the substrate activity coefficient of the medium. Rate constants were determined in 0.01 M hydrochloric acid at 40 °C. Ionic strength was varied using potassium chloride. ..................................................................................138

Figure III- 11: Effect of increasing organic solvent concentrations on the rate constant for hydrolysis of formanilide in aqueous organic solutions containing 0.010 M hydrochloric acid solutions at 40 °C. The lines are interpolated lines. ...............................................................................139

Figure III- 12: Arrhenius plot for the temperature dependence of formanilide hydrolysis in 0.010 M and 1.00 M hydrochloric acid solutions. .............140

Figure III- 13: Hammett plot for para and meta substituted formanilides. Open squares denote para substituted compounds (□) and open circles denote meta substituted compounds (○). Lines are not fitted to the data. ..........................................................................................................157

Figure III- 14: Hammett plots for meta and para substituents using electrophilic substituent constants. Open squares denote para substituted compounds (□) and open circles denote meta substituted compounds (○). The solid line is a linear fit to the Hammett equation which does not include p-nitro, p-carboxy, and p-phenyl substituents. ......................158

Figure III- 15: Hammett plot for para and meta substituents using various sigma values. The dotted line is a linear fit to the Hammett equation. .............159

Figure III- 16: The enthalpy-entropy compensation plots for para and meta substituted formanilides using activation parameters. Solid squares denote para substituted compounds (■) and solid circles denote meta substituted compounds (●). The error bars represent the standard errors. .........................................................................................160

Figure III- 17: Activation enthalpy-entropy compensation plots for para and meta substituted formanilides The line is a linear regression fit to the substituents showing inductive effects.....................................................161

xiv

Figure III- 18: Extrapolated Arrhenius plots for (A) meta and (B) para substituted formanilides. Solid squares denote para substituted compounds (■) and solid circles denote meta substituted compounds (●).The lines are linear fits of the data to the Arrhenius equation. ................................162

Figure III- 19: A AC 2 mechanism for acid hydrolysis of amides ......................................163

Figure III- 20: Hammett plots for para, meta, and ortho substituted formanilides using Hammett sigma values for ortho substituents. Solid squares denote para substituted compounds (■), solid circles denote meta substituted compounds (●), and open squares denote ortho substituted compounds (□). The values in parenthesis are the Taft- Kutter-Hansch values for the steric substituent E s . ..................................164

Figure III- 21: Hammett plots for para, meta, and ortho substituted formanilides using Hammett sigma values for ortho substituents (assuming steric inhibition of resonance). Solid squares denote para substituted compounds (■), solid circles denote meta substituted compounds (●), and open squares denote ortho substituted compounds (□). The line is a linear fit for the para and meta substituted formanilide using the selected sigma values and is used for comparison. ..................165

Figure III- 22: The actual versus predicted plot for log of the rate constants using the Fujita Nishioka equation. Open squares denote para substituted compounds (□), open circles denote meta substituted compounds (○), and the open triangles denote ortho substituents. The line is the correlation line with a slope of 1 and the dotted lines are 95% mean confidence intervals for the fitted equation. ............................................166

Figure III- 23: Activation enthalpy-entropy compensation plot for ortho substituted formanilides. Solid squares denote para substituted compounds (■), solid circles denote meta substituted compounds (●), and the open triangles denote ortho substituted compounds (Δ).The data for the para and meta substituted formanilides is used for comparison. The error bars represent standard errors..........................................................167

Figure III- 24: Enthalpy-entropy compensation plot for ortho substituted formanilides. Solid squares denote para substituted compounds (■), solid circles denote meta substituted compounds (●), and the open triangles denote ortho substituted compounds (Δ).The data for the para and meta substituted formanilides is used for comparison and the line is a straight line fit to the substituents which display pure inductive effects. The values in parenthesis are the E s values. ................168 Figure IV- 1: Representative chromatogram for the degradation of formanilide in 0.075 M sodium hydroxide solution using isocratic method with a C12 HydroRP Phenomenex 4μ 4.6×75 mm column using a mobile phase with 30:70 acetonitrile:water, at a flow rate of 0.8 mL/minute, an analytical wavelength of 235 nm and a runtime of 5 minutes. Peak at 2.7 minutes is formanilide and 3.5 minutes is aniline. ......................................................................................................193

xv

Figure IV- 2: Concentration-time profiles of hydrolysis of formanilide in 0.10- 0.025 M sodium hydroxide at 1.0 ionic strength and 60 °C; (A) pH 11.77 (0.10 M) (B) pH 11.69 (0.075 M) (C) pH 11.55(0.050 M) and (D) pH 11.29 (0.025 M). Solid circles (●) represent loss of formanilide; solid squares (■) represent appearance of aniline and solid triangles (▲) represent mass balance for the reaction. The lines are interpolations. .....................................................................................194

Figure IV- 3: Plot of concentration of formanilide versus time at pH 11.8 (●), pH 11.7 (■), pH 11.6 (▲), pH 11.3 (□) at 60 °C. The lines are first order fits to the data. ..........................................................................................195

Figure IV- 4: UV Spectra collected as a function of time for the hydrolysis of formanilide in 1.0 M sodium hydroxide solution at 60 °C. The arrows point to the isosbestic points. The spectrum with the highest absorbance at 250 nm corresponds to formanilide while the spectrum with the lowest absorbance corresponds to the reaction products. ...................................................................................................196

Figure IV- 5: Reaction scheme for hydrolysis of substituted formanilides in sodium hydroxide solution. ......................................................................197

Figure IV- 6: Concentration-time profile for the hydrolysis of p- hydroxyformanilide in 0.010 M NaOH at 40 °C. The ionic strength of the solution was adjusted to 1.0 using sodium chloride. The filled circles (●) represent the concentration of formanilide while the open boxes (□) represent the mass balance for the reaction. The line is a first-order fit for the hydrolysis of p-hydroxyformanilide. ......................198

Figure IV- 7: Plot of k obs against sodium hydroxide concentrations for hydrolysis of formanilides in alkaline solutions at 40 °C. The formanilides shown are formanilide (○), p-bromoformanilide (▲), o- bromoformanilide (♦), o-methylformanilide (■), and p- methylformanilide (●). The curves are interpolations. ............................203

Figure IV- 8: pH-rate profile for hydrolysis of formanilide using the k obs at 25 °C. The dotted line is a linear regression fit to the data for the linear portion of the pH-rate profile. ..................................................................204

Figure IV- 9: pH-rate profile for hydrolysis of formanilide using the observed rate constants (k corr ) corrected for ionization of the substrate at 25 °C. The solid line is represents a line obtained by linear regression. .............205

Figure IV- 10: pH-rate profile for hydrolysis of formanilide using the observed rate constants (k obs ) at 25 °C. The solid line was simulated using Equation IV-1 and estimates from Table IV-18. .....................................206

Figure IV- 11: Plot of log of the rate constants against the ionic strength of the medium. Rate constants were determined in 0.010 M sodium hydroxide at 40 °C. Ionic strength was varied using sodium chloride. The solid line is a linear regression fit to the data. ..................................210

xvi

Figure IV- 12: Effect of increasing organic solvent concentrations on the rate constants for hydrolysis of formanilide in aqueous organic solutions in 0.10 M sodium hydroxide solutions at 40 °C. The closed circles (●) represent reactions in dimethyl sulfoxide solutions and closed square (■) represent reactions in dioxane solutions. The lines are interpolations............................................................................................211

Figure IV- 13: Arrhenius Plot for the temperature dependence of formanilide degradation in 0.10 M sodium hydroxide solutions plot. Solid line is the fit to the linearized Arrhenius equation (Equation IV-6). ..................212

Figure IV- 14: Hammett plot for observed rate constant and normalized rate constants (k corr ) for substituted formanilides at different hydroxide concentrations at 25 °C; 0.010 M NaOH (▲), 0.10 M NaOH (○), 1.0 M NaOH (■), and 5.0 M NaOH (●). Lines are linear fits of the data to the Hammett equation. .........................................................................222

Full document contains 291 pages
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 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 AAC 2 mechanism. Ortho substitution led to 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 AC 2 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.