Correlation of the Acid-Catalyzed Hydrolysis Rates of Some Oxazolidines with Substituent Effects

This dissertation has been 65—1170 microfilmed exactly as received

CLEARY, Robert William, 1935- CORRELATION OF THE ACID-CATALYZED HYDROLYSIS RATES OF SOME OXAZOLIDINES WITH SUBSTITUENT EFFECTS.

The Ohio State University, Ph.D., 1964 Chemistry, pharmaceutical University Microfilms, Inc., Ann Arbor, Michigan CORRELATION OF THE ACID-CATALYZED HYDROLYSIS

RATES OF SOME OXAZOLIDINES WITH

SUBSTITUENT EFFECTS

DISSERTATION

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

Robert William Cleary, B.S., M.Sc*

The Ohio State University

1964

Approved by

1 Adviser College of Pharmaoy ACKNOWLEDGMENTS

My sincere appreciation is extended to Dr. Jules B. e LaPidus, my adviser, for his suggestions, and constructive criticism, and for financial assistance in the form of a Research

Assistantship made possible by his grant from The National

Institutes of Health.

I will always be grateful to Dr. David E. Guttman, and many others, faculty members and fellow graduate students, for their suggestions and criticism.

To my wife, Joan, without whose love, understanding and continual encouragement, this tenure would not have been possible, sa'yiag thank you is completely inadequate.

ii VITA

October 2, 1935 » • • Born— Milwaukee, Wisconsin

1959 B.S. Pharmacy, University of Wisconsin

1959-1961 Teaching Assistant, College of Pharmacy The Ohio State University, Columbus, Ohio

1961 Research Assistant, National Institutes of Health, The Ohio State University, Columbus, Ohio

1962 M.Sc. Pharmacy, The Ohio State University, Columbus, Ohio

PUBLICATIONS

"Chemical Factors Influencing Host Selection by the Mexican Bean Beetle Epilachna varivestis Mule." Agricultural and Food Chemistry, Vol. iTJ pp. *f62-*+63» Nov/Dec 1963

"Host-Plant Selection by the Mexican Bean Beetle Epilachna varivestis Muls." Annals of The Entomological Society of America, Vol. 57* pp. 127-13*N January, 196**

FIELDS OF STUDY

Major Field: Pharmacy

Studies in Organic Chemistry. Professors Harold Shechter, Melvin S. Newman, Michael P. Cava, and Richard A. Finnegan

Studies in Pharmaceutical Chemistry. Professors Jules B. LaPidue and Loyd E. Harris

Studies in Physical Chemistry. Professor Quentin Van Winkle

Studies in Physical Pharmacy. Professor David E. Guttman

ill CONTENTS Page

ACKNOWLEDGMENTS...... 11

VITA ...... ill

T A B L E S ...... vl

FIGURES ...... vil

STATEMENT OF PROBLEM ...... 1

INTRODUCTION ..... 2

EXPERIMENTAL...... 1^

Synthesis of diastereoisomers of 2-(p-substitutedphenyl)-3f*t—dimethyl-5-phenyloxazolidine...... 1**

Reagents ...... 1^+

Synthesis of erythro-oxazolidines . 15

1. Preparation of erythro-2„5-diphenyl-51***- dimethyloxazolidine 15 2. Preparation of erythro-2-p-methylphenyl- 3»^-dimethyl-5~phenyloxazolidine • • • • • 16 3. Preparation of erythro-2-p-bromophenyl- 3»**— dimethyl-5-phenyloxazolidine • • • • • 16 k. Preparation of erythro-2-p-cyanophenyl- 3*^-dimethyl-5-phenyloxazolidine ..... 18 5. Preparation of erythro-2-p-dimethylaminophenyl-3)^-dimethyl-5-phenyloxazolidine • 19 6. Preparation of erythro-2-p-nitrophenyl- 3)^-dimethyl-5-phenyloxazolidine ..... 20 7. Preparation of erythro-2-p-hydroxyphenyl- 3i ^f-dimethyl-^-phenyloxazolidine • • • • • 21 8. Preparation of erythro-2-p-earboxyphenyl- 3)^-dimethyl-5-phenyloxazolidine ..... 22 9. Preparation of er^thro-2-p-chlorophenyl- 3(^-dimethyl-5-phenyloxazolidine . . . . • 23

Synthesis of threo-oxazoli dines ...... 2*t

1. Preparation of threo-2-p-chlorophenyl- 3)^-dimethyl-5-phenyloxazolidine ...... 26 lv CONTENTS— (Continued) Page

Infrared spectra ...... 27

Determination of the rate of acid-catalyzed decompo sition of diastereoisomeric oxazolidines ...... • • . 29

Materials and measurements ...... • . • . 29 Determination of hydrolytic products • • • 31 Assay determination . • ...... 33 Aqueous hydrolysis of 2,5-diphenyl-3»^-dimethyloxazolidine ...... 33 Determination of rate of acid hydrolysis of 2,5- diphenyl-3t^-dimethyloxazolidine ...... •••• 3& Effect of hydrogen-ion concentration on observed rate of hydrolysis of 2,5-diphenyl-3»^-dimethyloxazolidine ...... *tl Effect of p-substituent on rate of hydrolysis of 2-(p-substitutedphenyl)-3*i<—dimethyl-5-phenyloxazolidines ...... ••••••••••• ^3

Hydrolysis of erythro-2-p-methylphenyl-3«^- dimethyl-5-phenyloxazolidine ...... • • Mf

Determination of rate of change of specific rotation 51

DISCUSSION...... 51*

S y n t h e s i s ...... 3^

Kinetics ...... ••••••••• 5&

Effect of concentration on the observed rate of hydrolysis of 2,5-diphenyl- 3 ^ - dimethyloxazolidine 57 Effect of hydrogep-ion concentration on rate of hydrolysis of 2,5-diphenyl-3*^-dimethyloxazolidine 59 Correlation of the rate of hydrolysis of oxazolidines with the polar substituent constants 59

Effect of change in specific rotation 66

Mechanism ...... 67

SUMMARY ...... 70

APPENDIX...... ?2

BIBLIOGRAPHY...... 73

v TABLES Table Page

1 er^thro-2-(p-substitutedphenyl)-3i^— dimethyl-5- phenyloxazolidines ...... • ...... 7

2 threo-2-(p-substitutedphenyl)-3♦4-dimethyl-5- phenyloxazolidines ••••• ...... •••••• 8

3 Infrared spectrum of -O-C-N- system and pK& values of erythro-oxazolidines • •.•••••••••• 28

4 Infrared spectrum of -O-C-N-system and pK values of threo-oxazolidines ...... 29

5 The degradation of 2,5-diphenyl-3»4-dimethyloxazolidine in water at 23*0 and pH 6*33 • • • • 40

6 Observed rate constants for hydrolysis of 2,5- diphenyl -3 »4-dimethyloxazolidine varying con centration ...... 42

7 Observed rate constants for the hydrolysis of erythro-215-diphenyl-3.4-dimethyloxazolidine as a function of hydrogen-ion concentration at 25*0 . 44

8 Absorboncy of p-methylbenzaldehyde as a function of concentration ...... •• 46

9 Observed hydrolysis rates for erythro-oxazolidines in aqueous "buffer" at 25*0 and pH 2.03 • • • • • 50

10 Observed hydrolysis rates for threo-oxazolidines in aqueous "buffer" at 25.0° and pH 2 . 0 3 ...... '• 50

11 Values obtained for n the order of reaction calcu lated for varying concentrations...... « 58

12 Polar substituent constants and observed rate constants for the 2-(p-substitut*dphenyl)-3i4- dimethyl-5-phenyloxazolidines •••••••••• 6l

vi FIGURES Figure Page

1 Ultraviolet spectra of ephedrine, benzaldehyde, and 2t5-diphenyl-3,4-dimethyloxazolidine . • • • • 35

2 Change in absorbency of 2,5-diphenyl-3»4- dimethyloxazolidine as a function of t i n e ...... 36

3 A plot showing the linear relationship of log Aoo - A. vs. time for hydrolysis of 2,5-diphenyl- 3.4-dimithyloxazolidine 39

4 A plot showing application of Beer's Law to p-methylbenzaldehyde ...... 47

5 First-order plot for decomposition of 2-p-methylphenyl- 3.4-dimethyl-5-phenyloxazolidine ...... • • 49

6 A plot showing the first-order dependency of the change in specific rotation of 2t5-diphenyl-3»4- dimethyloxazolidine ...... 33

7 A plot showing the first-order dependency of the decomposition of 2,5-diph^nyl-3»4-dimethyloxazolidine on the hydrogen-ion concentration • • 60

8 A plot showing the linear relationship of log and

9 A plot showing the linear relationship of log Rq15S and 0 ~ values for threo-isomero ...... 63

vii STATEMENT OF PROBLEM

It is generally known that oxazolidines prepared from

N-substituted y^-aminoalcohols and carbonyl compounds are subject to hydrolysis in solution, and that this reaction is rapidly ac celerated by the presence of acids. A search of the literature, however, failed to reveal any systematic study of this hydrolysis or any correlation of the influence of either steric or chemical substituent effects upon the rate and extent of hydrolysis. The purpose of this investigation was to prepare a series of dlastereoisomeric oxazolidine derivatives through the condensation of ephedrine and its isomer pseudo-ephadrine with selected p-substituted benzaldehydes. Acidic hydrolysis under specific conditions was to be carried out on the diastereoisomers, and a correlation of the effects of structure and substituent upon the rates of hydrolysis was determined.

1 INTRODUCTION

The first reference to oxazolidines in the literature was the description by Knorr and Mathes (1) and Knorr and Roessler

(2) of the cyclic structure obtained by the reaction of ethanol- amine with aldehydes or ketones. Reaction (1)

(1)

R R

Their investigation did not take into account the possibility of the reaction of the components to yield the well-known Schiff bases. Reaction (2)

Not until the investigations of McCasland And Horswill (?) was the conclusion arrived at that Mno simple oxazolidine without a substituent on the N^ nitrogen atom of well-established structure and purity is known; however, when the oxazolidine nitrogen atom bears an alkyl group instead of hydrogen, rearrangement to Schiff base structure is precluded." The literature abounds with reports of condensation products of amino alcohols and oarbonyl functions

2 in which the products are entirely Schiff bases or mixtures of the cyclic structure and its tautomeric Schiff base (*t-22). The literature also contains reports of numerous investigations in which the reacting amino alcohol is of a secondary nature, thus precluding the possibility of any product other than the cyclic oxazolidine (*f, 6, 8, 10, 12-18, 23-27* 29* 30)* Bergmann (31) has compiled a comprehensive listing of the reported condensation reactions involving aldehydes and ketones and mono and dialkyl substituted amino alcohols.

Synthetic procedures utilized in the preparation of oxazolidines vary as widely as do the compounds reported* The original synthetic procedure of Knorr and co-workers (1, 2) in volved condensation of an amino alcohol and a carbonyl compound in boiling ether in the presence of solid potassium carbonate*

In some cases, however, aromatic carbonyl compounds were found to condense with amino alcohols to yield oxazolidines simply on com bination of reagents. Numerous reaction media and conditions have been proposed and verified for the condensation reactions.

Ethyl ether, reported by Zimkin and Bergmann (30* 32) and butyl ether reported by Meltsner et al. (20) have been successfully used as condensing solvents. Alcohol or alcohol ether mixtures as reported by Heinzelmann et al. (33)* Paquin (3*0* and Levin et al.

(35) are also useful solvents for the condensation reaction.

Water has been reported as a solvent for condensation reactions, especially those involving amino alcohols and formaldehyde (30).

The most common and useful solvent systems for reaction are those which yield an azeotropic mixture with the water formed in the condensation reaction. Benzene is the most widely utilized solvent for this purpose (10, 12, 13, 17-19* 28, 3 0, 3 2, 36, 37)*

Occasionally the use of toluene or xylene or mixtures of toluene, xylene and benzene have been recommended (30, 37)* Catalysis of the condensation reaction with traces of iodine (*+, 10, 30), or, in the case of azeotropic solvents, the addition of small amounts of acetic acid (4, 10, 3 0) has often proven useful, especially with more complex ketone compounds.

Oxazolidines have been formed as intermediates in several synthetic procedures. Pierce (37) utilized the condensation re action to form oxazolidines in his preparation of tris-(hydroxy- methyl) aminomethane derivatives. Engelhardt (36) prepared oxazolidines and Schiff bases as intermediates in the reductive alkylation of arylalkanolamines. Senkus (28) reacted Grignard reagents with oxazolidine intermediates to form new derivatives of amino polyhydric alcohols. Cope and Hancock (12, 13, l8) utilized the reactivity of aminoalcohols and carbonyl functions to form oxazolidines in their preparations of substituted amino alcohols and their ester derivatives. Attempts at preparing oxazolidines and their derivatives by the reduction of the cor responding oxazoles and oxazolines have proven quite unsatis factory because of the susceptibility of these compounds to re ductive fission. Fischer (38), in attempting to reduce 2,5- diphenyloxazole (I) with sodium and alcohol, obtained not the corresponding oxazolidine but rather the substituted amino 5 alcohol 2-benzylamino-l-phenyl-1-propanol (II)• Reaction (3)

- * o h ^ O ? H-CH2NHCH2 0 {3) H OH <3) i ix

Gabriel and Stelzner (39) obtained essentially the same results in their attempted reduction of 2-phenyloxazoline (III). They obtained N-benzylethanolamine (IV), Reaction (*0, rather than the expected oxazolidine.

■ > C^ C H 2NHCKj CHf N ' W 4h III IV

Schmidt (**0) prepared the unsubstituted oxazolidine

isomers'(V) and (VI) CHr'f-Nsc^y c H o t,^P ^ ,XrO1

H V VI

used in this study by condensing ephedrine and pseudo-ephedrine

(VII) and (VIII) with c h3 c h3 h- c- n h c h3 h—c —n h c h3 H-9-OH HO-9-H

o o VII VIII

benzaldehyde. He erroneously reported the products as "oxidative

decomposition products" and assigned to them the isomeric 6 structures of l,4-diphenyl-2-methylamino-4-hydroxybutene-l ,(IX)•

Stuart (4l), in 1930, described several non-oxidative decompo sition products obtained from the condensation of 1-ephedrine or dl-pseudo-ephedrine and a series of aliphatic and aromatic aldehydes, including benzaldehyde. His description of the products was "condensation products formed with the loss of one molecule of water." Stuart offered no proposal of structures for these com pounds but assigned values of melting points and optical rotations differing from those of the reactants, thereby precluding the structure proposed by Schmidt. The results of Davies (,2k) con firmed those of Stuart when he reported that ephedrine and benzaldehyde heated for a few seconds over a free flame and then for 15 minutes on the water-bath gave a compound, M.P. 73»5°» which is saturated, does not contain the -NH or -OH group, and exhibits the general properties of tetrahydrooxazoles. He as signed the structure of 2,5-diphenyl-3,4-dimethyltetrahydrooxazole

(V) to this compound. Pfanz and Kirchner (42) prepared the parent isomers of this investigation (V) and (VI) in their studies on the configuration in the ephedrine series.

The eighteen diastereoisomers used in this investigation were generally prepared by the azeotropic methods proposed by

Bergmann and co-workers (4, 10, 50). Deviations from the general procedure are described in detail in the experimental section of report. The prepared isomers, along with melting points, yields, and the results of analytical data are shown in Tables 1 and 2.

TABLE 1 erythro-2-(p-Substi tutedphenyl)-3.4-dimethyl- 5-phenyloxazolidines c h ^ m N-CH.

Analysis**

M.P.a Calcd. Found Yield X °C % CHN C H N

H 73.5 93.1 £ — — CH, 47.5 89.7 80.86 7.92 5.24 80.38 7.69 5.21 j Br 92.5 92.1 61.45 5*46 4.22 61.29 5.38 4.15 COOH 80.5 4-7.2 72.70 6.44 4.71 72.51 6.33 4.68 CN 114.5 87.6 77.66 6.52 10.07 78.16 6.48 9.78 n (c h 3 )2 89.5 85 .8 76.99 8.16 9.45 77.01 8 .3 0 9.40

OH 149.0 57.4 75.81 7.12 5.20 76.17 7.09 5.38 Cl 82.5 27.1 70.95 6.29 4.87 70.43 6.09 4.98 NO 2 104.5 8 5 .6 68.44 6.08 9.39 68.66 6.33 9.49

£ All melting points are uncorrected. ^Analysis by Alfred Bernhardt Microanalytical Laboratories, Mulheim Germany. °Compared with literature values (21, 4l, 42).

The science of chemical kinetics provides the best general method for suggesting the mechanism of reaction (**2). Although the susceptibility of oxazolidines to hydrolysis is well known, the literature reveals no systematic study, other them that of 8

TABLE 2 threo-2-(p-substitutedphenyl)-3,4-dlaethyl- 5-phenyloxazolidines

JL C H » v C ■ r' m

y y Analysis

Calcd. Found M.P.* Yield X °C % c H N C HN

H 65 97.3 8 0 .5 9 7.56 5.53 80.42 7.59 5.70 62 61.5 80.86 7.92 5.24 80.92 7.75 5.14 CH3 Br 69 4?.l 6 1 .4 5 5.46 4.22 61.36 5.44 4.17 COOH l89d 43.2 7 2 .7 0 6.44 4.71 72.50 6.39 4.89 CN 68 75.8 77.66 6.52 10.07 77.76 6.57 10.17 n(ch3 )2 99 83.4 76.99 8 .1 6 9.45 76.94 8.13. 9.61 OH 217d 49.3 75.81 7.12 5.20 75.56 6.97 5.41 Cl 82 41*8. 70.95 6.29 4.87 70.83 6*31 4.93 N02 63 63.7 68.44 6 .0 8 9.39 68.32 6.03 9 .6 0

All melting points are uncorrected* Alf red Bern hard t Mi croa nal ytic al L abor atori es,Analysis by Alfred Bernhardt Microanalytical Laboratories,Analysis Mulheim Germany*

Pfanz (42), into the effects of structure, or substituents, upon

the kinetics of hydrolysis* Hess and Corleis (MO noted, in the

formation of picrate derivatives of oxazolidines, that in a number of cases even recrystallization from alcohol caused hydrolysis and

formation of the picrates of the corresponding amino-alcohols*

p Hancock and Cope (18) took advantage of the ease of hydrolysis of oxazolidines in preparing N-alkyl derivatives of aminoaloohols• Bergmann (4) took note of hydrolysis of ethanol&mine derivatives of cyclopentanone by water and utilized the ease of hydrolysis for nitrogen analysis (3 2).

The variation in reactivity within a class of chemical compounds indicates that the effect of structure on the free energy of activation is a net result of the contributions of polar, resonance, and steric effects. These effects will combine in an additive manner to determine the free energy of activation. This makes possible assignment of numerical values (sigma constants) to groups, relating their effects on reaction rates and equilibria

(45). Hammett (46), investigating the ionization constants and rates of ester-hydrolysie of corresponding meta- and para- substituted benzoic acids, determined the existence of this simple quantitative .relationship. He determined, from his observations and those of Burkhardt (4?), and Burkhardt, Ford, and Singleton

(48) an existing corollary of an equation of linear logarithmic relationship between equilibrium and rate constants. Effects of substituents in meta- or para-positions of benzene on the rate or equilibria of a reaction involving a side chain can be represented by the formula: p Bi RTlnK + ETlnK - £ F = A/d (-= + B2) Eq. (1)

A F « Free energy change d s Distance from substituent to reaction center D *» Dielectric constant of reaction medium A,B^,B2 - Constants dependent upon temperature, and solvent.

Hammett experimentally determined that A is a constant depending only on the substituent, and that B^ and are dependent only 10 upon the specific reaction under investigation. Substitution of

these constants in equation 1 and rearrangement gives:

log K = log K° + p

CT * -A/2.303R Eq. (2)

Within a reaction series of the meta- and para-substituted side-

chain derivatives of benzene characterized by the absence of

neighboring group participation, and by no change iir the reaction

mechanism within a reaction series, the effect of structure on

rates and equilibria is nearly always determined by a single basic

factor: the polar effect of the substituent. Substituents of this

nature are held rigidly at such a distance from the reaction center

that no change in steric interactions can occur between the re

actants and the product. The substituents produce only free-

energy changes resulting from inductive, resonance, or a kinetic-

energy effect or combinations thereof. This results in the state

ment of the relationship of the effect of substituents on rates

or equilibria: the Hammett equation: (48)

log k/k° = p 0 ~ Eq. (3)

The substituent constant, (j— , is by definition determined by the

nature of the substituent and independent of the reaction. It

is a quantitative measure of the polar effect in any reaction of

a given meta- or para-substituent relative to a hydrogen atom. A

proportionality or reaction constant, p , is by the nature of the

linear relationship a constant for all substituents, dependent

only on the reaction series. A positive 0**value for a substituent 11

Indicates that the substituent is a stronger electron attractor than hydrogen. Substituents with negative

The purpose of this study was to prepare and determine the rates of acid-catalyzed decomposition of a number of 2-(p- substituted phenyl)-3,^-dimethyl-5-phenyloxazolidines and to correlate these rates with the Hammett polar constants of the p-substltuents. This quantitative correlation would be useful in several respects. The existence of the correlation would indicate a consistency in the reaction mechanism. The differences in rates between the isomeric groups of compounds would be an indication of the effects caused by the differences in steric factors between molecules. The reaction constants, if analogous to the reaction constants of other ring cleavage reactions, would lead to an indication of the mechanism involved. The rates of decomposition of oxazolidines not included in this series could be estimated from their substituent constants.

A rate expression for the decomposition of the oxazolidines must account for all the species that would be present in solution.

The rate equation for the reaction may be given by

ko (B)+ko (BH+ )+kH q +CHj O^XB)*!^ Q+ (H30+ )CBH+)

+kQH-< OH” )(BH+ )+kQH-(OH” )(B) Eq. W

The substituted oxazolidines studied have pK values ranging from 9l 7.73 to 3.97 - 0.1. In acidic aqueous solution they would exist mainly in the form of their conjugate acids, and the contribution of terms 1, 3» 5» and 6 can be neglected. The rate can then be given by

At a constant hydrogen-ion concentration at pH of 2.0 the rate expression reduces to

Eq. (6) a r - k '

If the effects of free oxazolidine (B) cannot be neglected, a plot of the observed rate constants vs. hydrogen-ion concen tration will not be linear. Corrections for the contribution of 13 the free base could be made by considering * the degree of ionization of the base* Thus the rate expression can be modified to be

-dB * k* (Bt ) Eq. (7)

w h e r e * ' "^Tcoh-J Eq- <8> It is apparent from equations 6 and 7 that at pH values below

2.0, k', the specific rate constant for the protonated base, will be equal to k0ê * °^served rate constant* However, at pH values above 2*0 k* = ôbsînvestigation tne pH of the hydrolytic medium was maintained at 2*0, and the ionic strength constant at 0.1. If the decomposition of the oxazolidines is first-order, integration of equation 6 results in

logc = logc - k obs ^ Eq. (9) ° 2*303 and a plot of log c vs. t should be a straight line with a slope -k ^ equal to -■ Rates were measured at constant pH and ionic c. *pt)^ strength and the effects of the substituents in the para position of the 2-phenyl group determined. The substituents of the 2-phenyl

group were chosen with regard to commercial availability and well- known 0"" values. EXPERIMENTAL

I Synthesis of Diastereoisomers of 2-(p-substituted)- phenyl-31^-dimethyl-5-phenyloxazolidine

Reagents

The ephedrine used in this investigation was Ephedrine

Alkaloid N.F. anhydrous obtained from Penick Company, New York.

The pseudo-ephedrine was obtained from L. Light and Company,

Colnbrook, England, as the hydrochloride salt. The free base was prepared by treating an aqueous solution of the salt with ammonia.

The precipitated base was filtered and recrystallized from ethyl ether. Benzaldehyde N.F. was obtained from the J. T. Baker

Company and purified by vacuum distillation under nitrogen. The constant boiling fraction collected was divided into about five- milliliter portions and stored in ten-milliliter Neutraglass ampoules at ambient temperature. The para-substituted benzaldehydes, p-cyanobenzaldehyde, p-bromobenzaldehyde, p-carboxybenzaldehyde, and p-tolualdehyde, were obtained from the Aldrich

Chemical Company, Milwaukee, Wisconsin, and were used without further purification. p-Dimethylaminobenzaldehyde, p-hydroxybenzaldehyde, p-nitrobenzaldehyde, and p-chlorobenzaldehyde were obtained from Eastman Organic Chemicals, Distillation Products

Industries, Rochester, New York, and were of reagent grade and used as such, with the exception of p-chlorobenzaldehyde (practical) which was purified by sublimation. Ik Solvents used for this investigation were obtained from

the Laboratory Supply Stores of The Ohio State University and were reagent grade and were not further purified with the exception of

reagent grade methyl alcohol which was made anhydrous by the method described by Vogel (52), and stored under anhydrous

conditions. The hydrochloric acid and potassium chloride solutions used as Clark and Luba "buffer" solutions were obtained from The

Ohio State University Reagent Laboratories. The A.G. iodine

catalyst used in some synthetic procedures was obtained from the

Allied Chemical and Dye Company, New York.

Synthesis of erythro-Oxazolidines

Preparation of erythro-2,5-diphenyl-3t**-dimethyloxazolidine.

1-Ephedrine base 16*5 G°>. (0.1M) and 10.6 Gm. (0.1M) of redistilled

benzaldehyde were placed in a 250 ml. round bottom flask. Benzene

(175 ml.), was added and the flask equipped for reflux with a

water separator attached. The mixture was refluxed for 2k hrs.

Droplets of water appeared at the beginning of the distillation

and continued for several hours. Approximately 1.7 ml. of water

was collected. The flask was equipped for distillation and 150 ml.

of benzene was removed. The remainder of the benzene was removed

under a nitrogen stream. The resulting solid mass was dissolved

in a minimum amount of hot 80# ethyl alcohol. The solution was

treated with charcoal and filtered. Water was added dropwise to

the cloud point and the solution was placed in a refrigerator to

crystallize. After three days no apparent increase in crystal

formation was evident. The precipitate was filtered and washed 16 with cold 80% ethyl alcohol, followed by cold water. The product was dried in a vacuum oven over phosphorous pentoxide at a tem perature of 45°C for 48 hrs. M.P. 73*6; Yield 93*1#>

Preparation of erythro-2-p-methylphenyl-3.4-dimethyl-3- phenyloxazolidine.— p-Tolualdehyde 5 Gm. (0.04M) and 6.6 Gm.

(0.04m ) of ^-ephedrine were combined in a 250-ml. round bottom

flask and 200 ml. of benzene added. The flask was equipped with

a reflux condenser and a water separator. Refluxing the solution

for a period of 8 hrs. yielded approximately 0.6 ml. of water.

The benzene was distilled, leaving a yellowish viscous oil. Hot

absolute ethyl alcohol was added to dissolve the oil. The hot

solution was treated with charcoal, filtered and cooled. This

resulted in the formation of crystals which were filtered by using

suction, washed with cold absolute ethanol and then with cold dis

tilled water. The crystals were dried in a vacuum desiccator.

Recrystalization was effected from absolute ethyl alcohol. The

alcohol solution was treated with charcoal; filtered and distilled

water was added to the cloud point. The water alcohol solution

was cooled and the precipitate filtered with suction. The product

was dried in a vacuum desiccator for 8 hrs. M.P. 47.3; Yield 89.7%.

Preparation of erythro-2-p-bromophenyl-3.4-dimethyl-5-phenyl-

oxazolidine.— p-Bromobenzaldehyde 5.0 Gm. (0.03M) and 4.7 Gm.

(0.03M) of 1-ephedrine were dissolved in 173 ml. of benzene in a

250-ml* round bottom flask. The flask was equipped with a reflux

condenser and water separator. The solution was refluxed for 24

hrs. No water separated. A few crystals of iodine were added to the reaction mixture and refluxing again carried out for a period of 2k hrs. Droplets of water appeared rt the beginning of reflux and continued until approximately 0*4 ml. of water had distilled.

The benzene was removed by distillation and the resulting yellow- white solid dried in a vacuum desiccator. The product was dis solved in a minimum amount of hot absolute ethyl alcohol. The alcohol solution was treated with charcoal, filtered and water was added to the cloud point. The solution was placed in a refrigerator. No crystallization had occurred after one week.

The solution was warmed on a steam bath and distilled water added until the entire solution was cloudy. Hot absolute ethyl alcohol was added drop wise to the warm solution until the solution became clear. The solution was cooled in an ice bath and placed in the freezer section of a refrigerator. No precipitate had formed after two days. The side of the flask was scratched with a soft glass rod, causing crystals to form. The flask was allowed to remain in the freezer for a period of one week. The precipitate was filtered with suction and dried in a vacuum oven over phos phorous pentoxide for 2k hrs. at 40°C. The crystals were dissolved in hot absolute methyl alcohol. The solution was treated with charcoal and filtered. The solution was cooled in an acetone dry- ice bath while the sides of the flask were scratched with a soft glass rod. Crystals formed and the flask was placed in a refriger ator for 10 hrs. The crystals were filtered and washed with cold methyl alcohol, followed by cold distilled water. The product was 18 dried in a vacuum oven at 40°C over phosphorous pentoxlde for 24 hrs. M.P. 92.5°; Yield 92.1%.

Preparation of erythro-2-p-cyanophenyl-3.4-dimethyl-5- phenyloxazoIidine.--p-Cyanobenzaldehyde 5«0 Gm. (0.04m ) and 1- ephedrine 6.3 Gm. (0.04m ), were dissolved in 175 ®1» of toluene in a 250-ml. round bottom flask. A few crystals of iodine were added and the flask equipped with a reflux condenser and water separator. The solution was refluxed for 6 hrs. Approximately

0.6 ml. of water was collected. Approximately 140 ml. of toluene was removed by distillation and the remaining solution cooled in an ice-bath. . Crystallization of the product occurred immediately.

The crystals were filtered with suction, washed with cold toluene and dried in a vacuum desiccator for 24 hrs. The product was dis solved in hot absolute ethyl alcohol, the solution was treated with charcoal, filtered and placed in the cold to crystallize.

No crystallization occurred after a period of four days. The solution was warmed on a steam bath to boiling and distilled water added to the cloud point. The solution was allowed to reach ambient temperature, and placed in a refrigerator. No crystals were evident by the third day. The alcohol-water solvent was

distilled under reduced pressure leaving a viscous clear liquid.

The liquid was dissolved in toluene and placed in a round bottom

flask equipped with a reflux condenser and water separator. The solution was refluxed for 24 hrs. Less than 0.1 ml. of water dis

tilled and separated. The toluene was removed on a rotary film

evaporator under reduced pressure. The viscous liquid that 19 remained was cooled in an acetone dry-ice bath* Precipitation of the product occurred. The precipitate was filtered and washed with cold absolute ethyl alcohol then with cold distilled water.

The product was dried in a vacuum oven at 4o°C for 24 hrs* M.P.

114.5°; Yield 87.6%.

Preparation of erythro-2-p-dimethylaminophenyl-314- dime thyl-5-phenyloxazolidine.— p-Dimethylaminobenzaldehyde 7*5 Go*

(0.05M) and 1-ephedrine 8 .2 5 Gm. (0.05M) were combined in a 500-ml. round bottom flask. Toluene, 400 ml., was .added and the flask equipped with a reflux condenser and water separator. A crystal of iodine was added and the solution refluxed for 24 hrs. Ap proximately 0.8 ml. of water had distilled. Three hundred milli liters of toluene was distilled under reduced pressure and one hundred milliliters of absolute ethyl alcohol were added. Dis tillation was continued, 100 ml. fractions of distillate being collected at which time 100 ml. of absolute ethyl alcohol was added. This was continued until 500 ml. of alcohol had been added.

The solution was distilled so that approximately 125 ®1* of solvent remained. Charcoal was added and the solution filtered and allowed to cool. Crystallization began at once and the solution, after being cooled to ambient temperature, was placed in an ice-bath.

This resulted in further crystallization. The crystals were filtered with suction and washed with ice-cold alcohol and then cold distilled water. The resulting product was dried in a vacuum oven at 40°C for 24 hrs. M.P. 89*5°i H e l d 85*5#* 20

Preparation of erythro-2-nitrophenyl-3i4-dimethyl-5- phenyloxazolidine.— p-Nitrobenzaldehyde 15*1 Gm. (0.1M) and 1- ephedrine 16.5 Gm. (0.1M) were dissolved in 4-00 ml. of benzene in a 500-ml. round bottom flask. The flask was equipped with a reflux condenser and water separator. A crystal of iodine was added and the solution refluxed for 48 hrs. Approximately 1.5 ml. of water was collected. Three hundred milliliters of the benzene was dis tilled. The solution was allowed to cool which resulted in the formation of yellow crystals. The residual benzene was evaporated under a stream of nitrogen. The crystals were dissolved in hot absolute ethyl alcohol. The hot solution was treated with char coal, filtered and cooled. Crystallization had not occurred after

48 hrs. The alcoholic solution was warmed on a steam bath to boiling. Water was added dropwise to the cloud point. The solution was allowed to cool to room temperature and placed in a refriger ator. After two days no crystals had formed. The alcohol water

solvent was removed by vacuum distillation. The remaining liquid

residue was dissolved in 150 ml. of toluene in a 250-ml. round

bottom flask equipped with a reflux condenser and a water separator.

The solution was refluxed for 24 hrs. with no apparent production

of water. A crystal of iodine and 10 ml. of absolute ethyl alcohol

were added to the solution. Refluxing was continued for 24 hrs.

collecting approximately 0.04 ml. of water. The toluene was re

moved on a rotary film evaporator under vacuum. Hot absolute methyl

alcohol was added to the viscous liquid residue. The alcohol

solution was decolorized with charcoal, filtered and allowed to 21 reach ambient temperature* The solution was placed in an acetone dry-ice bath for three hours. Crystals formed in the cold and were filtered, washed with cold absolute methyl alcohol and then with cold distilled water* The white crystals were dried in a vacuum oven at 40°C for a period of 8 hrs* M.P. 104*5°; Yield

85.6%.

Preparation of erythro-2-p-hydroxyphenyl-3.4-dimethyl-5- phenyloxazolidine.— p-Hydroxybenzaldehyde 6 Gm. (0.05M) and 1- ephedrine 8*3 (hit. (0.05M) were dissolved in 200 ml* of benzene in a 250-ml. round bottom flask. A few crystals of iodine were added to the solution and the flask equipped with a reflux condenser and water separator* The resulting red solution was refluxed for a period of 24 hrs. No water had distilled at this time* About

20 ml* of absolute ethyl alcohol was added to the benzene solution*

Water droplets appeared immediately in the distillate and continued to distill until approximately 0*5 ml. of water had been collected*

Charcoal was added to decolorize the solution which had become faintly yellow* The solution was filtered and the benzene dis tilled. The remaining viscous liquid solidified upon cooling. The solid mass was broken, and dissolved in hot absolute methyl alcohol*

The hot solution was filtered and allowed to cool to room temper ature and was then placed in the refrigerator* Crystals formed over an 8 hr. period. The crystals were filtered, washed with cold absolute methyl alcohol and then by cold distilled water. The product was dried in a vacuum oven at 45° for 24 hrs* M.P* 149°;

Yield 57.4%* 22

Preparation of erythro-2-p-carboxyphenyl-3.*+-dimethyl-5- phenyloxazolidine.— p-Carboxybenzaldehyde 5*0 Gm, (0.03M) and 5*5

Gm. (0.03M) of 1-ephedrine were dissolved in **-00 ml. of toluene in a $00-ml. round bottom flask* The flask was equipped with a reflux condenser and water separator* The solution was refluxed

for JfS hrs* Approximately 0*3 ml* of water had distilled. The

toluene was removed on a rotary film evaporator under reduced pressure leaving a slightly yellow viscous liquid. The viscous liquid was dissolved in hot absolute methyl alcohol* The solution was decolorized with charcoal, filtered and allowed to stand at

room temperature. No crystallization occurred and the solution

was placed in the cold for a period of two days with occasional

scratching of the flask. No crystals had developed by the end of

this period. The solution was warmed on a steam bath and water

added to the cloud point. Recooling the solution produced no

crystals. The solution was placed in a refrigerator for one week*

No crystals had formed at the end of this period. The solvent was

removed by vacuum distillation and the resulting clear viscous

liquid cooled in an acetone dry-ice bath* A solid clear mass

formed which reliquified upon reaching ambient temperature. The

viscous liquid was dissolved in benzene in a 250-ml. round bottom

flask. The flask was equipped for reflux and water separation*

No detectable amount of water distilled. The benzene solution was

passed through a 30x 1 .5 cm. neutral alumina column prepared by

the slurry method using Woelm neutral alumina activity grade I and

benzene. The eluate was placed in a 250-ml. round bottom flask and the solvent removed under vacuum on a rotary film evaporator.

The remaining viscous liquid was dissolved in hot absolute methyl alcohol and transferred to a 2 5 0-ml. Erlenmeyer flask. The flask was immediately placed in an acetone dry-ice bath and the side vigorously scratched with a soft glass rod. Crystals formed almost immediately. The crystals were filtered and washed with absolute methyl alcohol and then with a 50# methyl alcohol-water solution. The crystals were dried in a vacuum desiccator over phosphorous pentoxide for 12 hrs. Recrystallization was effected with hot absolute methyl alcohol. Crystallization was forced by immersing the flask containing the hot alcohol solution into an acetone dry-ice bath, and seeding the mixture with a few crystals of the compound obtained previously. The product was dried in a vacuum oven at 40CC for 2k hrs. M.P. 80*5°; Yield 47.2%.

Preparation of erythro-2-p-chlorophenyl-3«*<— dimethyl-5- phenyloxazolidine.— p-Chlorobenzaldehyde 5 Gnu (0.035M) and 5*8

Gm. (0.035M) of 1-ephedrine were dissolved in 200 ml. of benzene in a 250-ml. round bottom flask. The flask was equipped for re

flux and water separation. The solution was refluxed for 2k hrs. which resulted in the distillation of approximately 0.l8 ml. of water. The benzene was removed under reduced pressure and the remaining viscous liquid dissolved in hot absolute methyl alcohol.

Treatment of the solution with charcoal followed by filtration and cooling did not produce crystallization. The solution was heated to boiling on a steam bath and warm distilled water added with constant stirring until the entire solution acquired a cloudy appearance* The solution was cooled by placing in a refrigerator*

After 48 hrs. only the presence of a small amount of viscous oil had appeared. The solution was cooled in an ice-bath and 50 ml. of water added. After standing in the cold for 4 hrs. a viscous liquid had separated. The liquid was withdrawn and dissolved in benzene in a 1 0 0 ml. round bottom flask equipped for reflux and water separation, and refluxed for 8 hrs. No water appeared*

Absolute ethyl alcohol, 20 ml. and a crystal of iodine were added to the refluxing solution and refluxing continued for 8 hrs* The separated water benzene solution had a cloudy appearance but no measurable amount of water. The benzene was removed under reduced pressure with a rotary film evaporator. The remaining viscous liquid was dissolved in hot absolute ethyl alcohol, decolorized with charcoal and filtered. The hot alcohol solution was placed immediately in an acetone dry-ice bath and the Sides of the flask scratched to induce crystallization. Crystals formed immediately and were separated by suction filtration, washed with cold absolute ethyl alcohol, 50# ethyl alcohol water, and finally cold distilled water. The crystals were dried in a vacuum oven at 40°C over phosphorous pentoxide for 24 hrs. M.P. 82.5°; Yield 27*1%.

Synthesis of threo-Oxazolidines

Preparation of the threo isomers of the 2-p-(substitutedphenyl)-5-phenyl-3|4-dimethyloxazolidinee, with the exception of

2-p-chlorophenyl-5-phenyl-3•4-dimethyloxazolidine, was accomplished in generally the same manner as that used for the preparation of the corresponding erythro isomers. The reagents were combined in 25 benzene, toluene, or benzene-toluene mixtures and refluxed In a flask equipped with a water separator for a minimum period of 8 hrs* or until the volume of water distilled remained unchanged*

The solvent was removed under reduced pressure with the aid of a rotary film evaporator* The resulting residues were dissolved in hot methyl or ethyl alcohol. The hot alcohol solution was treated with charcoal, filtered and allowed to cool in a refrigerator*

Crystallization occurred in every case within one week* The crystals were filtered with suction and washed with cold solvent and then by cold distilled water* Recrystallization was effected using hot methyl alcohol* The hot solution was treated with charcoal, filtered and water added to the cloud point. The alcoholic solutions were then cooled in a refrigerator for maximum crystal lization. The crystals filtered and washed with cold absolute methyl alcohol, 5096 methyl alcohol-water, and cold distilled water*

The products were dried in a vacuum oven over phosphorous pentoxide at **0°C for 2k hrs. The following products were obtained: threo-

2,5-diphenyl-3,**— dimethyloxazolidine, M.P. 65*0, Yield 93*796; threo-2-p-cyanophenyl-5“phenyl-3,4-dimethyloxazolidine, M.P. 6 8,

Yield 75*896; threo-2-p-dimethylaminophenyl-5-phenyl-3,Jf-dimethyloxazolidine, M.P. 99t Yield 83«**96; threo-2-p-hydroxyphenyl-5- phenyl-3, dimethyloxazolidine, M.P. 217°d, Yieid *19*396; threo-2- p-nitrophenyl-5-phenyl-3,^-dimethyloxazolidine, M.P. 63°c, Yield

6 3*796} threo-2-p-carboxyphenyl-5-phenyl-3.**-dimethyloxazolidine.

M.P. l89*5°d, Yield **3*296; threo-2-p-bromophenyl-5-phenyl-3.*f- 26 dimethyloxazolidine, M.P. 69°» Yield 47.1#; and threo-2-p-methylphenyl-5-phenyl-3,4- dimethyloxazolidine, M.P. 62°, Yield 61.59&.

Preparation of threo-2-p-chlorophenyl-3«4-dimethyl-5- phenyloxazolidine.— p-Chlorobenzaldehyde 14.7 Gm. (0.1M) and 16*5

Gm. (0.1M) of dl-pseudoephedrine base were dissolved in 400 ml. of benzene in a 500-ml. round bottom flask. The flask was equipped for reflux and water separation. A crystal of iodine and 15 ml. of absolute ethyl alcohol were added. The solution was refluxed for 24 hrs. Droplets of water appeared in the distillate and continued to distill until a total volume of 1 .2 ml. had separated.

The solvent was removed by distillation under reduced pressure.

The remaining yellow viscous liquid had the characteristic odor of p-chlorobenzaldehyde. Attempts to crystallize the liquid from ethyl alcohol, methyl alcohol, and water mixtures of these solvents was unsuccessful. The viscous liquid was redissolved in 200 ml. of benzene and refluxed with water separation which resulted in the separation of approximately 0.0? ml* of water. The benzene was evaporated under reduced pressure with the exclusion of any atmospheric moisture. The resulting liquid was subjected to vacuum distillation under reduced pressure in an atmosphere of nitrogen.

A constant boiling fraction (179°/1.7 mm) was collected. Infrared spectra of this fraction indicated the lack of either a carbonyl or hydroxyl function. The liquid was dissolved in hot absolute methyl alcohol in an Erlenmeyer flask and Immediately placed in an acetone dry-ice bath. Scratching of the flask with a soft glass rod resulted in crystallization. The crystals were filtered and 27 washed with cold absolute methyl alcohol. The product was dried in a vacuum desiccator for 8 hrs. The crystals were dissolved in hot absolute methyl alcohol and the solution treated with charcoal, filtered and immediately cooled in an acetone dry-ice bath with constant scratching of the flask. Seeding of the mixture was necessary to induce crystallization. The product was filtered, washed with cold 50% methyl alcohol-water and then with cold water.

The product was dried in a vacuum oven at kO°C for 2k hrs. M.P.

82°, Yield *H.8 #.

All oxazolidines were stored in one-ounce amber dry-square bottles over calcium chloride in a vacuum desiccator.

Infrared spectra

The infrared spectra of the dlastereoisomeric oxazolidines prepared for this investigation were obtained in the following manner. Samples of the dry recrystallized oxazolidine were thoroughly mixed with anhydrous potassium bromide in a mortar in a qualitative manner. Sufficient mixture was placed in the 2 x

0 .5 cm. opening of a 2 .5 x 3*5 cm. piece of white blotter paper to yield after compression in a KBr press a clear film. The blotter was placed in the round sodium chloride cell holder of a

Perkin-Elmer Infrared Spectrophotometer and the spectrum of the sample determined on a Perkin-Elmer Model 237 Spectrophotometer at a fast scanning speed. The contribution of the various isomers to the wavelength of absorption of the characteristic oxazolidine

0-C-N- system (31) ere listed in Tables 3 end k • Also included 28 in these tables are the observed pK values (5 3) of the diastereo- & isomeric oxazolidines.

TABLE 3 Infrared Spectrum of -O-C-N System and pK Values of erythro-Oxazolidines

Substituent Wavelength Cm“^

H 1 1 7 0, 1137 6 .1 0 1115 CH, 1 1 9 0, 1162 6 .1 6 3 1108 Br 1 1 9 2, 1161 5 .2 8 1125 VD COOH 1 1 6 0, 1145 1122 CN 1 1 8 3, 1132 4.66 1105 N(CH_)_ II8 5 , 1165 7.73 p £- 1130 OH 1 1 9 2, 1160 6 .1 8 1105 Cl 1190, 1160 5.4l 1125 NO- 1 1 8 5, 1132 4.55 1102

Acknowledgment is made to Mr. Sobhi Soilman and Dr. David E. Guttman for the determination of these constants. Not available. TABLE 4 Infrared Spectrum of -O-C-N- System and pK Values of threo-Oxazolldines

Substituent Wavelength Cm"*^ PC

H 1195. 1140 5.1 3 1120 CH 1 2 0 0, 1 1 3 8 5 .2 8 7 1120 Br 1185, 1156 4 .45 1118 COOB 1 1 6 0, 1 1 2 0 4*26 1100 CN 1192, 1135 4 .0 0 1107 N(CH,)p 1190, 1165 6 .8 5 3 * ■ 1118 OH 1 1 6 5, n 4 o 5 .2 8 1117 wD Cl 1 1 9 0, 1140 1123 NO. 1 1 8 8, 1140 3 .7 9 1107 A Acknowledgment is made to Mr. Sobhi Soliman and Dr* David E. Guttman for the determination of these constants* ^Not available*

II Determination of the Rate of Acid Catalyzed Decomposition of Diastereoisomeric Oxazolidines

Materials and measurements

Compounds subjected to acid catalyzed degradation were those prepared as described in the synthetic procedure* They were repurified before use by recrystallization or microvacuum distil lation* The "buffer" solutions used to vary and maintain the hydrogen-ion concentrations of the kinetic solutions were composed of 0.5001N HC1 and 0*5007 N KC1* Both solutions were prepared by 30

-The Ohio State University Reagent Laboratory. These solutions

function as buffers by virtue of the fact that the high concen

tration of the hydrogen-ion is only slightly affected by moderate

additions of either acid or base* The potassium chloride serves

to maintain a constant ionic strength in the solutions* The range

of concentrations of "buffer" and oxazolidine used are such that

all activities may be assumed to be equivalent to concentration*

The methyl alcohol used for dissolving the oxazolidines was made

anhydrous as previously described* All aqueous or "buffer"

solutions were maintained at a constant temperature of 25*0 -

0.0 5° by means of a circulating constant temperature water bath*

pH values of all solutions used were determined at the temperature

of investigation. A Beckman Model GS pH meter using the B scale

was used for all measurements. A Beckman "general purpose" glass

electrode and a sleeve type calomel reference electrode were used

for all measurements* The pH meter was standardized both before

and after pH measurements with Beckman Buffer No* H+OVf pH 4*0*

The pH was calculated at 25° according to the formula

«■ 0*200(r. - r ) pH . pli o s 59.15

pHg = pH of sample, pH^ =t pH of buffer, r^ « Duodial reading in

buffer, r ■ Duodial reading in sample* The pH value of a test 6 solution for each kinetic determination was also measured at 2 5*0°

before and after each run to determine whether the pH remained

constant* In all instances the two comparative measurements agreed

within experimental error* Preliminary absorbency measurements 31 were determined using either Perkin Elmer Model 4000 or Cary Model

15 Recording Spectrophotometer* Absorbency measurements for the actual kinetic determinations were obtained using a Beckman Model

Du Spectrophotometer equipped with a photomultiplier attachment and a thermostated cell compartment* The temperature of the cell compartment was maintained at 25*0 - 0*05° with a Labline circu lating constant temperature bath*

Determination of hydrolytic products

A solution of approximate pH of 2*0 was prepared by com bining concentrated hydrochloric acid and distilled water*' The pH was determined with pHydrion paper A. Approximately 10 Gm. of

2 ,5-diphenyl-3»4-dimethyloxazolidine was combined with 100 ml. of the acid and placed in a 250-ml. round bot'tom flask* The flask was equipped with a reflux condenser and magnetic stirring bar*

The solution was stirred for 24- hrs. The solution was extracted with five 100 ml. portions of anhydrous ethyl ether. The ether extracts were combined in a one-liter Erlenmeyer flask and satu rated with anhydrous hydrogen chloride gas. The ether solution was transferred to a one-liter separatory funnel and extracted with five 100 ml. portions of distilled water. The water washings were discarded. The ether solution was then extracted with a saturated solution of potassium acid carbonate until the ether was neutral to pHydrion paper. The ether was concentrated to a volume of approximately 50 ml. with the aid of a rotary film evaporator*

Anhydrous sodium sulfate was added and the solution dried for 24 hrs. The ether was filtered into a 100-ml* round bottom flask and evaporated on a rotary film evaporator. The oily liquid remaining had the characteristic odor of benzaldehyde. The refractive index of the liquid was determined and found to be 1.5448. Literature values for benzaldehyde vary from 1.5440 to 1*5465* The infrared spectrum of the liquid was determined in chloroform. The char acteristic aromatic carbonyl absorption at 1700 cm ^ was observed along with the characteristic absorptions for the aromatic nucleus.

A 2,4-dinitrophenylhydrazine derivative was prepared as described in the literature (54), M.P. 237°. This corresponds to the melting point of the 2,4-ENPH derivative of benzaldehyde.

The remaining acidic aqueous portion of the hydrolyzed oxazolidine was made basic to a pH of 12 (pHydrion paper) with a saturated solution of sodium hydroxide. The solution was extracted * with ether in a liquid-liquid extractor for 24 hrs. The ether was separated in a separatory funnel and the volume reduced to 100 ml.

The ether was dried over anhydrous sodium sulfate for 8 hrs. e Anhydrous hydrogen chloride gas was passed through the ether solution. A white gummy precipitate was formed. The precipitate was filtered, washed with anhydrous ethyl ether and dried in a vacuum desiccator for 8 hrs. The precipitate was dissolved in a minimum amount of hot 95% ethyl alcohol. Charcoal was added and the solution filtered into a 250-ml. beaker. The beaker was heated on a steam bath to boil the alcohol. Portions of anhydrous reagent grade benzene were added to the boiling alcohol solution. A stream of anhydrous nitrogen was passed over the top of the beaker. After addition of approximately 100 ml. of benzene crystals began to 33 appear at the bottom of the beaker. The volume of the solution was reduced to about 50 ml. and the beaker placed in a refriger ator. Crystallization appeared complete after 8 hrs. The crystals were filtered with suction, washed with cold benzene and dried in a vacuum desiccator containing phosphorous pentoxide. The M.P.

218° and infrared spectrum corresponded to that for ephedrine hydrochloride (55)•

Assay determination

The determination of reaction rates by conventional methods reduces to a study of concentrations as a function of time. In

general analytical procedures are divided into two categories,

chemical and physical. Chemical analysis implies a direct deter mination of one of the reactants or products. Preliminary 'experi ments for the use of various chemical or combined chemical/physical methods of analysis were considered. Differential titration of

the two basic components, the unhydrolyzedr oxazolidine and

ephedrine, as a function of time was considered. Nonaqueous ti

tration with perchloric acid in dioxane of a mixture of these com

pounds indicated an insufficient base strength differential for

convenient analysis. Problems were also foreseen in the assay if

rates were to be determined in an aqueous medium. The formation

of a classical derivative of the aldehyde formed followed by

spectral measurement was considered. Problems were foreseen with

this type of analysis because many of the major derivatives of

aldehydes suitable for preparation require restrictive conditions

for formation. Application of chemical or physical chemical 3** methods of assay seemed to exemplify the classical restriction imposed upon this type of assay procedure. The assay must be rapid compared to the reaction under investigation, or some process must be developed for stopping or freezing the reaction. Indi cation that the method of vapor phase chromatography might be applicable to assay was determined from the report of Brochmann-

Hanssen (5 6)* Difficulties encountered in column selection and component separation observed in preliminary experiments led to the conclusion that variability control of this procedure was in sufficient for reproducible quantitative measurements.

Physical methods of analysis are usually more convenient and often times restrict or reduce entirely the introduction of unnecessary errors. Preliminary experiments and previous infor mation from the literature of the spectral characteristics of the reactants and products indicated the possibility of the use of a spectrophotometric method of analysis. Ultraviolet spectral de terminations on the reactants and products indicated a sufficient difference existed in the molar absorptivities. Figure 1 il lustrates that a measurable difference exists at selected wave lengths in the ultraviolet region, Figure 2 shows the resulting change in the ultraviolet spectrum of the oxazolidine under hydrolytic conditions, as a function of time. Further investi gations of the effect of benzaldehyde on absorbency in the presence of ephedrine, pseudo-ephedrine, and the oxazolidine indicated a strict adherence to Beer's Law at selected wavelengths, A cor relation of absorbency with concentration could also be derived ABSORBANCE 5 x 10"^ m/1. Solvent HC1/KC1 u 0.1, pH 2.0, t 25.0 ^ t25.0 2.0, pH 0.1,u HC1/KC1 0.05°C. Solvent m/1. 10"^ x 5 ihnl3^dmty xzldn n ezleye all benzaldehyde, and oxazolidine diphenyl-3i^-dimethyl 260 :t5 - D ipheny|-3,4'dim « « thyloxazolidine ipheny|-3,4'dim D - :t5 i. -Asrto setao ehdie 2,5- ephedrine, of spectra .--Absorption 1 Fig. WAVELENGTH inWAVELENGTH nju 280 dehyde d y h e ld a z n e 300 320

* D i p h e n y l3 * ,4 ”dim ethyl“ oxazoiidlne

Ui O CD

- r m i — 280 300 ;

WAVELENGTH in nyj 3 2 q Fig* 2.— Change in spectral characteristics of >.0,ctant t as2 5 .a 0 function- 0 . 0 5 ° C .of time. Solvent HClACI u 0 . 1 , 37

(57)• An experimentally convenient oxazolidine concentration and hydrogen-ion concentration were determined. These conditions were used to investigate the effects of para-substituents on rate of hydrolysis.

Aqueous hydrolysis of 2,5-diphenyl-3» 4-dimethyloxazolidine

A saturated solution of the oxazolidine was prepared by placing 1 Gm. of the compound in a 100-ml. volumetric flask, and adding to volume, 0.1 N potassium chloride solution. The pH of the solution was measured and found to be 6.53* The volumetric flask was placed in a constant temperature bath maintained at

25*0°• The flask was rotated continuously except for the short period when samples were withdrawn. At 1 hr. intervals an aliquot was removed with a 5~ml. volumetric pipet whose tip was wrapped with cotton and covered with two layers of filter paper. This cotton filter paper guard was used to exclude withdrawal of any suspended material. Approximately 3 of the solution was placed in a Beckman 1 cm silica cell and the optical density determined at 280 mu. A Beckman 1 cm silica cell containing 0.1 N potassium chloride solution was used as a blank. Samples were withdrawn continuously at 1 hr. intervals until no detectable change in optical density was apparent. A plot of the logarithm of the ab sorbency at infinite time minus absorbency ai time, versus, time in hours was found to be linear up to 85# of the reaction. The equation for the best straight line through the experimental points was obtained by the method of least squares (Appendix 1). The estimating equation for this method is given by

log Av - At a log A + (slope)t Eq. (10) where log A - A^. is the logarithm of the value of absorbency at an infinite time minus the absorbency at time t, and log A«o is

the intercept. The pseudo first-order rate constant was calcu lated from the relationship

kobs = “2 '5°3 (slope) Eq. (11)

and has the dimensions of hours”^". Figure 3 illustrates the

linear relationship between log Aeo - A^ and time. The equation

for the best line through the experimental points was calculated

to be log A o o - Afc » -.333^ - .0280t Eq. (12) and, from equation 11

kobs 3 -2.303(-.0280> = 0.06^6 hours”'*'

The agreement between the experimentally determined values of log

A oo - A^ and those calculated by equation 12 is shown in Table 3*

Determination of rate of acid hydrolysis of 2.5-diphenyl-3.4-dimethyloxazolidine at proposed experimental conditions

A "buffer" solution consisting of hydrochloric acid and

potassium chloride was prepared. The two solutions were combined

according to the method of Clarke and Lubs. Dilution of the

solution volumetrlcally to 2000 ml. gave a "buffer" solution of

an approximate pH of 2.0. The flask was placed in a constant

temperature bath which was maintained at 23.0 - 0.03°. After

temperature equilibrium, the pH was measured and calculated to be 39

< 1.2 CD

0 10 20 30 40 TIME in HOURS Fig. 3.— A plot showing the linear relationship between log A «o - A . and time. The circles are experi mental values and tne line was calculated from equation 12. 4o

TABLE 5 The Degradation of 2,5-Diphenyl-3»4-dimethyloxazolidine in Water at 25.0° pH 6*53

Time - log A q q - A. - log A 0 0 ~ A. (hours) (obs d) (calc)

1 .356 .361 2 .3 8 6 .389 3 .428 .418 4 .443 .446 5 .482 .474 . 6 .499 .502 7 .525 .529 8 • 554 .558 9 .585 .5 8 6 10 .6 1 1 .614 15 .757 .754 20 .903 .894 25 1 .0 3 6 1.034 30 1.173 1.175 35 1 .3 1 0 1.314 40 1.456 1.455

2.03* The ionic strength of the solution was calculated to be

0.1. The contribution to ionic strength of any added oxazolidine was assumed to be negligible. Concentrations of all kinetic solutions were assumed to be equivalent to activities. Samples of the oxazolidine were weighed and placed in a 1 0-ml. volumetric flask. Exactly 3 ml. of the "buffer" was pipeted into a Beckman

1 cm silica cell. Absolute methyl alcohol was added to volume to the 10-ml. flask containing the oxazolidine. A Hamilton 50-ul syringe was used to inject sufficient oxazolidine solution into the "buffer" to yield a concentration of approximately.5 x 10 moles/liter. The cell was Inverted twice to insure mixing, capped with a ground glass stopper, and placed in the cell compartment.

The cell compartment was equipped with thermospacers and the temperature maintained at 2 5 .0 - 0.05° with a circulating constant temperature bath. A Beckman 1 cm silica cell containing 3 nil. of the "buffer" was used as a blank. The absorbence of the oxazolidine solution was measured as a function of time at a wavelength of

280 mu. Zero time was taken as the time of injection of the alcohol solution into the "buffer." Absorbency readings were recorded until no apparent change in absorbence was evident over a 2-hr. period.' A plot of the logarithm of absorbency versus time was not linear. A plot of the logarithm of absorbency at infinite time minus absorbency at time, versus, time was linear over 90% of the reaction. The absorbency obtained at an infinite time agreed to the absorbency obtained from an equivalent concentration of benzaldehyde in a Beer's Law determination. The observed rates of hydrolysis were obtained by treating the data by the method of least squares (Appendix I) and multiplying the slope obtained by

-2.303* Table 6 lists the concentrations of oxazolidine studied 1 and the observed rate constants calculated.

Effect of hydrogen-ion concentration on observed rate of hydrolysis of 2,5-diphenyl-3« ^-dimethyloxazolidine

"Buffer" solutions at constant ionic strength but varying

hydrogen-ion concentration were prepared by combining various

ratios of 0.3001 N hydrochloric acid and 0.3007 N potassium chloride

solutions in 100 ml. of volumetric flasks. Dilution to volume with

demineralized double distilled water gave the desired hydrogen-ion

concentrations. The ionic strength of all solutions was 0.1.

Samples of oxazolidine were weighed and placed in a 1 ml. volumetric 42

TABLE 6 Observed Rate Constants for Hydrolysis of 2,5-Diphenyl-3,4- dimethyloxazolidine Varying Concentration a 2 Oxazolidine Concentration x 10 (moles/liter)

1.01 2.589 2.10 2.571 3.01 2.570 3.98 2.559 5.05 2.596 6.04 2.543 7.02 2.578 8.17 2.605 8.99 2.552 10.11 2.557 Average: 2.572 - 0.015 flask. Three ml. of the ."buffer" solution was pipeted into a

Beckman 1 cm silica cell. Absolute methyl alcohol was added to the oxazolidine to volume. A Hamilton 50>ul syringe was used to inject a sufficient amount of oxazolidine solution into the

"buffer" to yield a concentration of approximately 5 x 10 moles/ liter. The cell was inverted three times to insure complete mixing.

A ground glass stopper was used to cap the cell and the cell placed in a thermostated cell compartment. Absorbence values were re corded at 280 mu as a function of time. A Beckman 1 cm silica cell containing 3 mi* of the "buffer" solution being studied was used as a blank. Absorbency values were recorded until no apparent change in value occurred. At the beginning of each run 3 nil. of the "buffer" was pipeted into the electrode cup supplied with the

Beckman Model GS pH Meter. The pH was calculated at 25.0°• The same volume of oxazolidine solution injected into the silica cell was also injected into the "buffer" in the electrode cup and the pH of this solution measured. The cup was placed in a 10 ml* beaker containing a sufficient amount of water to surround the cup but not enter it* The beaker was placed in a constant tem perature bath maintained at 25*0 ^ 0*05°» and covered with an inverted 50-ml. beaker to inhibit evaporation. The beaker remained in the constant temperature bath until the end of the run. The

electrode cup was removed and the pH of the solution determined.

In all cases the values obtained agreed within experimental error.

Three determinations were carried out at each hydrogen-ion con

centration. The observed rate constants were calculated from the

average slopes of the lines. The lines were obtained by plotting

the values of log A oo ~ versus, time t. The slope of this line « lc is equal to ■.£ from equations 10 and 11. Table 7 lists the c.• yj 5 hydrogen-ion concentrations studied and the observed rate con

stants obtained. The rate constants are listed as an average of

the three determinations.

Effect of p-substituent on rate of hydrolysis of 2-(p-substitutedphenyl) -3i*+-dime t hyl-5-phenyloxasolidines

The same experimental procedure was used in the determi

nation of the observed rate constants for all diastereoisomers.

The "buffer" solution used for all hydrolysis reactions was pre

pared in advance and maintained at a temperature of 2 5 .0 - 0.05°.

It was prepared by combining 0.3001 N hydrochloric acid and

0*3007 N potassium chloride solutions in a ratio which on dilution

to *+000 ml. with demineralised double distilled water gave a 44

TABLE 7 Observed Rate Constants for the Hydrolysis of erythro-2,5- Diphenyl-3«4-dimethyloxazolidine as a Function of Hydrogen-ion Concentration at 25°

lc x 10 Hydrogen-ion Concentration obs , (moles/liter) (min~ )

1.00 X 10"1 22.1 - 0.04 5.63 X 10-2 12.7 - 0.02 3.17 X IQ"2 9.78- 0.07 1.66 X io“2 4.7 - 0.04 9.34 X 10-3 2.57- 0.01 5.90 X 10-3 1.7 - 0.01 3.10 X 10”3 I.l4l 0 .0 3 1.78 X 10-3 .69- 0 .0 6 O H . vx X 10“3 •43- 0 .0 8 6 .1 8 X 10-4 .27- 0 .0 9 3.02 X io‘k .16- 0 .0 6 1.78 X io~k .11- 0.04 „ -k + 1.00 X 10 .09- 0.01 solution of pH 2.03 and ionic strength of 0.1. Activities of all constituents were assumed to be equivalent to concentrations. A description of the procedure used for the hydrolysis of erythro-

2.*p-methylphenyl-5-phenyl-3*4-dimethyloxazolidine will serve as an example »

Hydrolysis of erythro-2-p-methylphenyl-3f4-dimethyl-5- phenyloxazolidine.— A sample of the oxazolidine was weighed and placed in a 1 ml. volumetric flask. Three milliliters of the

"buffer" pH 2.03f u 0.1, was volumetrically pipeted into a Beckman

1 cm silica cell. Absolute methyl alcohol was added to the 1 ml. volumetric flask to volume* A Hamilton 50-ul syringe was used to inject a volume of the oxazolidine solution into the "buffer" to .if give a concentration of approximately 5 x 10 moles/liter of oxazolidine* The cell was inverted to mix the solutions and the ultraviolet spectrum determined between 350 mu and 250 mu* The spectrum was determined with either a Perkin-Elmer Model *f000 or

Cary Model 13 Recording Spectrophotometer as rapidly as possible to minimize contributions to the spectrum of the hydrolytic products. A Beckman 1 cm silica cell containing "buffer" was used as a blank. A sample of ephedrine sufficient to yield the same concentration (3 x 10 moles/liter) was weighed and dissolved in the "buffer." The solution was placed in a Beckman 1 cm silica cell and the ultraviolet spectrum determined over the same wave length range. A silica cell containing "buffer" was again used as a blank. A sample of p-methylbenzaldehyde was weighed and placed in a 1 ml. volumetric flask. Absolute methyl alcohol was added to volume. With a Hamilton 30-ul syringe 23 ul of the solution (5 x 10”** m/1) was injected into 3 ml* of the "buffer" in a Beckman 1 cm. silica cell. The ultraviolet spectrum was determined from 350 mu to 230 mu. A "buffer" solution containing .If approximately 5 x 10 moles/liter of ephedrinet p-methylbenzalde hyde and the oxazolidine was prepared. The ultraviolet spectrum was determined as rapidly as possible on a recording spectro photometer from 350 mu to 230 mu. Again a silica cell containing

"buffer" was used as a blank. The four spectral curves obtained were superimposed on a glass tracing board. A wavelength, in the 46

350 mu to 250 mu region* where the molar absorbtivities of ephedrine and the oxazolidine did not interfere with or were negligible compared to the molar absorbtivity of the aldehyde was determined* This wavelength was then used for measurement of extent of hydrolysis of the oxazolidine* Solutions of varying concentration of p-methylbenzaldehyde in buffer were prepared.

The absorbency as a function of concentration, was determined at

the selected wavelength on a Beckman Model DU Spectrophotometer*

The cell compartment of the instrument was maintained at a con stant temperature. Table 8 lists the concentrations of aldehyde used and Figure 4 indicates a linear relationship between concen

tration and absorbency* A sample of 2-p-methylphenyl-3»4-dimethyl-

TABLE 8 Absorbency of p-Methylbenzaldehyde as a Function of Concentration* Solvent HC1/KC1 "buffer" pH 2.03* Ionic Strength 0*1* Temperature 25*0 • Wavelength 290 mu ..... ' ' if Concentration x 10 (moles/liter) Absorbency

4.895 1.245 4.405 1.127 3.961 .995 3.427 .8 8 8 2.937 .758 2.448 .6 3 0 1.958 .514 1.468 .392 0.979 .2 6 5 0.489 .135 0.245 .070

5-phenyloxazolidine was weighed and placed in a 1 ml. volumetric

flask* Three milliliters of "buffer" were pipeted into a Beckman ABSORBANCE o benzaldehyde to Beer's Law. pH pH Law. Beer's to benzaldehyde C O N C E N T R A T I O N moles/liter moles/liter x 10“ N O I T A R T N E C N O C Fig. 2 1 --Plot . 4

showing adherence of p-methyl- of adherence showing 3 2.03 u 0.1, 25.0 - 0.05 C. 0.05 - 25.0 0.1, u 2.03

47 48

1 cm silica cell. Absolute methyl alcohol was added to the

oxazolidine flask to volume. A Hamilton 50-ul syringe was used

to inject a sample of the oxazolidine solution into the "buffer."

The volume injected was sufficient to yield a concentration of

' approximately 5 x 10 moles/liter. The cell was inverted to mix

the solutions and stoppered with a ground glass top. The cell

was placed in the cell compartment of a Beckman DU Spectrophoto

meter. The cell compartment was maintained at a temperature of

25*0 “ 0.05° by means of thermospacers and a circulating constant

temperature bath. The absorbency of the solution was determined

as a function of time at a wavelength of 290 mu. Zero time was

recorded as the time of injection. A Beckman 1-cm silica cell

containing "buffer" was U6ed as a blank. Absorbence values were

recorded at one-minute intervals, and as the reaction proceeded

at five-minute intervals, until no observed change in absorbency

was detected. The pH of the solution was determined.before in

jection of the oxazolidine and again after the completion of the

reaction. In both cases the pH agreed within experimental error.

Values of the absorbence at infinity minus absorbence at any time

were calculated and the logarithmic value plotted against time.

The linearity, Figure confirms the first-order kinetics. Five

determinations were carried out on each diastereoisomer and the

observed rates of hydrolysis that are listed in Tables 9 and 10

are average values obtained by the procedure described. The

tables also list the wavelength at which the assay was carried

out. 49

< .4 o

-I

0 20 40 60 80 TIME in MINUTES Fig. 5*— First-order plot for the decomposition of 2-p-methylphenyl-5-phenyl-3*4-dimethyloxazolidin«.

i 50

TABLE 9 Observed Hydrolysis Rates for erythro-Oxazolidines in Aqueous "Buffer" pH 2.03 Ionic Strength 0.1 at 25.0 - 0.05°

k . x 102 Wavelength of Assay obs . Substituent (mu) (oin~ )

H 280 2.572 t 0.15 c h 3 290 2 .2 8 0 £ 0 .0 9 Br 285 3 .0 0 8 £ 0.17 COOH 255 3 .1 8 5 - 0.14 CN 300 3.701 - 0.19 n h (c h 3 )2+ 320 5 . ^ 9 - 0 .1 1 OH 290 2.011 £ 0.13 Cl 285 2.933 * 0.12 N02 320 3.9^6 £ 0 .0 8

TABLE 10 Observed Hydrolysis Rates for threo--Oxazolidines in Aqueous "Buffer" pH 2.03 Ionic Strength 0.1 at 2 5 .0 - 0.05°

k . x 102 obs . Substituent Wavelength of Assay (min” ) (mu)

H 280 1 1 .8 1 £ 0 .0 1 5 c h 3 290 9.v? £ 0 .0 2 5 Br 285 1 5.3* £ 0 .0 1 1 COOH 255 1 8 .5 3 - 0 .0 1 0 CN 300 2 3 .6 6£ 0 .0 0 9 n h (c h ,)2+ 320 1 1.3^ £ 0 .0 1 1 OH 290 7 .3 2 £ 0 .0 2 1 Cl 285 1 ^ .5 7 £ 0.013 n o 2 320 26.33 £ 0 .0 0 7 51

Ultraviolet spectra were determined for all the para- substituted aldehydes and for pseudo-ephedrine. A Beer's Law plot was determined for each aldehyde. All hydrolysis reactions were carried out by the procedure described for the p-methyl isomer. With the p-nitro, p-cyano, p-carboxy, p-bromof and p-chloro derivatives of the threo-isomer, the rate of hydrolysis occurred too rapidly for practical manual measurement of absorbency.

For these isomers while hydrolysis was studied in an identical manner, the method of obtaining absorbency values differed. The photomultiplier of the Beckman DU was attached to a Beckman

Energy Recording Adapter. The leads of the ERA were connected to a Varian Model l*f strip chart recorder. The span of the recorder was set to the 0 to 100 millivolt range and calibrated with a blank comprised of "buffer" solution. When the oxazolidine alcohol solution was injected into the "buffer," the switch of the chart was simultaneously actuated. Transmittance was recorded as a function of time. The measurement was allowed to continue until no change in the transmittance value was apparent. Ab sorbency values were calculated from transmittance values. All observed rate constants were obtained as previously described.

Determination of rate of change of specific rotation 4 A sample of 2,5-diphenyl-3»^-dimethyloxazolidine was weighed and placed in a 100-ml. volumetric flask. A solution consisting of 100 ml. of the "buffer" and 100 ml. of absolute ethyl alcohol was prepared. The apparent pH of this solution was 52 measured and found to be 2.10* The solution was placed in a constant temperature bath and after reaching equilibrium was added to the oxazolidine to volume* This resulted in a concentration of

1*9 x 10 1 moles/liter. A portion of the oxazolidine solution was placed in a 0*5 decimeter polarimeter tube* A second tube was filled with solvent. The tubes were placed in a Zeiss

Circular Scale Polarimeter set at a wavelength of 589 mu* ?he temperature in the polarimeter was 26°• The change in optical rotation as a function of time was recorded at one-minute inter vals* The zero time was taken as the time the oxazolidine com pletely dissolved. Specific rotations were calculated from the expression r 100 o< L ° 9 d “ dc Eq. (1*0 where[ofJjj is the specific rotation, oQ is the observed rotation in degrees, d is the length of the light path in decimeters and c is the solution concentration in grams per 100 ml. A logarithmic plot offcorD) - (Ofp)^ versus time is linear and indicates a first-order kinetic relationship (Fig. 6). The observed rate of change in was calculated by determining the slope of the line obtained in the plot by the method of least squares (Appendix I) and multiplying that value by -2.302. The observed rate of change -2 -1 for the erythro isomer was calculated to be 5*91 x 10 min • A similar procedure w-s carried out to determine the observed rate of change of specific rotation for the threo isomer. The value -2 -1 obtained for that isomer is 13*75 x 10 min •

20 Fig. Fig. 6.— The change in specific rotation of . TIME in MINUTES in . TIME erythro 2f5-diphenyl-3,^-dimethyloxaaolidino in HC1/KC1 pH pH 2.0 u 0.1 at 25.0 C. 2 O .6 1.0 L4 n»)- «(»)) son DISCUSSION

Synthesis

The successful preparation of the dlastereolsomeric oxazolidine* by condensation reactions confirms the suggestions of Bergmann• The conditions of choice are those which employ solvents which will form azeotrople distillation mixtures with water* Davies concluded that oxasolidines prepared from ephedrine and benzaldehyde will form simply on heating* Reaction 1

CH h-9hch3 ► V N C H 3

Any conditions which will affect this equilibrium will subse*

quently provide a greater yield of product* The addition of

catalytic substances such as iodine or small amounts of acetic

acid results in a more rapid formation of the oxazolidine* Ad*

dltlon of small amounts of absolute methyl or ethyl oloohol9 when

benzene or toluene are reaction solventst results in a more rapid

formation of the product* Apparently the aloohol functions by

forming a ternary azeotropic mixture distilling at a lower tern*

perature and faster rate than the toluene*water or bensene-wmter

aseotrope*

No quantitative investigation of the relationship between

the para*substltuent of bensaldehyde and rdte or yield of & 55 oxazolidine formation was undertaken. An apparent qualitative relationship wast however, noted in the preparation of the isomers.

The solubility of the aldehyde, energy (in the form of heat) re quired to separate the water, and time required for water to dis till was obviously effected by the substituent of benzaldehyde.

The apparent ease of formation of the oxazolidine was also noted to differ depending upon the isomer of ephedrine reacting. The relationships that were observed were theses (a) isomers of pseudo- 4 ephedrine (discounting differences in solubility) formed at a more rapid rate than ephedrine isomers, (b) para substituents on benzaldehyde which are stronger electron withdrawing groups than hydrogen require more vigorous and longer heating conditions for condensation. The difference in rate of formation of the isomers « of pseudo-ephedrlne and ephedrine is in complete agreement with the findings of Pfanz and Kirchner. Their results indicated that oxazolidines formed from isomers of ephedrine have corresponding configurations to that of the starting isomer. For oxazolidine

formation, the amino and hydroxyl functions must of necessity be nearly or fully eclipsed. In ephedrine (I) and the corresponding erythro-oxazolidine (II) this will result in a phenyl-methyl type interaction. The preferred ground state of ephedrine would probably not be eclipsed but some staggered conformation (III).

MHCH,

(I) (II) (III) In pseudo-ephedrine and the corresponding threo-oxazolidine (IV) and 1

(IV) (V) this phenyl-methyl interaction is nonexistent. A greater amount of energy should he required, therefore, for formation of the erythro-oxazolidines (II) than for the threo-oxazolidines (IV) to overcome this rotational barrier difference*

The effects, within the isomeric series, of the para substituent on ease of formation of oxazolidines was noted.

Because this observation was purely qualitative no explanation will be offered. It is noteworthy to mention this observation and indicate that a quantitative investigation of such effects would be of interest* A comparison of the data obtained in such an investigation with the data obtained on the effects of substituent on hydrolysis would add valuable information to the elucidation of either the condensation or hydrolysis reaction mechanism, or both*

Kinetics

The most important circumstancial evidence as to reaction mechanism is the identity of the products which are formed (57)*

The isolation and identification of ephedrine and benzaldehyde as the products formed from acidic hydrolysis of 2,5-diphenyl-3ti*— dimethyloxazolidine is of significance* The conclusion can be made that analysis of any of the species involved in the reaction: oxazolidine, ephedrine, or the substituted benzaldehyde, will yield evidence as to the kinetics and possible interpretation of reaction mechanics. This data and the results of the spectral change observed of oxazolidines as a function of time (Fig. 2) indicate that analysis by ultraviolet identification of benzalde hyde is a valid procedure. The evidence that at selected wave lengths in the ultraviolet region the molar absorbtivities of the oxazolidine and ephedrine are negligible further substantiates the applicability of the assay procedure. The stoichiometry of the * reaction allows for the conclusion that any determination of the substituted aldehydes will be a direct measure of the reaction progress. The linear relationship obtained from the plot of log

A o O - versus time (Fig. 3) is a direct indication of a pseudo first-order kinetic dependency. The value of ^ ^ for uncatalyzed »2 -I hydrolysis of the oxazolidine (6.*f6 x 10 hours ), and that value obtained of the at pH 2.05, the pH of the investigation (2.57 _2 —1 x 10 min ), proves the validity of application of equation 6 to the investigation.

Effect of concentration on the observed rate of hydrolysis of 2.5-diphenyl-3.^— dimethyloxazolidine. pH 2.03 at 25.0°.— The data listed in Table 7 show that the rate of hydrolysis of the oxazolidine is pseudo first-order kinetically with respect to concentration. Verification of first-order dependency was also substantiated by calculating the order of reaction for varying concentrations through application of the Noyes Equation (59)* where n is the order of reaction, t^' and t^ are the half life periods for concentrations a 1 and a respectively* Table 11 lists

the values obtained for n, the order of reaction, from equation

16 for varying concentrations.

TABLE 11 Values Obtained for n the Order of Reaction Calculated by Equation 16 for Varying Concentrations

a x 10^ a* x 10^ (moles/liter) (moles/liter) n 1

3-16 1.07 1.017 5.02 3.16 1.103 7.01 5.02 1.002 9.00 7*01 1.112

Results from calculations by the Noyes Equation and the

data obtained in Table 7 allows the reasonable assumption to be

drawn that the hydrolysis of 2,5-dipbenyl-3,^-dimethyloxaaolidine

is of a first-order kinetic nature. Evidence of an unchangeable

reaction mechanism or order with the introduction of para sub

stituents on the 2-phenyl substituent of the oxazolidine (VI)

should be clearly indicated in a correlation of the rates of

hydrolysis as a function of substituent (Equation 3). 59

Effect of hydrogen-ion concentration on rate of hydrolysis of 2,5“diphenyl-3«**— dimethyloxazolidine at 25.0°.--Data complied in Table 6 indicates that the rate of hydrolysis of 2,5-diphenyl-

3,^-dimethyloxazolidine is dependent upon the concenti‘atlon of the hydrogen-ions present. A linear relationship is observed in the region of hydrogen-ion concentration studied. A plot of the logarithmic value of the observed rate constants versus the logarithm of the hydrogen-ion concentration is linear as shown in Figure 7* This indicates a pseudo first-order kinetic de pendency on hydrogen-ion concentration. The value of q +, the specific catalytic constant, was calculated by the method of least —2 —1 —1 squares (Appendix X) to be 81.7 x 10 liter mole minute .

Correlation of the rate of hydrolysis of oxazolidines with the polar substituent constants.— The polar substituent (sigma values) for meta- and para-substituents involved in the reaction of benzene derivatives have been well verified and defined (*+5» i *t8, 49). Table 12 lists the substituents of the para position of the 2-phenyl group. The observed rate constants and the cor responding sigma value are also listed.

0 The polar substituent constants for p-amino (VII), p- dimethylamino (VIII) and protonated p-trimethylamino (IX) func

tional groups are available in the literature (51).

NH2 • N O &

(VII) (VIII) (IX) 60

1.0

( 3

3.0

4j0

Fig. 7.— A plot showing the first-order dependency of the decomposition of 2,5-diphenyl-3*^-dimethyloxazolidine on the hydrogen-ion concentration. TABLE 12 Polar Substituent Constants and Observed Rate Constants for the 2- (p«substitutedphenyl)-3,4-dimethyl-5-phenyloxaaolidines

k . x 1 0^ min”^ k . x 10^ min”^ obs obs 2-p-substituent (threo isomers) (erythro isomer)

+ + OH 7.52 0.02 2.01 0.1 -0.36 + + 9.47 0.02 2 .2 8 0.1 -0.17 CH3 H 1 1 .8 1 0.01 2.57 0.2 0.00 + + Cl 14.57 0.01 2.93 0.1 +0.22 + + Br 15.34 0.01 3.01 0.1 +0.23 + + +n (c h 3 )2h 11.3^ 0.03 5.^5 0.2 +0 A 6 ‘ + COOH 18.55 0.01 3.18 0.04 +0.27 + + CN 2 3 .6 6 0.02 3.70 0.2 +O.6 3 + + N0? 26.33 0.01 3.95 0.1 +O.7 8

aCalculated value.

No value is available for the protonated p-dimethylamino (X) group.

n (c ^ ) 2 h

(X)

At a pH of 2.03 (experimental conditions) the hydrogen-ion concen tration Is sufficient to partially or completely protonate the basic p-dimethylamino function. The effect of partial or complete protonation of this group on the polar constant is uncertain. The sigma value for the p-dimethylamlno function is -.205* The value for the positively charged p-trimethylamino is +0.86. A positively- charged p-dimethylamino group should have an intermediate value.

The value for this substituent was calculated from equation 3*

This value is listed in Table 12 and was in agreement in both the erythro and threo series. The observed rate constant for the p- dimethylamino substituted oxazolidine was not used in any calcu lations of reaction constants. Correlation of polar constants with reaction was limited to the remaining eight pairs of isomers.

The observed rate of hydrolysis of threo isomers was determined in this study to be significantly faster than the erythro isomers. Pfanz and Kirchner (*+2) postulated that the erythro isomers are less stable than the threo isomers and therefore would hydrolyze at a faster rate. This postulation was based only on stereochemical considerations. They state that the phenyl-methyl interaction imposed by configuration results in an unfavorable conformation leading to Instability. This was not observed in this investigation. The threo isomers are subject to a much more rapid hydrolysis rate than are the corresponding erythro compounds.

Methods employed by Pfanz and Kirchner lead to the question of whether measurements were of rates of hydrolysis or the amount of t oxazolidine hydrolyzed. Their procedure was to combine an isomer of 3i^-dimethyl-5-phenyloxazolidine (XI) with sulfuric acid.

(XI)

The formaldehyde formed by hydrolysis; Reaction 2 was steam distilled and measured, A plot of grams of formaldehyde versus total volume of distillate was used to give rates of hydrolysis* This would appear to be a measure of extent rather than rate of hydrolysis*

A good agreement was obtained between the observed rate constants and the corresponding polar substituent constants

(Equation 3)* Figures 8 and 9 show the linear relationship which was obtained in both the erythro and threo series respectively*

As the polar substituent constant becomes numerically larger (more positive) the observed rate of hydrolysis becomes larger (log becomes less negative)* The reaction constant f> for both series was calculated by the method of least squares (Appendix I)* The values found are +0,26l - 0.021 for the erythro isomer hydrolysis and +0*^95 - 0.036 for the threo isomersn A positive p value signifies that the rate of reaction increases with an increase in

electron withdrawal* The literature does not indicate any mecha

nistic investigations of a correlatable nature. It is worthy of

mention, however, that both the sign and approximate magnitude of

the reaction constant in both series is similar to that value ob

tained for the hydrolysis of para-substituted benzamides by Reid

(60, 6l). The results clearly indicate that the mechanism of

hydrolysis remains consistent throughout the reaction series*

Allowing for the possible effects of difference in conformation,

the effect of substituent on base strength, and the Influence of

the base strength on reaction rate fair agreement of reaction

mechanism is also observed between each series of isomers* ’ LOG k 1.2 1.4 1.6 1.8 flg n vle fr erythro-iaomers. for values and log of i. .- lt hwn h ier relationship linear the showing plot 8.--A Fig. E r y t h r oS e r i e s +.2 r < .4*

65 O - o +.2 o - Threo Series Threo Fig. Fig. 9•--A plot showing the linear relationship of log an^ values for threo-isomere. 1.2 S<1°^ 901 Effect of change in specific rotation

Hartung and Andrako (62) pointed out in their review on stereochemistry that oxazolidines prepared from ephedrine (XII) or pseudo-ephedrine and benzaldehyde contain an added asymmetric center (XIII). The optical properties of this compound differ from either of the reacting isomers, the of (XII) not being

(XII) (XIII) equivalent to that of (XIII). If the initial step in hydrolysis of oxazolidines is the heterolytic cleavage of either the carbon- nitrogen or carbon-oxygen bond, a relatively stable benzylic carbonium-ion might be formed (Reaction 3)* An immediate change of the value of specific rotation should be evident* The changes

NHCH NHCH 3

observed in specific rotation of the isomers (Fig. 6) indicates

a rate of change of a pseudo first-order nature* The observed

rate constants calculated by the least squares method (Appendix I), 67 were of a greater magnitude than observed rate constants obtained spectrophotometrically by analysis of benzaldehyde formed. This < indicates that the reaction mechanism might proceed in two stages,

k. k- A =-^ B ^ C in which k^ is the slower or rate determining step. The differences of observed rate of change of specific rotation carry little weight because of the different nature of

the solvent systems used. The rate of change between series is of the same nature as that observed in the hydrolysis determined by spectral methods. The observed rate for the threo isomer is

faster than that for the erythro isomer.

Mechanism

A mechanism for the hydrolysis, consistent with the ob

served results may be postulated based on the logical assumption

* that the initial step in the hydrolysis of oxazolidines, under

the experimental conditions, is the heterolytic cleavage of the

carbon-nitrogen bond (Reaction 3A) . The resulting carbonium-ion

then reacts with the solvent to form the proposed hemiacetal

intermediate (Reaction 4). The acceptance of the electrons by the

O NHCH, u O i i 3 2 > O NHCH NHCH-. w H» H H 0

positively charged nitrogen seems a more reasonable assumption than

acceptance of electrons by the electronegative oxygen atom. The

rate determining step of the hydrolysis then becomes a function

of the dehydration of hemiacetals formed. 68

Everett and Hyne (63)1 and Prelog and Hafliger (6*0 de

termined that the difference in basicity of ephedrine and pseudo-

ephedrine is a result of the distance between the hydroxyl function

and methylamino function imposed by the preferred conformation of

the respective isomers. They determined that in ephedrine the

preferred conformation imposes an angle of l80° (XIV). The im

posed angle in the isomert pseudo-ephedrine, is only 60° (XV). In

an analogous manner, the angle between the protonated nitrogen and

H OH

HCH. NHCH^

(XIV) (xv)

the alcohol oxygen of the hemiacetals would, in some degree, be

influenced by the preferred conformation of the isomer. The angle

present in the erythro hemiacetal being greater than the angle in

the threo hemiacetal as a result of the phenyl-methyl steric

interaction in the erythro compound.

The mechanism of acid catalyzed dehydration of hemiacetals

has been well elucidated (63* 6 6). The dehydration of the

alk&loid-aldehyde, hemiacetals formed by hydrolysis of oxazolidines

can be considered to be internally acid catalyzed by the conjugate

acid of the amino function of the alkaloid (Reaction 69 H—CHCH

H tNHCH- s H * 3 + + H O (5)

The conformation required for internal proton catalysis

imposes the restriction that the protonated nitrogen and alcohol

oxygen be eclipsed. In the erythro isomer this results in a steric

interaction between the phenyl-methyl group. The energy barrier produced by this interaction results in the lower observed rate

of hydrolysis of the erythro isomers of the oxazolidines. SUMMARY

1. Eighteen diaetereoisomere of 2-p-(substituted)- phenyl-5-phenyl-3t^-dimethyloxazolidines were prepared. The general reaction was condensation of the p-substltuted benzaldehyde and ephedrine or pseudo-ephedrine In am azeotropic solvent with water separation.

2. An assay procedure for the determination of extent and rate of hydrolysis was proposed and developed.

3. The order and rate of reaction of 2,5-diphenyl-3*^- dimethyloxazolidine was determined. The rate of reaction was assumed to be consistent in hydrolysis of all isomers.

k. Effect of hydrogen-ion concentration on observed rate of hydrolysis was determined. Results indicated this effect was pseudo first-order.

3* Rates of hydrolysis of eighteen diastereoisomeric oxazolidines were determined at constant hydrogen-ion concentration, constant ionic strength, and constant temperature. A reasonable correlation between the logarithm of the observed rate constants and the polar substituent constants was obtained.

6. The reaction constant for the hydrolysis of the sub stituted oxazolidines was calculated. The values of erythro and threo isomers are in reasonable agreement with respect to sign and magnitude.

70 7. The rate of change of iKIp of erythro- and threo-2.5- diphenyl-3**f-dimethyloxazolidine was determined. The rates appear to be more rapid than rates obtained by analysis of the aromatic aldehyde formed.

8. The following conclusions can then be stated:

A. The rates of acid catalyzed hydrolysis of the

substituted oxazolidines quantitatively parallel

the polar constants of the substituents.

5. The reaction constant obtained suggests that the

mechanism of hydrolysis is consistent in the

compounds studied.

C* Preliminary evidence indicated that the reaction

might be a complex A— ^ B— ^ C type reaction.

D. A mechanism consistent with experimental evidence

is proposed. APPENDIX I

Linear Correlation of Two Variables. The Method of Least Squares (51)

The estimating equation for the line is given by y - * + *x where b is the slope of the line and a is the intercept. These parameters can be evaluated from the following equations.

€ x y .fX Y -(£XY) f v.£Y*-(fcYf Then N b =*xy_ a* y- bx where y and x are the averageY - values andX - values respectively. The standard deviation of the correlation is given by £y*-(£xyj/£x* Sd - N-2 and the standard deviation of the slope is given by S d

The coefficient of determination for the correlation is evaluated

from the expression r« (€xyf/(£x*)-(fc y*)

72 BIBLIOGRAPHY

1. Knorr, L., and Mathes, H. , Ber., 14, 3^84 (1901).

2. Knorr, L., and Roessler, P., Ber., ^6* 12?8 (1903)*

3* McCasland, G. E., and Horswill, E. C., J. Am, Chem. Soc., 21. 3923 (1951)*

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38. Fischer, E.t Ber.f 2£, 205 (1 8 9 6).

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