The reaction between phenyl magnesium bromide and cyclic acetals

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DATE

NORTHWESTERN

UNIVERSITY

THE REACTION BETWEEN PHENYL MAGNESIUM BROMIDE AND CYCLIC ACETALS

A DISSERTATION SUBMITTED TO THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

for "the degree DOCTOR OF PHILOSOPHY

DEPARTMENT OF CHEMISTRY

BERNARD ANDREW NELSON

EVANSTON, ILLINOIS AUGUST, 1942

P ro Q u es t N u m b e r: 10101787

All rights reserved INFORM ATIO N TO ALL USERS The q u a lity o f this re p ro d u c tio n is d e p e n d e n t u p o n th e q u a lity o f th e c o p y s u b m itte d . In th e unlikely e v e n t th a t th e a u th o r did n o t send a c o m p le te m anuscript a n d th e re a re missing p a g e s , th e s e will b e n o te d . Also, if m a te ria l h a d to b e re m o v e d , a n o te will in d ic a te th e d e le tio n .

uest P roQ uest 10101787 Published by P roQ uest LLC (2016). C o p y rig h t o f th e Dissertation is h e ld by th e Author. All rights reserved. This work is p r o te c te d a g a in s t u n a u th o rize d c o p y in g u n d e r Title 17, U nited States C o d e M icroform Edition © P roQ uest LLC. P roQ uest LLC. 789 East Eisenhow er Parkw ay P.O. Box 1346 A n n Arbor, Ml 48106 - 1346

ACKNOWLEDGEMENT

The author wishes to express his most sincere appreciation to Dr* R. K. Summerbell for his encouragement,

supervision and many

suggestions during the course of this work.

TABLE OF CONTENTS Page INTRODUCTION ................................................

1

HISTORICAL 1. 2. 3. 4. 5. 6.

Acyclic A c e t a l s ....................... Acyclic Ketlas ....................................... Cyclic Acetals Cyclic Ketals . . . . . . . . . . . . . . ......... Uses For Cyclic Acetals and K e t a l s .......... Heterocyclic Acetals Containing A Dioxane N u c l e u s ......................... 7. The Reaction Between Acyclic Acetals and Ketals And Grignard Reagents ........................... 8. C o n c l u s i o n ...............

2 4 4 10 11 11 13 15

DISCUSSION OF RESULTS 1; The Isomeric Naphthodioxanes ...................... 2* The Reaction Between Glycol Acetal And Phenyl Magnesium Bromide ............ 3. Reactivity Of Compounds Having A Vicinal Aldehyde Structure Toward Phenyl Magnesium ........................................... Bromide a. 1,4,5,8-Naphthodioxane ................ h. 2,3-Diethoxy-l, 4 - D i o x a n e ................... c. Tetraethyl Acetal Of Glyoxal .................. 4. The Development Of A New Problem For Investigation . . . . . ............................ 5. Compounds Having A n Alcohol And An Aldehyde Oxidation State On Vicinal Carbon A t o m s ........... a. 2,5-Diethoxy-l, 4 - D i o x a n e ....................... b. Mono ethoxy-1,4 - D i o x a n e .......................... c. 1,1,2-Trie t h o x y - E t h a n e .......................... d. 2-Ethoxymethyl-l, 3 - D i o x a l a n e .................... 6. A Study Of The Reaction Between 2-Methyl-1,3Dioxane And Phenyl Magnesium Bromide . . . . . . . . 7. Concluding R e m a r k s .................

16 20

22 22 23 26 29 30 30 35 37 38 41 43

EXPERIMENTAL 1. Preparation Of Glycol Acetal ........................ 2. Preparation Of Phenyl Magnesium Bromide. A General P r o d e d u r e ............ 3. Reaction Between Glycol Acetal And Phenyl Magnesium Bromide ............... . . . . . . . . . . 4. Preparation Of The p-Nitro-Benzoate Derivative Of 4-Phenyl-3-Oxapentano1-1

47 47 48 . . . . . 49

Page

5. Preparation Of 1,4,5,8-Naphthodioxane (m.p. 136°) 6. Attempted Separation Of The Lower Melting Isomer. 7* Reaction Between 1, 4, 5,8-Naphthodioxane And Phenyl Magnesium Bromide ................. . . . . . . . 8. Preparation Of 2,3-Diethoxy-l,4-Dioxane ......... 53 9. Hydrolysis Of 2,3 - D i e t h o x y - l , 4 - D i o x a n e .. 10. Reaction Of 2,3-Diethoxy-l,4-Dioxane With Phenyl Magnesium Bromide.......................... 54 11. Synthesis Of Glyoxal Tetraethyl Acetal. a. Preparation Of Glyoxal Sulfate........... b. Preparation Of Glyoxal Tetraethyl Acetal. . . 12. Reaction Between Glyoxal Tetraethyl Acetal And Phenyl Magnesium B r o m i d e ................. 56 13. The Refractive Index-Percentage Composition Curve For Glyoxal Tetraethyl Acetal And Biphenyl. 14. Preparation Of 2,5-Diethoxy-l,4-Dioxane ......... 15. Reaction Between 2,5-Diethoxy-l,4-Dioxane And Phenyl Magnesium Bromide ........................ 16. Oxidation Of 2-Phenyl-3-0xapentanol-l.... 60 17. Synthesis Of Monoethoxy-1,4-Dioxane...... 61 a. Preparation Of p - D i o x e n e ................ 61 b. Preparation Of Crude Monochloro-1,4-Dioxane . c. Preparation Of Monoethoxy-1,4-Dioxane ... 18. Hydrolysis Of Monoethoxy-1,4-Dioxane............. 19. Reaction Between Monoethoxy-1,4-Dioxane And Phenyl Magnesium B r o m i d e .......................... 20. Synthesis Of 1,1,2-Triethoxy-Ethane ............. a. Preparation of Ethyl Bromoacetal ............. b. Preparation Of 1,1,2-Triethoxy-Ethane . . . . 21. Reaction Between 1,1,2-Triethoxy-Ethane and Phenyl Magnesium Bromide .......................... 22. Synthesis Of 2-Ethoxymethyl-l,3-Dioxalane . . . . a. Preparation Of Crude Bromoacetaldehyde . . . . b. Preparation Of 2-Bromomethyl-1,3-Dioxalane . . c. Preparation Of 2-Ethoxymethyl-l,3-Dioxalane. . 23. Reaction Between 2-Ethoxymethyl-l,3-Dioxalane And Phenyl Magnesium B r o m i d e .........* .............. 24. Preparation Of 2-Methyl-1,3-Dioxane.......... 25. Reaction Between 2-Methyl-1,3-Dioxane And Phenyl Magnesium B r o m i d e ................... .............. 26. Preparation Of The p-Nitro Benzoate Derivative of 5 -Phenyl-4-0xa-Hexanol-l ........................ 27. Relationship Between Molar Ratios Of Acetals To Grignard Reagent and Percentage Yield of Products . S U M M A R Y .................................................... BIBLIOGRAPHY VITA

50 50 52 52

55 56

57 58 59

62 62 63 63 64 64 64 65 66 66 66 67 68 68 69 70 70a 71

INTRODUCTION

The formation of acetals, both acyclic and cyclic, has been reported by such early workers as Wurtz1 and Geuther,3

Since their

time, a large number of compounds belonging to this class have been prepared and their properties studied. A property that has received considerable investigation has been the displacing of an alkoxy group with an alkyl or aryl group by reacting an acetal with a Grignard reagent.

This displacement

of alkoxy groups has provided a method to synthesize ethers which have been difficult to prepare by the ordinary procedures.

It might

be anticipated that a reaction between a cyclic acetal and a Grignard reagent would be advantageous in producing a series of ether-alcohol compounds. The purpose of this investigation has been to determine whether or not cyclic acetals with varying structures could be differentiated by a study of their reaction with a Grignard reagent.

The study

included simple cyclic acetals, naphthodioxane, the ethoxy-dioxanes and certain acyclic acetals, which were employed for comparative purposes.

As a result of this investigation, several new compounds

were prepared and a new synthesis of cellosolves (ether-alcohols) was developed.

(1) (2)

Wurtz, Ann., 108, 226 (1857); 120, 328 (1861) Geuther, Ibid., 126, 63 (1863)

HISTORICAL

1.

Aoyolio Acetals.

When an aldehyde and an alcohol have been allowed to react together upon standing, an equilibrium results with the formation of an ether-like substance, called an acetal.

In the presence of

a small quantity of some condensing agent, usually an inorganic acid, the reaction time can be materially decreased.

The general reaction

can be expressed by the equation:

RCHO

+

2RiOH

'

RCH(OR1)3

+

H20

It was Geuther® who first effected a direct condensation, when he treated acetaldehyde with ethyl alcohol at 100° C* in the volume ratio of one to three in the presence of glacial acetic acid.

The

same product was previously obtained by Wurtz1 through two steps when he first prepared the 35 The quantity of boron trifluoride necessary to catalyze the reaction was found to be 5 x 10"*^ grams per cubic centimeter of the glycol* Nieuwland, et al,35 have been able to prepare cyclic acetals from the butyl and amyl acetylenes* A probable mechanism for acetal formation from acetylene and a glycol has been indicated by Hill and Pidgeon*

■z2

They have pro­

posed that the ethylene glycol has added to the acetylene and formed the intermediate /3 -hydroxyethyl vinyl ether, III, which then con­ densed with itself to give the cyclic acetal, IV.

CH......................H |||

+

|

*

CH s =CH s -0 -C H j3CHs 0H

CH......................O-CHoCHoOH

(III)

C H «=CH— 0

i :

: •

IS

O ^C H o

/

«

\

c h 3 -c h

(IV)

They have synthesized the f i -hydroxyethyl vinyl ether and have found that it rapidly rearranged into the cyclic acetal. The same authors have postulated that the condensation between an aldehyde and a glycol yielded the intermediate, -0xapentano 1-1. 2-Phenyl-3-oxapentanol-l (0.5 gm.) was placed in a 100 cc. boiling

flask, equipped with a reflux condenser.

Water (40 cc.), potassium

permanganate (2 gms.) and sodium hydroxide (1 cc. 10% solution) were then added and the mixture refluxed for two hours. benzaldehyde was noticeable.

The odor of

The solution was acidified with

dilute sulfuric acid and the manganese dioxide dissolved with sodium bisulfite.

When a solution of phenylhydrazine hydrochloride was added,

an orange precipitate was obtained* which upon recrystallization from alcohol melted at 157.5-158° C.

This corresponded to the melting

point of the phenylhydrazone of benzaldehyde, 158° C. point showdd no depression in value.

A mixed melting

61. A second oxidation was carried out in the same manner as that outlined above except 2.5 gms. of potassium permanganate were used. Benzoic acid, melting at 120-120.5° C., was isolated upon acidifying the solution and dissolving the manganese dioxide.

j-_7. a.

Synthesis Of Monoethoxy-1,4-Dioxane. Preparation Of p-Dioxene. p-Dioxene was prepared according to the method of Summerbell and

Umhoef er*73 except for a slight modification, which brought about an increase in the yield.

Magnesium turnings (82.6 gms.; 3.4 moles)

and dry ether (1200 cc.) were placed in a five liter three-necked flask, equipped with a separatory funnel, reflux condenser and a mercury-sealed Hirschberg stirrer.

Iodine (91.5 gms.; 0.4 mole)

was then added in small quantities in order to keep the reaction from becoming too violent. When the mixture became colorless,

2,3-dichlorotdioxane (314 gms.;

2 moles), dissolved in dry ether (200 cc*), was added dropwise, with vigorous stirring, at such a rate that the color of the mixture due to the liberated iodine was never darker than light brown. required was nine to ten hours.

The time

The vigorous stirring was continued

until the mixture became colorless, after which it was allowed to stand overnight.

The mixture was then poured onto cracked ice and the

ether layer separated.

The water layer was extracted with three

100 cc. portions of ether, which were added to the ether layer. ether solution was dried over anhydrous sodium sulfate.

The

The solution

was then fractionally distilled, and the fraction boiling between 93—95° C. was collected.

The yield was 92.5 gms., representing 53*7

per cent of the theoretical. (73 )

Summerbell and Umhoef er, J. Am. Chem. Soc., 61, 3019 (1939)

62. — — H rePara-tion Of Crude Monochloro-1,4-Dioxane. p-Dioxene (64.5 gms.; 0.75 mole) was placed in a weighed 200 cc. three-necked flask, equipped with inlet tube, reflux condenser and mechanical stirrer. with an ice bath.

The flask and its contents were cooled to 0C C. Hydrogen chloride, obtained by the action of con­

centrated sulfuric acid upon sodium chloride, was then passed into the dioxene until the calculated amount (27.4 gms.) had been added. The amount of sodium chloride that was r e q u i r e d weighed 117 gms. p.

Preparation Of Monoethoxy-1.4-Dioxane. A sodium ethoxide solution was prepared by adding sodium (23 gms.;

1 mole) to absolute alcohol (500 cc.).

The solution was cooled in an

ice bath and the crude monochloro-dioxane was added gradually with continued cooling and shaking.

The mixture was then allowed to stand

overnight at room temperature.

The precipitated sodium chloride was

filtered off and the alcohol removed by distillation.

The residue

was distilled under reduced pressure in order to separate the liquid from the excess sodium ethoxide. distilled. obtained.

The distillate was then fractionally

A yield of 60 gms., boiling at 58-60° C. (18 mm.), was This represented 58 per cent of the theoretical yield,

based upon the amount of p-dioxene taken. Physical constants: Observed:

B.p. 50-60° C. (18 ram.);

ngo’ 1.4258;

M.R. 31.75;

Mol. Wt. 129.

Reported: M.R. 32.64;

Mol. Wt. 132.

D30 1.0646;

Analysis: Substance, 2.S63 mg.; Calculated for C 6H 1J303 : Found:

C, 54.42;

C03, 5.912 mg.; C, 54.54;

H, 9.35.

H s0, 2.477 mg.

H, 9.09.

63. 18.

Hydrolysis Of Monoethoxy-l,4-Dioxane. Monoethoxy-1,4-dioxane (l gm.) was placed in a 100 cc. boiling

flask.

Water (25 cc.) and concentrated hydrochloric acid (1 cc.)

were then added and the mixture heated on a steam bath for two hours. The solution was cooled and p-nitro-phenylhydrazine hydrochloride (1.3 gms.

in 50 cc. water) was added.

An orange precipitate, the

p-nitrophenylhydrazbne of 5-hydroxy-3-oxapentanal, was obtained. It was recrystallized from 50 per cent alcohol and melted at 140.5141.5

C.

The yield was 1.4 gms., representing 80 per cent of the

theoretical.

Reaction Between Monoethoxy-1,4-Dioxane And Phenyl Magnesium Bromide. Monoethoxy-1,4-dioxane (19.8 gms.; 0.15 mole), dissolved in dry toluene (100 cc.), was added to a phenyl magnesium bromide (0.2 mole) solution.

The mixture was heated on an oil bath to a temperature of

105-110° C. within the flask.

The temperature was maintained at 105-

110° for one and one—half hours*

The ether was removed through the

double condenser system during the process of heating the reaction mixture.

After cooling, the mixture was hydrolyzed wit h ice and dilute

sulfuric acid.

The toluene layer was separated and dried with anhy­

drous sodium sulfate.

The water layer was extracted with three 50 cc.

portions of ether, which were combined and dried.

The toluene and

ether solvents were distilled off, the residues combined and frac­ tionally distilled.

The fraction boiling 55-60° C. contained 14 gms.

of monoethoxy-dioxane. starting material.

This represented a 71 per cent recovery of the

No other product was isolated.

3.98 gms. of monoethoxy-dioxane were recovered from the hydrolysis solution as the p-nitro-phenylosazone of glyoxal. starting material was then accounted for.

SI per cent of the

64. 20 « a*

Synthesis Of 1,1,2-Triethoxy-Ethane, Preparation of Ethyl Bromoacetal. The method of Filachione60 was followed*

Vinyl acetate (50 gms.,:

0.58 mole) and absolute alcohol (175 cc.) were placed in a 500 cc. three-necked flask, equipped with inlet tube, mechanical stirrer and reflux condenser.

Bromine (90.5 gms.; 0.57 mole) was slowly added

by passing a stream of dry air over its surface and then bubbling the bromine-air mixture through the vinyl acetate.

The reaction

mixture was stirred constantly and kept at -10° C. with an ice-salt bath.

The time required for adding the bromine was four and one-

half hours.

After allowing the mixture to stand overnight at room

temperature,

it was poured onto an equal volume of cracked ice.

The

ethyl bromoacetal readily separated and was taken up with two 200 cc. portions of ether.

The ethereal solution was washed in succession

with two 100 cc. portions of water, 10 per cent potassium carbonate solution until free from acid (50 cc. required) and one 50 cc. portion of water.

It was then dried over calcium chloride.

The ether solvent was removed by reducing the pressure and the residue fractionally distilled. 70-74° C., was obtained.

A yield of 67.5 gms., boiling

This represented 60.3 per cent of the

theoretical. Physical constants: Observed:

B.p. 73-74° C* (21 mm.);

Reported:

B.p. 62—63° C. (15 mm.);

b.

n^° 1.4389. 1.4395;

D 30 1*276.

Preparation Of 1,1,2-Triethoxy-Ethane* Ethyl bromoacetal (59.1 gms.; 0.3 mole) was added with shaking

and cooling to a sodium ethoxide solution, prepared by adding sodium

65. (6.9 gms.; 0.3 mole) to absolute alcohol (100 cc.) in a 200 cc. round, bottom flask, equipped with a reflux condenser.

The mixture

was then heated gently on a steam bath for five hours.

The pre­

cipitated sodium bromide was filtered off and the filtrate distilled under reduced pressure to remove the liquid fraction from the excess sodium ethoxide.

The distillate was then fractionally distilled.

A yield of 29 gms., boiling 67-70° C (22 mm.), was obtained.

This

represented 59.6 per cent of the theoretical. Physical constants: Observed:

B.p. 67-70° C. (22 mm.);

Reported?1 B.p. 168° C. (761 mm.);

ng° 1.4023. n^° 1.4009;

DS1 0.8924.

Reaction Between 1,1,2-Triethoxy-Ethane and Phenyl Magnesium Bromide. 1,1,2—Triethoxy-ethane (16.2 gms.; 0.1 mole), dissolved in dry toluene (100 cc.), was added to a phenyl magnesium bromide (0.12 mole) solution.

The ether was distilled off through the double condenser

system, while the mixture was being heated to 105-110° C., at which point the temperature was maintained for one and one-half hours. After cooling, the mixture was hydrolyzed with ice and dilute sulfuric acid.

The toluene layer was separated and dried with anhydrous sodium

sulfate.

The water layer was extracted with three 70 cc. portions of

ether, which were combined and dried. The two solvents were distilled off, the residues combined and fractionally distilled.

A fraction, boiling 70-75° G. (27 mm.),

contained 9.5 gms. of the 1,1,2-triethoxy-ethane* a 58.6 per cent recovery of the original material.

This represented A yield of

2.2 gms. of 1-pheny1-1,2-diethoxy-ethane, boiling 100-102° (6 mm.), was obtained.

This represented 10.8 per cent of the theoretical.

Physical constants: Observed:

B.p. 100-102* 0. (6 ram.);

Reported:

B.p. 105-106° G. (10 mm.);

1#6064. ^ M.R. 57.30.

^

^

66. — a.

g ^ t b e s i s Of 2-Ethoxymethyl-l,3-Dioxalane. Preparation Of Crude Bromoacetaldehvde. The method of Hibbert and Hill31 was followed.

Paraldehyde

(200 gms.) was placed in a one liter three-necked flask, equipped with a separatory funnel, reflux condenser and a mechanical stirrer. A calcium chloride drying tube was placed in the top of the conden­ ser.

Bromine (575 gms.) was added slowly with constant stirring to

the paraldehyde, which had been previously cooled to -10° C.

The

time required to add the bromine was four and one-half hours.

The

reaction mixture was illuminated wittja 100 watt Mazda lamp. When the bromine addition was complete and the mixture became colorless, an aqueous sludge of sodium acetate (300 gms.) was gra­ dually added.

The mixture was allowed to stand overnight at 0° C.

(The sludge was prepared by dissolving the sodium acetate in a minimum amount of hot water and then cooling to 0° C.)

Ice water

(about 500 cc.) was then added to dissolve any solid present and the solution extracted with four 300 cc. portions of ether.

After neu­

tralizing the ethereal solution with 10 per cent sodium hydroxide solution, the ether layer was separated, washed with two 200 cc. portions of water and dried with anhydrous sodium sulfate. The ether was evaporated by reducing the pressure, leaving a faint yellow oily liquid.

b.

The yield was 183 gms.

Preparation Of 2-Bromomethyl-l,3-Dioxalane. The procedure of Hibbert and Hill was followed.

The crude bromo-

acetaldehyde (100 gms.) was placed in a 500 cc. three-necked flask, equipped with a reflux condenser and a mechanical stirrer.

Ethylene

glycol (45.5 gms.; 0.75 mole) and eight drops of concentrated sulfuric acid were then added.

The mixture was heated on a steam bath for nine

67. hours with vigorous stirring and then allowed to stand overnight. The mixture was extracted with ether (125 cc.) in order to separate the unreacted ethylene glycol.

The ethereal solution was neutralized

with 10 per cent sodium hydroxide (10 cc.), washed with 10 per cent sodium bisulfite (15 cc.) and then with water (40 cc.).

It was then

dried wi-fch anhydrous sodium sulfa*te. The ether was taken off by reducing the pressure and the residue fractionally distilled. was obtained.

A yield of 45 gms., boiling 74-76° C. (18 mm.),

This represented 36 per cent of the theoretical.

Physical constants: Observed:

B.p. 74-76° G. (18 mm.);

ng° 1.4822;

D a0 1.6422;

M.R. 28.93. Reported:

c.

B.p. 174-176° G. (760 mm);

M.R. 28.59.

Preparation Of 2-Ethoxymethyl-l,3-Dioxalane. 2-Bromomethyl-l,3-dioxalane (37 gms.; 0.22 mole) was added with

shaking and cooling to a sodium ethoxide solution, prepared by adding sodium (5.6 gms.; 0.25 mole) to absolute alcohol (100 cc.), in a 500 cc. round bottom flask, equipped with a reflux condenser. was then heated for six hours on a steam bath.

The mixture

The precipitated

sodium bromide was filtered off and the filtrate distilled under reduced pressure to remove the liquid fraction from the excess sodium ethoxide.

The distillate was then fractionally distilled.

9 gms., boiling 55-57° C. (21 mm.), was obtained.

A yield of

This represented

31 per cent of the theoretical value. Physical constants: Observed:

B.p. 55-57° C. (21 mm.);

Reported:

M.R. 32.64.

ng° 1.4122;

Ds0 1.0274;

M.R.

31.98.

68* Analysis: Substance,

2.998 mg.;

C0S , 5.779 mg.;

Calculated for C6H l203 : Found:

—

c,

52.57;

H,

C, 54.54;

H a0, 2.429 mg.

H. 9.09.

9 .0 6 .

— Reaction Between 2-Etho^ymethyl-l.5-Dioxalane And Phenyl Magnesium -■■■■