Title: Theoretical studies on the Mannich reaction
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Title: Theoretical studies on the Mannich reaction
Physical Description: 48 leaves : ; 28 cm.
Language: English
Creator: Fernandez, Jack E., 1930-
Copyright Date: 1954
 Subjects
Subject: Mannich reaction   ( lcsh )
Chemistry thesis Ph. D
Dissertations, Academic -- Chemistry -- UF
Genre: bibliography   ( marcgt )
non-fiction   ( marcgt )
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Thesis: Dissertation (Ph.D.) - University of Florida, 1954.
Bibliography: Bibliography: leaf 48.
Additional Physical Form: Also available on World Wide Web
General Note: Manuscript copy.
General Note: Vita.
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Bibliographic ID: UF00098035
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
Resource Identifier: alephbibnum - 000554275
oclc - 13379240
notis - ACX9109

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THEORETICAL STUDIES

ON THE MANNICH REACTION














By
JACK EUGENE FERNANDEZ


A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY










UNIVERSITY OF FLORIDA
August, 1951













CHEMIS TRY
LIBRARY

































UNIVERSITY OF FLORIDA

3 1262 08552 2893111111
3 1262 08552 2893










TABL' OF COIITEITF


Page
I. IITRODUCTIOIT. . . . . . . . . 1

II. EXPERII TIITAL . . . . . . . . 6

A. General Considerations . . . . . 6

B. Description of Materials . . . ... 7

C. Rate Studies on the Reaction of 2,4,6-

Trinitrotoluone with Tetracthylmcthyl-

enediamino . . . . . . . . 7

D. Rate Studies on the Reaction of 2,4,6-

Trinitrotoluene with Totraethylmethyl-

enediamine . .. . . . . . 12

E. Rate Studies on the Reaction of 2,4,6-

Trinitrotoluene with Tetraothylmethyl-

enodiamine . .. . . . . . . 1

F. Attempted Rate Studies on the Mannich

Reaction of p-Bromoacetophenone with

Tetraethylmethylenediamine . . . . 15

G. Attempted Preparation of Diethyl-

amino-p-bromoacetophonone. . . . . 17

H. A Study of the Yields Obtained in the

Reaction of Acetone with Formaldehyde

and Various Secondary Amincs . . . 19

I. Attempted Mannich Reaction of Triphenyl-

nethane with Tetraethylmethylenediamine. 20

i










Page
J. Attempted Mlannich Reaction of

Methylethylactophenone. . . . . . .21

K. A Study of the Reaction of Diethyl-

anino with Formaldehyde. . . . . .25

L. Attempted Preparation of

S Hydratropic Acid . . . . . ... .32

III. DISCUSSION OF RESULTS . . . . . . .36

A. Rate Studies on the Reaction of

2,4,6-Trinitrotoluene with

Tetraethylmethylenediamine . . .. .36

B. A Study of the Yields Obtained

in the Reaction of Acetone with

Formaldehyde and Various Secondary

Amines . . . . . . . . . .37

C. The Storic Factor in the Mannich

Reaction . . . . . . . . .39

D. A Study of the Reaction of Diethyl-

anine with Formaldehydo. . . . . .41

IV. SUR-IARY. . . . . . . . . . . 41

V. BIBLIOGRAPHY. . . . . . . . . .47

VI. ACKIIOILERDGLNT ... . . . . .. .48

VII. BIOGRAPHICAL IIOTES. . . . . . . . .49









I. INTRODUCTION


The Mannich reaction may be defined as the cordensa-

tion of ammonia, or a primary or a secondary aminc, with

formaldehyde and a compound containing a hydrogen atom of

pronounced reactivity due to proximity to an electron

withdrawing group. The original work by Mannich and his

coworkers was concerned primarily with aldehydes and

ketonos as the active hydrogen compounds but subsequent

work has broadened the scope of the reaction to include

carboxylic acids, esters, keto acids, acetylenes, nitro-

alkanes, nitro phenols, etc. The amino is usually employ-

ed as the hydrochloride, although in many cases the free

amine can be used to better advantage. The formaldehyde

is used either as the 37^ aqueous solution or as para-

formaldehyde whenever an organic solvent is cc'loyed.

From the above discussion it can readily be seen that

the Mannich reaction is one of great scope and utility.

Perhaps one of the most important applications of the

Mannich reaction in synthesis is in the production of

othylenic compounds by decomposition of the corresponding
Mannich bases. Thus unsaturated aldehydes, ketones, etc.,

may be prepared. The :annich bases ro al.o used as

alkylating agents.

The mechanism of the Mannich reaction has been the

object of much study in recent years and many views have

1









been brought forth, some of which are quite contradictor/.

Since the study of any reaction mechanism must always in-

clude a study of the intermediates involved, this portion

of the problem has probably received the most attention

and has been the object of the nost controversy. Bodendorf

and Koralewski (2) state that neither the methylol of the

amine nor that of the active hydrogen compound completely
satisfy the conditions of an intermediate. They also state

that the mothylol derivative of dinethylamine and pi::-

eridino could not be r.urified by distillation since they

readily decompose on heating. They have shown further

that these compounds were unstable in the presence of acid_

and would not form derivatives such as acetates or ben-

zoates.

Johnson (3) and Scnlkus (4) have demonstrated the re-

action of aliphatic amines with formaldehyde and both

primary and secondary nitro paraffins. They have shown

that the same product is obtained by the use of either of

the following reaction sequences:

R2lTI / HCHO R2TCT20H
R2ICiiHO2H z HC (Ci 3)2I2 2: C.2C ( '1)2 1102 1120

or HC:0 ,/ :C(CH3c )2170 IIOCH2C(CI ) 202

HOCiI2C(CIT )2II02 R2 '2 C 2(C'3 )2 102 / H20
Johns-n indicates that the work < scrib d does not give

sufficient evidence for establishing tl.e mechanism of the









reaction. oe, however, suggests that :hen the n-thylol

of the nitro paraffin is used the initial stop is a decom-

position of the nothylol into formaldehyde and nitro

paraffin followed by reaction of the anino with form-

aldehydo. Here again the arinoraethylol worre neither

isolated nor identified.

Alexander and Underhill (5) studied the reaction cf

ethyllmalonic acid with formaldehyde and diomthylamine.

These authors concluded that (a) the reaction follows

third order kinetics in acid solution, first order with

respect to each of the three components; (b) the rate of

the reaction shows a critical dependence on pH, it passes

through a maximum at about pH 3.8; (c) under the conditions

of the experiment no reaction takes place between ethyl-

malonic acid and formaldehyde; and (d) smooth third order

curves are obtained for the reaction only if the amino and

formaldehyde are mixed and allowed to stand for 12 hours

before adding the ethylmalonic acid, but if the formalde-

hyde and amine are replaced by dimethylaminomethanol, the

reagents may all b? nixed at once. They postulate that

the reaction is initiated by a reversible condensation of

dinothylamine an] formaldehyde to give dirnethylaninomethan-

ol. A hydrogen bonded adduct of the aminomethylol and acid

HA could then attack the ethyinalonic acid, probably in

the enol form, to produce, by the elimination of water

and the conjugate base A", a protonated molecule of dicethyl-









aminomethylethylmalonic acid. Reaction of this species

with A-" would give the free Marnich base.

This mechanism does not soon plausible from several

points of view'. The formation of the salt of dimethyl-

acino, for example, is no':here taken into account. It

s:-ems unlikely that free dinethylmaine or dimethylamino-

methanol could exist in acid solution. Moreover the meth-

ylol compound is probably a poor choice for an inter-

mediate since it has been shown by the author (7) that

the principle product in the reaction of secondary amines

with formaldehyde is the mothylenedianine and not the

aminomnthylol. The author has also shown that the re-

action of amines with formaldehyde is quite rapid compared

to the Mannich reaction proper, hence the reaction of

anine with formaldehyde uould not be a rate determining

step as was postulated by Alexandor and Underhill. Lie-

berman and Wagner (6) were the first to propose the ncth-

ylenedianinc as an intermediate. That this compound is

a better choice for an intermediate was shoim by the

author's previous work (7) and will be further substan-

tiated lnter in this dissertation. Liob2rman and Wagner

state that the ncchanisn of the Hannich reaction prob.aly

involves the fornntion of the cation1 IpCC+ from the

nothylnodiomino or aminomothylol, and -ubsoquent co'-

bination of this ion vith the anion formed by thie removal

of a proton from the active hydrogen compound. Those










authors state that the formation of the cation is induced

by added acid or by the acidity of the active hydrogen

compound or both. Experimental results supported the

following inferences: (1) excessive acid interferes

with the primary condensation of amine and carbonrl con-

pound and depresses the ionization tendency of the active

hydrogen compound, and (2) excessive alkocli decreases

or prevents the formation of the cation, and therefore

obstructs or stops the reaction.

This mechanism is howovor inconsistent with the form-

ation of methylonediamino if this can be considered an

example of the Mannich reaction in which one molecule of

amine is the active hydrogen compound, sinae the removal

of a proton fr-n an amine to forn an amide ion requires a

tremendous amount of energy especially in acid solution.

In all other respects the mechanism seems to be consistent

with the experimental facts.

Since all the previous work on the mechanism of the

Mannich reaction has dealt with the reaction in aqueous

solution and with the acid-base relationships, ti'is work

was undertaken to study the reaction in nonaqueous and

nonpolar solvents. A study of the steric factors was also

undertaken since in previous work this problem has been

almost completely ignored.










II. EXPERIMENTAL


A. General Considerations

In distilling the secondary amines used in this re-

search, a 20 inch column packed with Berl Saddles was used.

In all the other distillations a Claisen distilling appa-

ratus was used. Whenever the distillations were carried

out under reduced pressure, a Zimmerli gauge was used.

Temperatures are all uncorrected, and in keeping with

scientific works, they are all recorded in degrees centi-

grade.


B. Description of Materials

The following is a tabulation of the chemicals used

in this study containing the source, and, or, method of

purification.

2,4,6-Trinitrotoluono, Eastman Organic Chemicals, used as

received.

Triphenylmethane, Eastman Organic Chemicals, used as re-

ceived.

Sec-Butyl alcohol, Eastman Organic Chemicals, used as re-

ceived.

Trioxane, DuPont, used as received.

Trioxymethyleno, Eastman Kodak Co., used as received.

Hydratropic aldohyde, Givaudan-Delawanna, Inc., used as

received.










Karl Fischer reagent, Fisher Scientific Co.

Standard water in methanol solution, Fisher Scientific Co.

Diethylamine, Carbide and Carbon Chemicals Co., used as

received.

Dibutylamine, redistilled, B.P. 159-600.

Diallylanine, redistilled, B.P. 1090.

N-Phenylpiperazine, rodistilled, B.P.
Morpholino, redistilled, B.P. 128.50.
Piperidino, redistilled, B.P. 1060.
Dibenzylamine, Eastman Kodak Co., used as received.


C. Rate Studies on the Reaction of 2,4,6-Trinitrotoluene
with Tetra ethylethylenediamine
(1) A 0.1000 molar TIT solution was prepared by dis-

solving exactly 22.714 g. of TIIT in enough toluene (dried

over calcium chloride) to make a total volume of one liter

at 230. A 0.1000 molar totraethylmethylonediamine solution

was prepared by dissolving exactly 7.9291 g. of the methyl-

onodianine (prepared according to the method described by

Lewis (8)) in sufficient toluene to make a total volume of

500 il.
Fifty milliliters of each of these solutions, measured
from a 50 ml. volumetric flas:, wore mixed in a 100 ml. vol-
uretric flask and enough toluene added to bring the volume
up to exactly 100 ml. The solution was well shaken noting

the time and then poured into a 300 ml. 3 necked standard










taper flask fitted with a mechanical stirrer, thermometer,

and micro reflux condenser. The entire flask was immersed

in a water bath maintained at 23 0.10.

Samples of ca. 3 ml. were withdrawn at noted time in-
tervals and the reaction stopped in each by washing with

two 4 ml. portions of approximately 4 N hydrochloric acid

followed by one 4 ml. portion of distilled water. The

samples were then placed in glass stoppered weighing bottles

over calcium chloride and kept for analysis.

The optical density of each sample was determined di-

rectly from the infrared spectrogram.
In order to determine the extinction coeficient a in

the Bougeur-Beer equation (A = abc, whore A is optical den-

sity, a is the extinction cooficient, b is the cell thick-

ness, and c is concentration) several dilutions were made

from the previously described 0.1000 molar TNT solution

and the optical density determined for each. Table I lists

the values of optical density obtained from the 7.44 micron

band for each concentration of TNT used. A graph of optical

density vs. concentration is given on the next page. The

concentration determinations in this experiment were made

directly from the graph and not by substituting in the

equation itself. In this way, small deviations from lin-

earity were taken into account and a more consistent set

of values uero obtained. The true concentrations of TNT








Figure I


Optical Density
ve.
Concentration


1.4


1.3


1.2


1.1


1.0


0.9


0.8


0.7


0.03 0.04 0.05


Concentration
Moles/ liter


71


0.3


0.2


0.1


0.0


.00


0.02










were determined by plotting the values of CTrI (concen-
tration of TIIT) vs. time obtained from the infrared
spectrograms and extrapolating to zero time. The differ-
ence between this value and 0.0500 was subtracted from
each value to correct for the error which resulted from
the washing process.

Table I

CTUT A a

0.1000 1.32 66.0
0.0500 0.778 77.8
0.0400 0.647 80.9
0.0300 0.503 83.8
0.0200 0.342" 85.5
0.0100 0.169 84.5
0.00500 0.087 87.0

Average a 83.3 omittingg the 66.0 value).
In Table II are reproduced the data derived from this
experiment along with the values of the specific velocity
constants which were calculated from these data. The
equations used ore: kI .03log( C ), k2 1( )
t C x t x)
and k3 a (C--x)2--2) whoro k2, 13 are the first,
second, and third order specific velocity constants; t
time; C z concentration of THT and MDA (totraothylmothyl-
onediamino); and x a the amount of Mannich base formed.








Figure II



70


65 -


60 -


55


0 -


4b -


40 -





030-


25 -





15


10-





SI I I I I
0 2 4 6 8 10 12
ii ie


Second order curve

t ve. x
C(C-x)


14 16 18









Figure II is a graph of the second order function x
C(C x)
plotted against time.
Table II

Sample Ho. Time (hrs.) (C x) kI k2 k3

1 ,0.5 0.0473 0.1012 2.28 39.0
2 1.0 0.0465 0.0690 1.51 26.0
3 2.08 0.0416 0.042 1.94 35.3
4 3.08 0.0394 0.0725 1.75 32.5

5 4.0 0.0376 0.0645 1.65 31.4
6 .5.42 0.0348 0.0620 1.61 31.7
7 6.42 0.0321 0.0641 1.74 35.5
8 7.42 0.0322 0.0546 1.50 30.4
9 .19 0.0271 0.0691 2.06 45.5
10 19.42 0.0193 0.0447 1.64 42.6
11 43.92 0.0110 0.0304 1.61 54.1

Average k2 1.39 liter/mole hour (determined graphically).
D. In this experiment the procedure of C. was repeated
with the exception that the initial concentration of MDA
was changed. This variation was introduced in order to
determine the order of the reaction with respect to each
component. If the reaction is second order with respect
to TI~ and zero order with respect to MDA, or vice versa,
the equation k2a )( ) would be obeyed. If the
reaction is 'first order with respect to each component, the
I









equation k2b 2.303-log10CMDA(CTT -x) would be obeyed.
t(CT1T1 CMDA) CTiT(CMDA -x)

The initial concentrations were CT0i = 0.0500 molar and

CMDA = 0.0250 molar.
Exactly 50.00 ml. of 0.1000 molar TMT solution, meas-
ured from a 50 ml. volumetric flask, was mixed with 25.00
nl. of MDA, measured from a 25 ml. volumetric flask. The
time was noted and the resulting solution was diluted to
exactly 100 ml. in a volumetric flask. The entire operation
was conducted at a constant temperature of 230. The solu-
tion was then poured into the reaction vessel and treated
as in C. Table III contains the data collected from this
experiment.
Table III

Sample No. Time (hrs.) CTNT x CMA x k2a k2b

1 1 0.0482 0.0232 3.103 1.531
2 2 0.0479 0.0229 1.833 0.900

3 4 0.0462 0.0212 1.793 0.862
4 6 0.0420 0.0170 3.14 1.407

5 18 0.0317 0.0067 6.07 1.91
6 20 0.0318 0.0069 5,25 1.676

7 25 0.0300 0.0050 6.30 1.758
8 40 0.0280 0.0030 7.33 1.541

Average k2b = 1.69 liter/mole hour.
As in the previous determination, constant values for









Figure III


Second Crder

t vs.
ogCMDA(CrNT-x)
C rNT -(7C1~,-x J


Curve
/

/


/


C;

0

/
/




/'
//
//~

/r





/


/


- o
-0/



-0/
/ __


r I I I


0.2 0.3
CLLgCDA(CTNT-x)
C-1NT(CKLDA-x)


12
10


0.1


0.4


0.5










k were obtained only from the second order rate equation.

The fact that the data conformed to the equation for k2b

and not to that for k2a indicates that the reaction is

second order and first order with respect to each com-

ponent. The graph of the k2b function against time is

given in Figure 111.

E. This experiment was merely a rerun of part C. and

was made as a check on the results obtained in that ex-

periment. The toluene, in this case, was redistilled

just before use. Both the 0.1000 molar TIIT and the

0.1000 molar MD1' solutions were prepared using the re-

distilled toluene. Fifty milliliters of each solution

were mixed in a 100 ml. volumetric flask and enough

toluene added to bring the volume to exactly 100 ml.

Samples uore then withdrawn and treated as in C. The

data are reproduced in Table IV. The second order curve

is shown in Figure IV.

F. Attempted Rate Studies on the Mannich Reaction of

p-Bronoacetophenono with Tetraothylmothylenediamino

In this study a 0.1000 molar p-bromoacotophonone

solution was prepared as described above for TIT. A

trial run employing 100 ml. of a solution which vas

initially 0.0500 molar in p-bromoacetophonone and 0.0500
molor in tetrnethylmethylenediamine was made in order to

determine the approximate rate of the reaction. Tuo











Figure IV


Second Order Curve

t vs. xC
C(C-x)


50 1-


_/
I


L L A_1- L


I- I


time


20 25 30


-J _









samples vcre withdrawn and treated as described above
for T!Q at the and of 0.5 hours and at the end of 3.0
hours. The infrared spectrograms showed no appreci-
able difference in concentration of the ketone which
indicated that no reaction had occurred.
Before any further work was attempted on rate deter-
ninations, it was decided to attempt to prepare the
lannich base of p-bromoacetophenone since this com-
pound has not been reported in the literature.
Table 1V
Sample No. Time (hrs) ki k2 k

1 1 0.0782 1.37 57
2 3 0.0587 1.33 58

3 5 0.0622 1.53 73
4 7 0.0631 1.71 89

5 11 0.0536 1.51 85
6 23 o0.406 1.60 123

7 28 0.0365 1.56 160
8 49 0.0266 1.48 166
Average k2 x 1.56 litcr/molo hour.
G. Attempted Preparation of Diothylamino-p-bronoacoto-
phenone, 3.2 g. (0.02 mole) of tetract.ylmethylenedi-
amino, and 5 ml. of toluene was heated on a stean bath for
5.5 hours. The mixture was extracted with 4 N hydro-
chloric acid and the resulting solution neutralized









irth aqueous sodium hrdroxide. The oil layer whicl

separated was removed and the aqueous layer extracted

with toluene. The toluene extracts were added to the

original oil layer and the resulting solution dried

over Drierite and evaporated to remove the toluene and

diethylamine. Three grams of starting material was

recovered.

(2) A mixture of 3.5 g. of the ketone, 3.2 g. of the

methylenediamine, and 5 ml. of 95% ethanol was warmed

on a steam bath for 5.5 hours. At this time 50 ml. of

ice water was added to precipitate the original ketone

and any Mannich base which might have formed. The pre-

cipitate was washed three times with 1:1 hydrochloric

acid and then with water leaving 2.8 g. of starting

material. No product was recovered.

A rerun of this experiment also failed to yield any

product.

(3) A solution of 37.8 g. (0.19 mole) of p-bromoaccto-
phonone, 14.6 g. (0.2 molo) of diethylamine, 8.4 g. (0.28

mole) of paraformaldohydo, 14 ml. of con. hydrochloric

acid, in 80 ml. of 95% ethanol was refluxod for 10 hours

on a stonm bath. The ethanol was distilled off and the

residue washed with dilute hydrochloric to extract and

Iannich base pronent. Neutralization of this solution

with sodium hydroxide yielded no product. The oil remain-










ing after the acid washing described above Wias treated

with sodium hydroxide solution to decompose the Nannich

base hydrochloride which right have been insoluble in

water. Fractionation of this oil gave only a small

amount of starting material B.P. 96-1000 at 2.5 mm. and

mostly a black tarry residue.

A rerun of the above using 0.2 mole of amine hydro-

chloride in place of amine and con. hydrochloric acid,

after heating for 18 hours an-] treating as above, result-

el in 5 g. of material B.P. 98-90 at 2.5 am. 2,4-dinitro-

phenylhydrazone: M.P. 225-80; oxime: M.P. 122-5. This

material was p-bronoacetophenone. Only a black tarry

residue remained in the distilling pot.

H. A Study of the Yields Obtained in the Reactions of

Acetone with Formaldehyde and Various Sccondary Amines.

A mixture of 30 ml. (0.41 mole) of acetone, 8.4 g.

(0.28 mole) of parafornaldchyde, 5 ml. of 95" ethanol, and

0.19 mole of the secondary amine was allowed to stand at

room temperature for one week with frequent shaking. At

the end of this time 55 g. of powdered sodium bisulfite

was added with vigorous stirring and cooling. After stand-

ing in the ice bath for several minutes the mixttro was

filtered and the solid bisulfite addition compound decon-

posed by dissolving in dilute sodium carbonate solution.

The oil layer was removed and the aqueous layer extracted









four timze with cther. The co.-ie.d other extracts and

oil Inyor urao dried over an! y-'rous calcium zulfato, placed
under an aspirator, cndl finally unler a vacuun of 2 4 mn.

to re~ovo the otf.cr and unreacted naotone. The resulting

material :a::; taken to be the total yiold of Mannich base.
Table V is a tabulation of the amines usC. tozothor
ith the yields of Mannich base obtained in each case.
..Tle V

Amino Yiold of Mannich bane(c.) S Yield

Diothylnaine 0.6 2.2

Dibutylaline 10.5 27.8

Diallylamino 0.5 1.6
N-Phonylpipcrazsri 7.1 16.1

Morpholino 0.1 0.3

Flperidine 1.2 1.1
Dibonzylainoo 2.9 5.7

I. Attemteod l'annich reaction of TriphonylLlthanc with
Totraetihylnothiylono-iminr.o

To 103 C. (0.11 mole) of triher'elr.othano dissolved

in 30) ml. of dioxano uas oaded 67 G. (0.43 mole) of totra-
ct!'ylm-tl.ylonecdiaino in cno portion. Tho apparoat s con-

sisted of a on liter 3 noc;ed FT flnsa: fitted lith a

therno=-t-r, "tirr.r, andl reflux condeonor tho top of
wI ich wa- connected dou.nwarl by a ia .s tub2) into a large









test tube immersed in an acetone-Dry Ice trap designed to

collect any diethylamine which formed. The reaction

vessel was armed to 85 5o and maintained at that tem-

perature for 4 days. At the end of this time no reac-

tion had occurred, i.e., no diethylamine had collected

in the ico trap. One milliliter of 20 sodium hydroxide
was then added to determine the effect of a basic catal-

yst. Heating and stirring were then continued for an
additional 4 days. At this time no distillate had coll-

ected in the ice trap. Mlost of the dioxane n.as then re-

moved by distillation under diminished pressure, after

which the mixture was poured into ice-water. After one

recrystallization from ethanol, the precipitated solid

was filtered off and dried in a vacuum dessicator over

con. sulfuric acid, N.P. 87-900. The recovery of tri-

phcnylmethane was nearly quantitative.

J. Attempted Ilannich Reaction of Methylothylacetophen-

one

The mothylethylacetophonone used in third experiment

was prepared as follows by the reaction sequence:
(a) C3CH2CIIOCCH3 2 1OCl2 C:3CH2C1Ci- / S02 / HC1
(b) CHI CI' C CHc / 1e dry CH CHCICH(CH )MC
32 2 3ther
CiH CH2CI(CH )MgCl / CO2 C CH 3C!2CI1(CII3 )COO(eCl
CH3CI2CHI(CIF3)C00M1;C 1 .2 > Cyi3CH2CH(CH3)COOH /
I;CC 101






22


(c) CH3 CH2 C(CH3 )COOH SCC12 CH 3CH2CH(CH )COC1

SO 2 HC1
AI1C1
CCH3CH(C2CH(C3 )COC1 / C6H---6 3 CH3CHI2CH(CH )COC6H6 /

HC1.
(a) To a solution of 296 g. (4 noles) of soc-butyl
alcohol in 348 g. (4.4 nolos) of pyridine in a 2 1. 3
necked flask fitted with a thermometer, reflux condenser,
addition funnel, and mechanical stirrer, was added, while
cooling, 619 g. (5.2 noles) of thionyl chloride at such
a rate that the temperature never rose above 200. When
the addition :as complete, the ice bath was removed and
the mixture allowed to warm up to room temperature. The
flask was then warmed to 50-600 and kept at that tempera-
ture for one hour. The mixture was poured into ice water
and the oil separated. Distillation of this material
yielded 89 g. of sec-butylchloride, B.P. 66-80, (24' of
theory based on the alcohol).

(b) To 13.4 g. (0.55 mole) of magnesium turnings in 50
ml. of anhydrous cther was added a crystal of iodine and

3 g. of sec-butylchloride. The reaction was allowed to
proceed of its omn accord for 10 minutes, after which 50
ml. of other was added. The remainder of the 46 c. (0.5
mole) of the butylchloride in 300 ml. of other was added
dropwise. When the addition was comploto the mixture was
rcfluxcd for one hour. The flask was then cooled in an










ice bath and poured slowly into a beaker of Dry Ice sus-
pended in 100 ml. of other. The reaction was allowed to

proceed for 10-15 minutes and then 250 ml. of 1 : 1

aqueous sulfuric acid was added slowly to hydrolyze the

product. The ether layer was separated and the aqueous

layer extracted with two 50 ml. portions of ether. The

combined ether solutions wore washed with 150 ml. of 25'

sodium hydroxide to produce the sodium sa.t. The dissolved
ether was removed from the aqueous solution by warming on

a steam bath. The acid was then liberated by the addition

of con. hydrochloric acid and separated. Distillation of

this material yielded 29.7 g. of mcthylethylacetic acid,
B.F. 165-720, (58.3' of theory based on the butyl chloride).

(c) The acid chloride of the above material was prepared

by reacting 53.6 g. (0.53 mole) of the acid with 89.4 g.

(0.75 mole) of thionyl chloride for one half hour followed
by rofluxing for two hours and then distilling off the
excess thio-yl chloride. The resulting acid chloride was
added dropwise to a cooled, well stirred mixture of 160 g.

(1.2 moles) of aluminum chloride in 800 ml. (9 moles) of
benzene. Aft:r addition was complete the mixture was

stirred for an additional 2 hours at room temperature and

thon pou-od into 500 g. of ice and 125 ml. of con. hydro-

chloric acid. The aqueous layer was extracted with bon-

zone and the combined benzene solutions was ed with









sodium bicarbonate solution and then with water. Distill-
ation yielded 69.4 g. of methylethylacetophcnone, B.P. 106-
100 at 10 em. (81.7. of theory based on methylethylacetic
acid.
In the attempted preparation of the Mannich base of
mothylethylacetophenone, three modifications were used:

(1) no catalyst added, (2) acid catalyst added, (3) basic
catalyst added.

(1) Into a 500 ml. 3 necked flask fitted iuth a thermo-
meter, stirrer, and reflux condenser was placed 68 g.
(0.42 mole) of methylethylacetophenone, 79 g. (0.5 mole)

of t-traethylmcthylonediamino, and 75 ml. of 95% ethanol.
The mixture was heated at reflux temperature for 16 hours.
The contents of the flask were then transferred to a

Claisen distillation apparatus and nost of the ethanol re-
moved (72-870). The residue was washed once with water and
then frattionated to yield 52.4 g. of ncthylethylacotophen-

one, B.P. 105-80 at 10 mm., (77& recovery of starting
material). Ho hiCher boiling material uas obtained.

(2) A mixture of 30.8 g. (0.19 mole) of the aceto-
phenone, 21 g. (0.19 mole) of diothylamino hydrochlorido,
8.4 g. (0.28 mole) of paraformaldchyde, and 25 ml. of
951 ethanol uas heated at reflux temperature for 24 hours
in tho apparatus described above. The mixture was then
treated with a solution of 15 g. of sodiun hydroxide in









75 ml. water to decompose the amine hydrochlorides. The
oil layer was removed and the aqueous layer extracted

several times with ether. The combined extracts and oil

layer was distilled to yield 23.5 g. of the original
ketone 7.P. 104-70 at 10 mm., (76.41 recovery of starting

material). Here again, no higher boiling material was

obtained.

(3) The procedure of (1) above was repeated with the
exception that 0.5 ml. of 20% sodium hydroxide was added

at the beginning of the reflux period. This experiment

resulted in 27.3 g. of the original ketone, B.P. 104-60,

(885 recovery). No higher boiling material was obtained.

K. A Study of the Reaction of Diethylamine with Formal-
dehyde

In this series of experiments the reaction between

diethylanine and formaldehyde was studied by measuring

the amount of water formed during the course of the re-

action -t21ini / HCIIO --- t21:ICH20H O A .t21TCH2IT t2 / 1120.
Exactly 1.50 molar trioxone solution was prepared by
dissolving 22.5 g. of trioxane in enough methanol (distil-
led from magnesium methoxide) to make a volume of 500 ml.
Similarly, 1.50 molar dicthylamino solution was prepared

by dissolvin- 54.75 g. of redistilled diethylamino (B.P.

56.50) in enough methanol to make a volume of 500 il. A
blank was determined for each of these solutions by titrat-







Figure v




- -A


__ h


Rw
R










ing 25.00 ml. of each with Karl Fischer roagent which had

been standardized against standard water in r.othnnol sol-

ution (1 ml. 1 ng. water) immediately before use. It

should be noted here that in all the titrations which vare

performed, the Karl Fischer reagent was standardized just

before use.

The titrations were performed conductometrically

using the apparatus lhowun in Figure V where (A) are two

50 al. burets, (B) is a CaC12 tube, (C) is the titration

cell, (D) are two platinum electrodes, (E) is a magnetic

stirring bar, (G) is a galvanometer, (H) is a 1.5 volt

dry cell battery, and (R) is a variable resistance. The

end point was detected by titrating until the cglvanometer

needle showed a deflection which did not drift back to

the zero point.

(a) Tuonty five milliliters of each of the above solutions

wuro pipetted into the titration cell (a 250 ml. three

necked standard taper flask) and stoppered. The mixty're

was stirred for 30 minutes at room temperature by means

of a magnetic stirrer and then titrated with Karl Ficchcr

reagent. The data obtained are as follows:

Mg. uvater found. . . . . . . . .15.23

Mg. lat2r in oriCinal solutions (diethylamine) . 9.39

(fornmldohydo) . 2.77
MS. water formed in the reaction . . . . . 3.07









Millinoles water formed in the reaction. . . .. 0.177

Theoretical yield of water . . . . .. .18.75

Percent yield of water . . . . . . . 0.94

(b) Two determinations were made as follows. To 50.00

ml. of 1.50 molar diethylanino solution was added 25.00 ml.

of the 1.50 molar formaldehyde solution. The mixture was

stirred for 30 minutes and then titrated with Karl Fischer

reagent. When the end point had been reached, an addition-

al 25.00 ml. of the formaldehyde solution was added. The

resulting solution was stirred for 15 minutes and then

titrated. The first titration indicated that 0.0094

millimole of water had formed in the reaction. The second

titration indicated that 0.096 milliroles of water had

formed in the reaction.

(c) A mixture of 25.00 ml. of each of the original solu-

tions was allowed to stand at room temperature for 48 hours

and then titrated with Karl Fischer reagent.

Found: 0.46 millimolos of water had formed, (2.45% com-

pletion).

(d) In order to determine the effect of the solvent in

this reaction it wns decided to carry out a series of ex-

periments similar to the ones described above using dioxane

as solvent. The diethylamine and formaldehyde solutions
were prepared exactly as doscribel above with the ex-

ception that dioxane was used instead of methanol. The










dioxone had been previously dried over calcium chloride.

A solution of 25.00 ml. of each of the 1.50 nolar

solutions was allowed to stand with frequent stirring

for 20 hours at which time it was titrated with Karl

Fischer reagent as described above.

Mg. water found. . . . . . . . . 124.42

:g. water in original solutions (diethylacine) . 63.51

(formaldehyde) . .5748

Mg. water formed in the reaction . . . . . 40

Millimoles water formed in the reaction. . .. . 0.19

Theoretical yield of water (millimoles). . .. 18.75

Percent yield of water . . . . . . .. 1.01

(e) Twenty five milliliters of each of the above solu-

tions were mixed and allowed to stand with frequent stirr-

ing for 72 hours. The solution was titrated with Karl

Fischer reagent and the fc]lowing data collected.

Mg. water found. . . . . . . . . 116.36

Mg. water formed in the reaction . . . . .-4.66

Millimoles water formed in the reaction. . . .-0.024

Percent yield of water . . . . . . . .

(f) Since the above experiments all resulted in only a

very scall degree of reaction, it is obvious that the rate

controlling step is that of the delolynerization of the

paraformaldehyde. Represented schematically:









(-c20-)3 3HCHO

HCHO / (C2HI5)2IH -- Products.

It was therefore decided to perform a series of experi-
ments using monomeric formaldehyde solution instead of

the solution of the trimer.

The formaldehyde solution was prepared by passing

formaldehyde gas ( Generated by heating 13 g. of trioxy-

methylene) into a weighed quantity of anhydrous methanol

in a 250 ml. volumetric flask. The gain in weight of the

flask was 12.00 g. (0.400 moles), so that the solution on

dilution to 250 ml. was 1.60 molar in formaldehyde.

A mixture of 25.00 ml. of this solution and 25.00 nl.

of the 1.50 molar mothanolic solution of dicthylanine was

stirred for one hour at room temperature and then titrated

with Karl Fischer reasnot as above.

Mg. water found. . .. .. . . . . . 216.2

Mg. water in original solutions.(diethylaminc) . 9.39

formaldehydee) . 27.77
Mg. water formed in the reaction . . . 179.0

Millimoles water formed in the reaction. .. .. 9.94

Theoretical yield of water . . . . . . 18.75

Percent yield of water ... . . 53.0

In the above eoperimont the end point faded very

rapidly and continued to do so until the theoretical

amount of water had reacted with the Karl Fischor reagent.









At this point 20.3 nillimolos of water had formed. The

first end point was taken as that which gave the first

large deflection of the galvanometer needle.

(g) Twenty five milliliters of each of the above solu-

tions were mixed and allowed to stand with stirring for

10 minutes. This mixture was titrated with Karl Fischer

reagent to determine the extent of the reaction in this

time interval. It vas observed that the first drop of

reagent caused a very large deflection of the galvanometor

needle. This end point faded very rapidly and every

subsequent addition produced the same effect until 50 ml.

had been added. At this point the titration was stopped.

The position of equilibrium could therefore not be estab-

lished in this experiment.

(h) Twenty five milliliters of each of the above solu-

tions was mixed and allowed to stand with stirring for

24 hours. At the end of this time the mixture was tit-

rated with Karl Fischer reagent to give the following

data.

Mg. water found . . . . . . . . .201.4

Mg. water in original solutions (diethylamine). . 9.39

(formaldehyde). . 27.77

Ig. wat-r formed in the reaction. . . . . .164.2

Millimoles wter forme! in the reaction . . . 9.12

T':eoretical yield of winter. . . . . . . 18.75









Percent yield of water . . . . . . .48.64

In this experiment the end point (point of equilibrium)

was determined as in (f).

L. Attempted Preparation of Hydratropic Acid

(a) Permanganate Oxidation of the Aldehyde

Ninety nine grams (0.74 mole) of hydratropic aldehyde

was dissolved in 20-30 ml. of acetone. One hundred grams

of potassium permanganate was dissolved in water and added
dropwisc, with stirring, to the acetone solution. After

all the permanganate solution had been added, 600 r'. of

3N HC1 was ndded with stirring to decompose the MnO2. The

organic layer v;as removed u;ith a separatory funnel and

filtered through a sinterod glass crucible. It was then

treated with a saturated solution of sodium bisulfite to

remove any unroacted aldehyde. This mixture was again

filtered and the organic layer washed twice .:ith dilute

HC1 and then three times with water. This material was

then separated and dried in a vacuum desiccator over

CaC12 at ca. 1 am. overnight. Yield: 37.5 g. of a sub-

stance which was insoluble in sodium carbonate.

A rerun of the above experimer.t in which the tomper-

atrre was never allowed to exceed 500 resulted in a

material which was also insoluble in sodium carbonate

solution.

(b) Filver Oxide Oxidation of ITydratropic Aldehyde










To a cooled suspension of 108 g. of silver oxide in

100 ml. of dilute sodium hydroxide solution was added

slowly 120 g. of hydratropic aldehydo. After refluxing

the mixture for one hour, it was filtered and the filtrate

acidified with dilute sulfuric acid. The oil layer was

separated and the water layer extracted with ether. The

combined ether extracts were added to the oil layer and

the resulting solution dried overnight over Drierite.

After removing the ether under reduced pressure, the prod-

uct was distilled under reduced pressure to yield 18 g.

of material B.P. 160-30 at 24-5 mm. It was noted that

considerable decomposition occurred during distillation

so that it varn decided not to purify further runs by this

method.

Several subsequent runs of this reaction using various

modifications of the conditions failed to pro-uce ar:

hydratropic acid and this method a'.a abando- 1. It was

believed that hydratropic acid might be prepared Via the

nitrile so the following experiments were performed.

(c) Alpha-chlorocthylbenzon2 vas prepared 4y passing dry

hydrogen c'lorido into 10) g. of freshly distilled styrene

(B.P. 400 at 13 nm.) cooled in an aceto e-Dry Ice bath

until the gain in ;eight of the reaction vessel and its

contents had reached 50 g. After the mixture had been
allowed to varm up to roo~ temperature it was distilled









to yield oc-chloroethylbenzene, B.P. 60-710 at 10 mm.

To a solution of 34.5 g. (0.53 mole) of KCli in a
mixture of 153 ml. of ethanol and 61 ml. of water at the

boiling point was added dropwise 63.2 g. of the chloro-

ethylbenzene. After addition was complete the mixture

was allowed to reflux for an additional hour. After

cooling, the mixture was separated and the water layer

extracted several times with ether. The combined extracts

were added to the organic layer, heated with charcoal,

filtered, and dried over Drierite. The ether was removed

under diminished pressure and the dark brown liquid

which remained was used without further purification.

The liquid obtained above was hydrolyzed by heating
under reflux with a mixture of 100 ml. of water and 100

ml. of con. sulfuric acid for two hours, then pouring

into a beaker of ice water. The oil uas separated, washed

once with water, dried, and distilled to yield 10 g. of a

clear liquid, B.P. 140-5 at 3-3.5 am. This material was

found to be insoluble in sodium bicarbonate solution.

Many subsequent trials of this experiment, using also

the bromo-derivative, failed to yield any hydratropic acid.

(d) To 14.6 g. (0.6 mole) of magnesium turnings in 100 ml.

of anhydrous other in a 3 liter flask ws added a few

milliliters of (-bromoethylbenzcne and a crystal of iodine

to initiate the reaction. The reaction was allowed to








proceed of its own accord for 13 minutes after which tino

the remainder of the 111 g. (0.6 mole) of the bronocthyl-

benzene was added through a separatory funnel while cool-

ing the flask in ice water. The reaction mixture urns

refluxed gently for 1.5 hours and then pieces of Dry Ice

were aided in excess while stirring. After about 15 min-

utes, dilute sulfuric acid was added to hydrolyze the

product and dissolve the magnesium. The organic layer was

separated and the aqueous layer extracted several times

with ether. The combined other solution was treated with

dilute sodium hydroxide and the resulting water solution

neutralized with hydrochloric acid to liberate any hydra-

tropic acid. No product resulted from this treatment.

Evaporation of the ether solution, however, loft a mater-

ial. which was partially liquid and partially solid. Some

physical constants of these products are given here.

Liquid fraction: B.P. 136-4o0 at 10 mm.

Solid fraction: M.P. 125.5-127.5P, molecular eight 212.
These products are believed to be isomeric diphenyl-

butanes. The literature (10) Gives for 2,3-diphenyl-

butane a B.P. of 1400 at 10 em., and for 2,2-diphenylbutane,

a M.P. of 127-80. The molecular weight of the diphenyl-
butanes is 210.3.










III DISC"S "IO~ OF R .CULTS


A. Rate Studios on the Reaction of 2,4,6-Trinitrotoluene

with Tetraethylmethylened iamine

The determination of the order of this reaction was

made by assuming each rate law and plotting the appropriate

function based on that particular equation against time.

The equation which resulted in a straight line was taken

as the one which satisfied this reaction. In this way,

assurance could be had that the data did not fit the equs-

tions which were discarded.

The rate studies on the reaction between TNT and tetra-

othylmethylenediamine which wore described in the experi-

mental section of this dissertation all led to the con-

clusion that the reaction obeys the second order rate law.

The results obtained by the use of unequal concentrations

of the starting natarials indicate that the reaction is

first order with respect to each component. The values of

the rate constants determined from the slopes of Figures

II, III, and IV respectively, are tabulated belou.


Experiment Initial Concentration Fecond Order
Ho. TiT IDA K liter/mole hour.

1 0.0500 0.0500 1.39

2 0.0500 0.0250 1.69

3 0.0500 0.0500 1.56









The mechanism of this reaction can then be represented
simply ns the combination of one molecule of T!'T with one
of MDA to form an activated complex uhich can break down to
form a molecule of Mannich base and a molecule of the
secondary amine. This can be represented schem-tically as

N02 ;(C2Hq)2 1102 ------N(C 2 )2
"20 /r- 2NO 2

1102 1 I(C25 5)2 ;02 iI(C 2 2


1102
NO2
-- !02 7 I2CH2CNH21(C2H5)2 / HIT(C2H5)2.
1102
IIO2

The prediction of an activated complex as shown here is
explained on the basis of the results obtained from the
experiments on triphenylmethano and nothylethylacetophenone
which will be discussci later in this section, (cf. pp.
3"-41).
B. A Study of the Yields Obtained in the Reactions of
Acetone with Formaldehyde and Various Secondary Amines
The percent yields of Hannich base obtained from the
reaction of acetone with formaldehyde and some secondary
amines are tabulated in Table V of the experimental sec-
tion. These values are reproduced here alon- ith the
ionization constants of the amines in order of ,ecr-asing










Kb.
Amine Fercent Yield Kb

II-Phenylpiperazine 16.1 ..........

Piperidine 4.1 3.40x10-l'

Diethylamine 2.2 2.26x10-

Dibutylanine 27.8 9.94x10-5

Diallylamine 1.6 3.12x10-6

M-orpholine 0.3 3.02x10-6
Dibenzylamino 5.7 1.48xl0-6
With the exception of !-phenylpipor zine whose ioniza-
tion constant could not be found, and dibutylamine and di-
bcnzylamino which do not conform, a correlation of percent

yield with Kb is quite obvious. That is, the yield of
Mannich base appears to fall off as amines of lower basic-

ities are used. This observation is completely in line

with the author's previous :ork (cf. reference 7) i-rich

indicated that the formation of methylonediamine was favored

by low basicity of the amino. This was explained by the
fact that the cnCrry requirement in removing a hydrogen

atom front an amine is louer the rcaklr the amine is as a

base. The phenorncnon un-lr dicc- scion hore can be cx-

plained by the same line of reasoning. Since the reaction

of a methylonediamino with acetor.- is dependent on the

rupture of the C-It bone, tlo reaction is on'anced by










instability of the nethylenedianine. The Mannich reaction

of acetone with secondary anines is therefore aided by a

high amine basicity since highly basic anines would, in

the course of the reaction, produce methylenediamines of

lower stability and therefore higher reactivity toward the

acetone.

C. The Steric Factor in the Mannich Reaction

Thoe conditions under which attempts were made to pre-

pare the Mannich base of triphenylmethane are described on

pages 20-21. It was found that no reaction occurred on

vigorous :arming over a period of 8 days with or without a

basic catalyst. The conditions under which the prepara-

tion of the Mannich base of methylethylacetophenone was

attempted are described on pagcs 24-25. This reaction also

failed to proceed regardless of the nature of the catalyst

used or the length of time of heating.

It is believed that the failure of these reactions to

procei as expected can be explained on the basis of steric

considerations since presumably the hydrogen atoms involved

are labile enough for reaction to occur. Furthermore, on

the basis of this argument, the intermediate can be predicted.

Fishcr-Iershfolder-Taylor models were made of the above

compounds. By removing a hydrogen atom from the methylene

carbon of a tetraothylmothylenediamino model, an attempt

was made to join this group to the models of t.e above con-









pounds to give respectively

(C2 ) 2 --(C )2 (C2H ) 2H--"-- (C2"5)2
CT 6"5- 6n and C- C--ig

C6k5 C-0


These r.odels uere found impossible to construct. If the

assumption is made that the nethylenediamine is the nec-

essary intermediate, the failure of these compounds to

react can be explained on a steric basis.

A nodel of diethylaminomethanol was constructed and

a hydrogen atom removed from the methylene carbon atom.

Adducts of this group with the above compounds represented
as

(C2 I5 )2-C -OH (C2H )21 -C:--oI
C 65-C-C -615 and CH3-- --C-25
c6H5 C-O

c6"5

were readily constructed which shows that if steric hin-
is the crucial factor in these reactions the nothylol is

not the intermediate. The true intermediate is then, based
solely on steric considerations, the mothylonediamino.
That methylothylocetophenone should react under the

conditions of the IMannich reaction were it not for steric

hindrance is suggested by the fact that n-butyrophonone does

react under these conditions cf. reference 11). The model










of the adduct of tetraothylnethyl-nedianinc and n-butyro-

phenone was found to be quite readily assembled. Photo-

graphs of the models of triphenylmothane and mnthylethyl-

acetophenono together with that of tetraethylmethylene-

dianine are shown on the following pages. Also shorn are

photographs of the models of the tetraethylmathylonedi-

anine-diphenylacetonitrile adduct, diphenylacetic acid,

and phonylcyclohexylacetonitrile. The Mannich base of

diphenylacotonitrile with dimethylamino has been prepared

(cf. reference 9) but these authors state that those of

diphonylacetic acid and phonylcyclohexylacetonitrile could

not be prepared. It is worthy of consideration that the

atomic models of the tetraethylmothylonediamine-diphenyl-

ac2tic acid and tetracthylaothylonediamine-phenylcyclohexyl-

acetonitrile adducts could not be assembled, since this

fact is in accord with the steric requirements postulated

herein.

Although the nasertion that the methylenediamine is

the necessary intermediate in these exao.les of the Iannich

reaction is of course not definitely proven by the above

facts, the evidence does point very strongly in that direc-

tion.

D. A Study of t' Reaction of Diethylamine with Formal-

dehyde

A summary of the data obtained from this series of

experiments is Given in Table VI.











Triphonylmethane and
Tetraethylmethylonediamine


Methylethylacetophenone
and
Tetraethylnethylonediarine


L


. .-........... .


Diphenylacetonitrile-
Totramethylmethylono-
diomine Adduct


-1











Diphenylacetic Acid and
Tetramethylmathylene-
diamine


I



i


2,4,6-Trinitrotoluene-
Tetraothylmethylenedianine
Adduct


L

I '


Phenylcyclohexylaceto-
nitrile and Tetraoethyl-
methylenedianmne







__jiih ^^^^*i ^


L


f ... .............. ...........








42







43
D r-I CM \0 lN r- *
0 0 O CM 4- 0 0
(-1 * *



P r i



GI-H O 0 4- H 0
S 3* * *
S 0 00 0 0 C 0
*nr
.--


S l tN r co 0 o
*C 0 H ON CM O O0 0 C




0 * *
oO r-1 C-O '0 0
40
H- r-












CV*
O \ V\ O O O O O
43 *I 0 0
> *Cr O O CO O C r-1 C



S* o *0
E-l r-l r l r-l r- E r-l
43 0 0 0 S






1- *
+ tr\ O lp\ tr\ 1f\ tri tf1




H re rl r4 r 0 r rl rl 3




o 0 80 0
0 z sIP\ t br\ z \ 1R C
C )C M C3 C C1 C C1 Oc



r-l 40
4 0 0 O


r-1 O
0 0 *r 0




0 H 0c cr tr\ '0 N
W









The information which has been derived from these

experiments is based on the following reaction which has

been proposed for the reaction of a secondary amine with

formalJehyde (cf. reference 7 ).

(C2H5)2t1H / HCHO (C2H )211CH20H

i-(C2H )2NCH2i(C2H )2 / iHC-0 / -H20.
By titrating the water formed during the course of the

reaction the amount of methylenediamine is known since the

molar quantities of wator and methylenediamine are equal.

The values determined in Experiments 6 and 7 Given in

Table VI are of course only approximate since the end points

were not sharp. These values therefore indicate mnrely

the approximate equilibrium position with respect to the

totraethylmethylcnediamine. INo information can be derived

from these experinmnts concerning the part played by the

aninomethylol. It is knorn that approximately 50 of

methylcnediamine had fornmd at equilibrium, but the rela-

tive quantities of the oth-r materials ware not known.

A point of importance which has been established by

thase experiments other than the position of equilibrium

with respect to tetracthylamthylenadiamine ir the fact that

the reaction proceeds quite rapidly to a point of very

dynamic equilibrium. It was impossible? to determin- the

velocity of the reaction by this method but it can be

assumed that it is quite rapid since the deterir.ations










made after 1 and 24 hours respectively resulted in essen-

tially the game value for the extent of the reaction. From

this, the assumption that the rate determining step in the

Mannich reaction is the reaction of the amine-formaldehyde

product with the active hydrogen compound is completely

justified. The phrase "amino-formaldehyde product" is

used here because it has not been definitely established

that the aminomithylol cannot serve as the intermediate,

although part C. of this section gives strong evidence

against this possibility.

In the case of experiments 1, 2, 3, 4, 5 of Table

VI the rate determining stop was depolymcrization of

trioxane to produce monomeric formaldehyde.










IV SUIMARY


A study has boon made of the rate of the reaction of

2,4,6-trinitrotoluene with tetraethylmcthylcnediamino in

toluene solution. These studies led to the conclusion

that the reaction follows second order kinetics, first

order with respect to each component. A mechanism has

been postulated for this reaction which involves the com-

bination of one molecule of each component to form an

activated addition complex which can decompose into the

:annich base and diethylamine. The postulate of an acti-

vated addition complex between the trinitrotoluene and

methylonedianine is substantiated by a study of the steric

factors which enter into the reaction. These studies

based on the theory of steric hindrance point to the meth-

ylenediamine as the necessary intermediate. Evidence has

also been found which leads to the conclusion that the

lMannich reaction is enhanced by high amine basicity.

The reaction of diethylamine with formaldehyde has

been studied and found to lead to a 50 formation of the

methylonedianino a' equilibrium. Although the rate of this

reaction was not determined, it was found to be quite high.

Equilibrium is probably attained in a matter of minutes.

This conclusion justifies the assumption that tlo rate deter-

mining stop in the I'annich reaction is the reaction of the

45






46


mnthylcncdiamine with the active hydrocon compound.

Several futile attempts uere made to prepare hydra-

tropic acid. The methods which were used are described.









BIBLIOGRAPHY


(1) Blicke, Organic Reactions, Vol. I, 303.
(2) Bodendorf and Koralewski, Arch. Pharn., 271, 101-16
(1933).
(3) Johnson, J, An. Chen. Soc., 68, 12-18(1946).
(4) Senkus, J. An. Che-. oc.,, $8, 10-12(1946).
(5) Alexander and Underhill, J. Am. Chem. Soc., 21, 4014-
19 (1949).
(6) Liebornan and :.agncr, J. Or,. Chcm., 14, 1001-12(1949).
(7) Fernandez, M. S. Thesis, University of Florida, 1952.
(8) Lewis, Ph.D. Dissertation, University of Florida, 1952.
(9) Zaugg, Horrom, and Vernsten, J. An. Chen. Toc. 5, 288
(1953).
(10)Feilbrcn, Dictionnr:- of Orranic Compounds, Vol. II,
page 405.
(11)Ruddy and Buckley, J. An. Cheo. Soc., 2,, 718-21(195C).










ACKIO'.,!LEDGI .1T


The author wishes to express his sincerest appre-

ciation to all the members of his supervisory committee,

and especially to Dr. George B. Butler who supervised

this research project. His friendship, guidance, and

constant inspiration made this work possible.

The author is also indebted to all the other men-

bers of the staff and to his follow students who aided

him greatly throughout the course of his research.

Thanks are also given to the author's wife for

her patience and encouragement.










BIOGRAPHICAL NOT.S


Jack 3. Fornnndoz was born in Tanpa, Florida on May

18, 1930. He entered the University of Florida in Sep-
tember, 1947 whero he held the positions of student assis-

tant and Research Corporation assistant as an undergrad-

uate.

He received the degree of Bachelor of Science in

Chemistry in Juno, 1951 and in the same year entered the

Graduate School of the University of Florida where he has

hold a U. S. Ilavy research assistantship ar.n an Army

Ordnance research assistantship. He receiv-d the degree

of pastor of Science in August, 1952.

He is a member of the Beta Alpha Chapter of Gna

Sigma Epsilon, Sigma Xi, and the American Chemical

Society.










COiMMITTEE REPORT


This dissertation was prepared under the direction of

the candidate's supervisory committee and has been

approved by all members of the committee. It was submit-

ted to the Dean of the College of Arts and Sciences and to

the Graduate Council and was approved as partial fulfill-

ment of the requirements for the degree of Doctor of

Philosophy.



August 9, 1954




Dean, College of Arts and Sciences



Dean, Graduate School


SUPERVISORY COMMITTEE:



C chairman





C. f
k/ .J ," 1




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