STUDIES W THICAMIDES
A THESIS
Presented to the Faculty of the Division of Graduate Studies
Georgia Institute of Technology
In Partial Fulfillment
of the Requirements for the Degree
Master of Science in Chemistry
by
John Angus Brown
June 1951 STUDIES ON THIQAMIDES
Approved^
Date Approved by Chairman l7tm^ 3^ iii
AGKNCffLEDGEMENTS
I irould like to express my appreciation to Dr* James
A. Stanfield for his suggestion of this problem and for his assistance in its prosecution, to Dr» William H« Sberhardt for his assistance with the infra-red work and his help in the molecular interpretations, and to Dr« Smmett Reid for his suggestions on amide syntheses* TABLE OF CONTENTS
I INTRODUCTION 1
II HISTORICAL 2
HI EXPERIMENTAL k
Iff DISCUSSION
v suMm 17
BIBLIOGRAPHT. 18
APPENDIX 1$ CHAPTER I
DraODUCTIQN STUDIES ON THIOAMIDES
CHAPTER I
INTRODUCTION
It has been shown previously that thioketones and
thioaldehydes will react with copper powder (or Raney nickel)
in a coupling reaction to give olefinic compounds^
R .R Rv /R
R R R R
The purpose of this investigation was to extend the
reaction to include thioamides which also contain the CSS
linkage* If theC«S linkage in thioamides is analogous to
that in thiocarbonyls, a symmetrical olefin with amino groups
adjacent to the double bond should result:
R
This class of compounds (ene-diamines) has not been
reported, nor has reference to such a reaction been found in
the literature*
1 Wood, Bacon, Meibohm, Throckmorton, and Turner, J* Am* Chem* Soc*, 63, 133U (191.1). 2
CHAPTER II
HISTORICAL
In 1876# Kllnger first observed the coupling reaction of
t hi ©aldehydes by finding in the distillation of trithiobenzaldehyde
considerable quantities of stilbene.1 He also found by heating
the thioaldehyde with copper powder much larger amounts of the
stilbene could be obtained*
Since that time investigators hare tried the reaction
on a variety of thioaldehydes and thioketones *2 In virtually
every case appreciable yields of olefinic compounds were reported;
however, this has not been true of dithioaMehydes*^
There is no report of the reaction being applied to
thioamides, although thioamides themselves are quite well
known* An extensive review- article which discusses the pre
paration and properties of a number of thioamides including
about 2^0 literature references appeared recently.£
"^linger, Ber., 9, 1893 (1876).
2 Campaigne, E*, Chem* Rev*, 39, 1 (191*6). 3
Wood and St an fie Id, J. Am* Chem* Soc*, 6k, 23U3 (19U2)* Sfinthrop, Master1 s Thesis, Georgia Institute of Technology, 19U9. Chabrier and Renard, Bull* soc* chim* France, 19k9, D, 272* CHAPTER II
HISTORICAL 3
There are several standard methods for preparing
thioamides .6 The earliest was the method of Cahours? who
prepared thiobenzamide by passing hydrogen sulfide gas into
an ammoniacal solution of benzanitrile. Thioamides have also
been prepared by treating amines with sulfur^, and by treat
ing aldehydes, ketones, alcohols, and olefins with ammonium
polys ulfide^ • However, the most widely-used preparation has
been the treatment of oxygen amides with phosphorus pentasulfide with benzene as a solvent 2*0,"^\
The reactions of thioamides have been reported exten
sively^, but no mention has been found of the reaction with
copper powder.
6Ibid. 7 ' Cahours, Compt. rend,, 27, 239 (18W). 8 "~ WaHach, Ann,, 2j>9, 300 (1890). 9 Willgerodt, Ber», 20, 21*67 (1887). 10
Hoffman, Ber., n, 338 (1&78)# 11
Kindler, Chem. Z., 1, 2633 (192h). k
CHAPTER III
EXPERIMENTAL
A. PREPARATION OF COPPER POWDER
Four hundred grams of copper sulphate pentahydrate was dissolved with stirring in about two liters of water, and then one hundred grams of zinc dust was added in one portion*
Stirring was continued for about thirty minutes longer to insure complete reaction and the precipitated copper powder filtered with suction* The powder was not allowed to stand exposed to air since it oxidized very rapidly, but was immediately washed several times with 9% ethyl alcohol* This served both to dis place the water and to retard oxidation* Some of the alcohol was removed by allowing the resulting mixture to stand overnight at room temperature under a total pressure of approximately 20 mm.
(water aspirator vacuum)* The alcohol-damp powder was stored in a tightly-stoppered bottle under nitrogen until time for use*
The material was thoroughly dried immediately before use by heating it in the reaction vessel under the same conditions as those to be used in the subsequent reaction*
B* PREPARATION OF THE THIOAMIDES
1* THIQACETAMJJDEj One hundred forty-four grams of acetamide was mixed with 108 g* of phosphorus pentasulfide in a round-bottom flask containing 7f>0 ml* of benzene and the mixture re fluxed on a steam bath for 30 minutes* The benzene solution was then poured off and another 750 ml* portion of benzene added CHAPTER III
EXPERIMENTAL 5
and re fluxed for a similar period of time. Four such extractions were made*
The benzene extract was allowed to cool to room temperature, whereupon crystals of thioacetamide formed* These were removed and the remaining solution distilled to about one-fifth its former volume* More crystals were recovered from the residue.
The combined product was recrystallized from benzene and almost-white crystals melting at H0-U1°C* (corrected) - one degree higher than previously reported - were obtained. The final yield was 11*3% of the theoretical amount* 6
2. TKIOPROPIONAMIDE: Thiopropionamide was prepared from propionamide in a manner exactly analogous to that described above for the preparation of thioacetamide• Its purification, however, was considerably more difficult since the cooled benzene extract did not deposit any crystals until frozen solid.
The product was finally obtained, by freezing the extract, allow ing it to warm until about half of it had melted, and then rapidly filtering the resulting mush. Crystals of thiopropionamide remained on the filter. These were quickly removed and dried between sheets of filter paper since they proved to be extremely
soluble in the mother liquor. The process was repeated with the filtrate, and continued until forther treatment gave no more crystals•
The thiopropionamide thus obtained melted at 38~40°C. and no further purification was made. The final yield was Z6fo of theoretical•
The propionamide used in the synthesis was prepared in this laboratory by the method of DTAlelio and Reid"^": Two moles of anhydrous propionic acid was refluxed with one mole of urea for four hours, and then distilled. All material distilling below 200°C. was discarded and the residue (propionamide) used without further purification.
D'Alelio and Reid, U. S. Patent 2,109,941. 7
3» THIOBUTYRAMIDE: Thiobutyramide was prepared in this laboratory by Ralph Earle in a manner similar to that used for the other two thioamides. The product obtained from the benzene extract was not a solid but a red-brown oil which gave no definite melting point. This oil was too soluble in benzene for crystallization and was obtained through removal of the benzene by distillation at 30°C# under a pressure of about l£ mm. The residue in the still-pot was accepted as the product. The yield was k7»5% of theoretical.
C. REACTION OF THE THIOAMIDES WITH COPPER POWDER
1. THIQACETAMIDE: Twenty-five grams of thioacetamide was thoroughly mixed with five times its weight of copper powder, placed in a distilling flask, and heated to around
200°C. The reaction proceeded with almost explosive violence after an induction period of about one minute. Consequently, in order to avoid loss of product, it was necessary to carry out the mixing of the reactants with great speed.
This apparatus was simple. It consisted of a 3>00 ml. distilling flask with the side arm bent so as to lead straight downward into a large test-tube cooled by a dry ice-acetone bath. The flask was provided with an inlet tube for nitrogen and heated with a Glass-Col heating mantle.
Once the initial vigorous reaction had subsided, heating was begun and continued for eight to ten hours (overnight). 8
During this time a slow stream of dry nitrogen was passed through the system in order to exclude atmospheric oxygen and help sweep the product into the test-tube receiver. The product was collected as a frozen solid, allowed to warm to room temperature (in order to allow the escape of condensed gases such as ammonia and to avoid frost) and weighed as a liquid* The crude yield was 12*7 g* of liquid from 2$ g. of thioacetamide*
Attempts were made to extract the residue In the dis tilling flask with several organic solvents such as benzene, acetone, alcohol, etc., and with water, but nothing more was obtained.
The liquid in the receiver, upon distillation through a
Yigreaux-type column, was resolved into three fractions, boiling respectively at 78°C., °7°C., and above 130°C. (There was not enough of this last fraction to establish equilibrium in the still.)
The 78° fraction proved to be the azeotrope of water and acetonitrile* The acetonitrile was recognized by its odor and confirmed by hydrolysis to acetic acid and subsequent conversion to the j^nitro-phenacyl ester, xising standard methods. The melting point of the ester was found to be 8£°C*, which is in agreement with that given in the literature. The presence of water was detected by the ability of the fraction to hydrate anhydrous copper sulfate to the blue salt* The composition of the mixture was determined in the following manner: A literature 9
reference^ revealed the existance of an azeotrope between water and acetonitrile boiling at 76°C. and having the composition 8$% acetonitrile and ]$% water. This boiling point agreed fairly well with the 78° boiling point of the fraction. The apparent molecular wei^it as determined in a modified Victor Meyer apparatus3,(35),also agreed reasonably well with the calculated apparent molecular weight of the azeotrope, (37•$)•
As an additional check, the infrared spectrogram of the acetonitrile from the fraction (after drying over magnesium sulfate) was compared with that of a known sample of acetonitrile and found to correspond at all points. (See Appendix)
The 97° fraction proved to be water* It was also detected by its ability to hydrate copper sulfate and was proven by the results of an attempted sodium fusion. This fraction reacted violently with metallic sodium to yield a white, fusible solid which proved to be sodium hydroxide. No charring (as of organic compounds) could be obtained under any circumstances, so it was deduced that no organic materials were present*
The highest-boiling fraction solidified after distillation and was found to be diacetonitrile, CH-fi-CH-CV/ r N 3 NH
^Horsley, Anal. Chem., 19, 508 (191*7),
^Eberhardt, Private Communication. 10
as shown by its quantitative analysis**:
Found Calculated % carbon % hydrogen 7.53, 7.28 7.37 % nitrogen 31..27, 3U.28 3U.32
Thus the original crude product was found to consist of:
U6.C# acetonitrile 1*2 .0$ water 12.0$ diacetonitrile
It was noted that the reaction also evolved hydrogen sulfide and ammonia, however these gases were not collected•
2. THIOPROPIONAltCBE. This reaction was carried out in a manner exactly like that used for thioacetamide. The behavior was essentially the same except that the reaction was even more violent than that of thioacetamide.
The products were analogous, too. Propionitrile was found and identified by hydrolysis to propionic acid and sub sequent conversion to the jjs-bromo-phenacyl ester, melting point
60-6l°C« Water was found and identified through the results of attempted fusion with sodium as in the case of the thioacetamide product described above.
Inasmuch as propionitrile is considerably less soluble in water than is acetonitrile, separation was much easier.
Performed by Clark Microanalytical Laboratory, Urbana, Illinois > 11
The raw product resolved itself into two layers, and could be separated by decantation. The upper layer, propionitrile, comprised approximately three-fourths the volume of the product; while the lower layer, the 21$ water azeotrope, comprised about one-fourth.
The yield obtained was 9*3 grams of crude product from
12.8 grams of thiopropionamide. The crude product consisted of about 8f$ propionitrile and 1% water* A few tiny crystals of solid were noticed in the delivery tube of the distilling flask, but these were too small for recovery.
3. THIOBUTYRAMIDE: This reaction employed a slightly different technique from the other two. Thiobutyramide is a liquid and could therefore be added to the copper powder through a dropping funnel inserted into the distilling flask.
The reaction was the most vrgorous of the three, evolving hot gases the moment a drop of thioamide touched the copper.
Six and seven-tenths grams of liquid product was obtained from ten grams of thiobutyramide. This product formed a two- phase system with the upper layer comprising about l*/5 the total volume. The upper layer boiled at ll6°c. and by analogy with the results from the other two thioamides was immediately suspected of being butyronitrile. Accordingly, an attempt was made to prepare the a^ha-lminoalkyljnercaptoacetlc acid - 12
hydrochloride derivative Iby saturating a solution of the suspected nitrile and mercaptoacetic acid in ether with gaseous HCl, according to the method of Condo, et aJ?, Cry stals were obtained which melted at 133-133>°C, confirming butyronitrile • As a check the infrared spectrogram of the liquid was determined and compared with that of known butyronitrile (prepared from butyramide and phosphorus pentoxide).
They were found to agree at all points. The spectrogram is given in the appendix.
The lower layer was found to be water and this was proven by the sodium fusion method, as detailed for thioacetamide.
In this case too, a trace of crystalline material was noted in the delivery tube of the distilling flask, but was too slight for recovery.
The yield was 5«U g» of butyronitrile and 1.3 g. of water from 10 g. of thiobutyramide*
D. MISCELIANEOUS
After the main body of this investigation had been completed, a few related reactions were tried in an effort to throw a little light on the mechanism of these reactions*
Condo, Hinkel, Fassero, and Shriner, J. Am* Chem* Soc. $9, 230, (1937). 13
1. THIQACET AMIDE WITH COPPER OXIDE: Three grams of thioaeetamide was mixed with V~> grams of cuprie oxide (made by heating copper powder in air at l£0°C for two days) and heated under conditions identical to those discribed earlier for thioaeetamide and copper* A reaction occurred, resembling the one with copper to all outward appearances and giving the same products, although quantitative measurements were not made* Some reduction of the black cupric oxide was noted* giving a red material which might have been copper or cuprous oxide*
2* OTHER MATERIALS WITH COPPER: Thiourea* urea* and thioacetanilide were all tried in this process* and none, gave any apparent reaction* CHA.FFER IV
DISCUSSION
i CHAPTER Iff
DISCUSSION
It has been observed that thioamides do not react with
copper to give coupling as do thioaldehydes and thioketones.
instead, they undergo loss of hydrogen sulfide and yield the
nitrile.
This is not difficult to justify. The C = 0 group in
oxygen amides is not known to give reactions characteristic of
that In oxygen aldehydes and ketones. An electronic configura
tion study reveals sharp differences in structure. If one
considers the carbon atom, the oxygen atom, and the nitrogen
atom to have a trigonal configuration, one would expect the
illustrated geometry, withjj orbitals left over on each atom.
These j> orbitals might be hybridized into molecular orbitals
as shown. As can be seen, these would be quite different in
the two cases* - ^v
This seems to be a reasonable postulate. Bond distance
data, which could furnish a fair check, are not available for amides; but data may be found for urea and thiourea, similar IS
compounds. These data show that the CO bond distance in urea
is a little greater than would be expected for a "pure" CO double band as in acetone (defined as the sum of the single- bond radii of carbon and oxygen)1, and that the CN link in urea is intermediate in length between a double and a single bond*
Similar data and conclusions apply to thiourea* These data agree with the postulate*
It is suggested that, if the postulate is valid, there should be some restriction of rotation around the CN bond, perhaps enough to produce isomers in some mono (or di) N-substi- tuted amides at very low temperatures* It would be interesting to search for such isomers.
No clear mechanism is suggested for the reaction. It is, of course, heterogeneous. The copper is believed to be an actual reactant rather than a catalyst, since it is needed in large quantities. Attempts to use less copper than about five times the weight of thioamide used resulted in decomposition products markedly different from the regular products. These were not investigated. Copper sulfide is formed as one product of the reaction. No quantitative measurement of the CuS was made, but it was there in much more than trace amounts. Some
1 Pauling, Nature of the Chemical Bond, Ithaca, New York: Cornell University Press, l&d. 16
hydrogen sulfide and some ammonia are also formed*
The source of the water in the azeotrope is fairly
clear* Both the thioamide and the copper powder were very carefully dried before each run, however the "copper" itself
is a likely source of oxygen* It was never possible to prevent v
entirely the oxidation of some of the surface copper to copper
oxide, a common oxidizing agent. Indeed, it was found that the
reaction would proceed smoothly with CuO, leaving metallic copper as one product (or perhaps CUgO). The thioamide itself
could, of course, supply the hydrogen for the water* It is suggested that this postulate could be checked by attempting the reaction with a di-N-substituted thioamide.
It is also quite possible that the copper contained some adsorbed water -yshich was not removed by simple heating but which was removed by the action of the reaction* CHAPTER 7 smsmm 17
CHAPTER V
SUMMARY
Thioaeetamide, thiopropionamide, and thiobutyramide have been heated with five times their molar quantities of copper powder under an atmosphere of nitrogen. It was found that Instead of the condensation to an olefinic compound which might be expected by comparison with the analogous treatment of thioaldehydes and thioketones, loss of hydrogen sulfide resulted, with the production of the corresponding nitrile.
Side products were hydrogen sulfide, ammonia, copper sulfide, water, and, in the case of thioaeetamide, a small amount of diacetonitrile •
These results are interpreted on the basis of the electronic structure, from the molecular orbital viewpoint*
Experimental conditions, results, analytical data, and infrared spectrograms are given. BIBLIOGRAPHY 18
BIBLIOGRAPHY"
Cahours, A., Comptes Rendes HeMomadaires des Seances de
L'academie des JScIences, zj9 lldljdj.
Campaigne, E», Chemical Reviews, 39, 1 (19U6).
Chabrier, P., and Renard, S. H., Bulletin de la Societe Chimique de France, 19h9 D, 272.
Condo, F. E«, Fassero, A., Hinkel, E. T«, and Shriner, R. L., Journal of the American Chemical Society, $9$ 230 (1937).
D'Alelio, G. F., and Reid, E. E*, U. S. Patent 2,109,9Ul.
Hoffman, A. Berichte der Deutschen Chemischen Gesellschaft, 11, 338 (18/57. ---
Horsley, L. H., Analytical Chemistry, Ig, £08 (19V7). Kindler, K., Chemiker Zeitung, 1, 2633 (19220 •
KLinger, H., Berichte der Deutschen Chemischen Gesellschaft, 9, 1893 (l37o7T^ ~
Pauling, L,, Nature of the Chemical Bond, Ithaca, New York. Cornell UnlversiTSy #ress, li&j.b'.
Wallach, 0., Justus Liebigs Annalen der Chemie, 2g9 300 (1890).
Willgerodt, C, Berichte der Deutschen Chemischen Gesellschaft, 20, 21.67 (13577.
Winthrop, S., Master's Thesis, Georgia Institute of Technology, 191.9.
Wood, J. H., Bacon, J« A., Meibohm, A. W., Throckmorton, W. H., and Turner, G. P., Journal of the American Chemical Society, 63, 133U (19U1).
Wood, J. H«, and Stanfield, J. A., Journal of the American Chemical Society, 61;, 23U3 (\9\&T7 * APPENDIX 19
APPENDIX
INFRARED SPECTROGRAMS
This appendix presents infrared spectrograms for most of the organic compounds encountered in this investigation.
These spectrograms were obtained with a Beckman Model
IR-2 Infrared Spectrophotometer equipped with a recording potentiometer and a variable slit-width drive arranged so as to keep the response of the instrument approximately flat throughout the range of 2 to l£ microns* Two curves were obtained for each compound. First a "blank" trace was run, i.e., the response of the instrument with the sample cell empty; second a 11 sample" trace was recorded on the same paper.
The reported curves are calculated curves obtained by dividing the numerical value of a point on the sample trace by the numerical value of the corresponding point on the blank trace.
This, of course, gives percentage transmission.
All samples were run in their natural state. Solids were deposited from ether solution on a rock salt plate, and liquids were placed in a rock salt liquid cell approximately
0.1 cm thick. 100,
9CH
2 3 4 5 6 7 8 9 10 II 12 wavelength, microns curve i ACETONITRILE curve m PROPIONITRILE
curve nz ACETAMlDE
100
curve "VTTT THI0PR0PI0NAMIDE