Textbook Errors, 708 C. R. Gambill, T. D. Roberts1, University of Arkansas Fayetteville, 72701 ond H. Shechter Ohio State University
Benzenesulfonyl Chloride Does React with Tertiary Amines
Columbus, 43210
The Hinsberg test in proper perspective
chemical tests which are frequently used to differentiate between primary, secondary, and tertiary amines involve their behavior with nitrous acid or benzenesulfonyl chloride (the Hinsberg test). An integral part of these tests are two long standing myths of organic chemistry in that tertiary amines supposedly do not react with nitrous acid or benzenesulfonyl chloride. These misconceptions prevail despite an impressive series of publications which date back more than a century. Recent papers (1) have pointed out that tertiary amines are cleaved by nitrous acid to carbonyl compounds, secondary nitrosamines, and nitrous oxide (eqn. (I)), and current texts are taking note of these facts.
However, almost without exception these same texts state that "tertiary amines do not react with benzenesulfonyl chloride," as they describe the Hinsberg test for amines.% The reader is left with the strong impression that this is so, n o matter what the conditions may be. The purpose of this report is to focus attention on this error by surveying briefly pertinent literature references, and then to make suggestions which should lead to a greater understanding- and reliability of the Hinsberg test. An interesting point which will appear upon examining the bibliography of this article concerning "unknown reactions" of tertiary amines and benzenesulfonyl chloride is that many of the references lie buried in the old Germanliterature. In these times when many graduate programs are reducing or dropping all language requirements, future chemists are effectively being cut off from Suggestions of material suitable for this column and guest columns suitable for publication directly should be sent with as many details as possible, and particularly with reference to modern texbaoks, to W. H. Eherhardt, School of Chemistry, Georgia Institute of Technology, Atlanta, Ga. 30332. Since the purpose of this column is to prevent the spread and continuation of errors and not the evaluation of individual texts, the sources of errors discussed will not he cited. In order to he presented, an error must occur in at least two independent recent standard hooks. ' Presented in part at the Joint Southeast-Southwest Regional ACS Meeting, New Orleans, La., December, 1970, ORGN 436. >One recently published text states, "Tertiary amines me recovered unchanged.. . They probably do react.. to give quaternary sulfoamide intermediates.. . These.. . would be hydrolyzed very rapidly by water."
.
communication with much of this vast literature, except by abstracts, which are admittedly inadequate and often misleading or incorrect. Literature
From the literature of reactions of tertiary amines and benzenesulfonyl chloride, I, it is possible to ferret out two major behavior patterns-one with tertiary alkylamines, RaN, and the other with tertiary aniliues, CsHsNR2. Tertiary Alkylomines
Early in this century Vorlander, K a d m a n , and Nolte (2)reported precipitation of N-benzenesulfonylN,N,N-trimethylammonium chloride, 11, a labile white solid, from reaction of trimethylamine and I in aqueous solution (eqn. (2)). Characterization of the quaternary ammonium ion as its chloroplatinate salt, 111, was possible.
Others (S), apparently unaware of the work by Vorlander, et al., reported similar adducts of I with triethylamine, tripropylamine, tribenaylamine, pyridine, a-picoline, quinoline, and acridine, respectively. When Jones and Whalen (4) conducted Vorlander's experiment in non-aqueous medium the precipitate obtained (eqn. (3)) was a mixture of tetramethylammonium chloride, IV, and N,N-dimethylbenzenesulfonamide, V.
The chloroplatinate prepared directly from this mixture has a wide melting point. Since this observation imputed error (4), Vorlander repeated the earlier work and compared the crystal habit of the chloroplatinate of the adduct and several representative chloroplatinates of ammonium ions to show that I1 indeed had formed (6). Unfortunately the differences in the results of references (6-5) were not explained, and "Vorlander's Adduct" remained a mystery for more than two decades. Meanwhile Schlegel (6) reported chloroplatinates from Vorlander type adducts of I with benzyldimethylamine and with dimethylethylamine. Volume 49, Number 4, April 1972
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More recently Horner and Nickel (7) took up the problem and reported a superior laboratory technique for preparing I1 along with experiments describing its properties. They found: (1) The earlier observations of Vorlander or of Jones and Whalen can he duplicated. The important diierence lies in the amount of trimethylamine usedone equivalent gives I1 (eqn. (2)), and two equivalents, yield IV and V (equ. (3)). (2) When a solution of I1 is placed in a high vacuum, at least 40% of the trimethylamine volatilizes with the solvent into cold traps. The result seems to indicate that I1 is in equilibrium with its components. (3) The adduct I1 serves as a benzenesulfonating agent. Thus: Benzenesulfanilide and I1 yields bis-henzenesulfanilide (SO%, eqn. (4)). I1
-
+ CsHsSOzNHCaHr
Hydroquinone and I1 gives the dihenzenesulfonic acid ester VI (850/0, eqn. (5)).
With I1 diethyl malonate undergoes substitution by phenylsulfonyl (eqn. (6)) to yield diethyl henzenesulfonylmalonate, VII. I1
-
+ CH3(CO%Et)~ +
CeH6SO~CH(COJt)n ( C H ~ ) ~ ~ + H C I(6) VII
(4) A mixture of thiophenol and I1 affords trimethylamine hydrochloride, diphenyldisulfide, VIII, and diphenyldisulfone, I X (eqn. (7)) instead of phenyl benzenethiosulfonate, X (eqn. (8)).
In a later paper Parsons and co-workers (8) reported that X and thiophenol in the presence of amines result in VIII and other products. Thus I1 and thiophenol may yield X which is not stable hut reacts further with thiophenol to provide VIII and IX. The current data can ,be explained by assuming that I1 is the quaternary salt claimed by Vorlander (2, 5) as shown in eqns. (9) and (10). 288
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Journal of Chemical Education
rapid
CdIsSOz-Nuoleophile
+ (CHl)sN
(10)
Addition of a nucleophilic reagent (another tertiary amine, thiophenol, hydroquinone, etc.) to I1 results in displacement of the excellent leaving group, trimethylamine, with transfer of the benzenesulfonyl moiety (eqn. 10)). However when the only nucleophile available is trimethylamine, no real change occurs since trimethylamine is the nucleophile and the leaving group. Then an alternate reaction, alkylation of trimethylamine, can occur by displacement of CsHsSO2N(CH&, V, from a methyl group of I1 to form IV [eqn. (9)]. Tertiary Aniline6
A different behavior pattern has been observed for reactions of tertiary anilines with I. As early as 1879 Hasencamp (9) observed intense color in neat mixtures of I and N,N-dimethylaniline, XI. I n that same year Michler and Meyer (10) identified bis-(p-dimethylaminopheny1)methane and, supposedly, p-dimethylaminophenyl(phenyl)sulfone (mp 82'C) and methyl violet, p-methylaminophenyl-bis-(p-dimethylaminopheny1)methyl chloride from reaction of I and XI. A half century passed before Bergel and Doring (11) and later Gehauer-Felnegg and Schwartz (12) prepared the reputed sulfone by an alternate method and found its melting point to he 178°C. Careful investigation showed that the previously reported "sulfone" was in reality N-methylhenzenesulfanilide. A further correction of earlier work was reported by Wahl (13). From p-toluenesulfonyl chloride and X I there was isolated not the expected methyl violet, but crystal violet, tris-(p-dimethylaminopheny1)methyl chloride. This latter dye was identical to that formed from I and XI. More recently Horner and Nickel (7) identified the major products of reaction of I and X I in ether-water in the yields indicated (eqn. (11)).
crystal violet
leucocrystal violet
The material balance for reaction of X I with I was 96%. Neat mixtures of I and X I afford these same products except for formaldehyde. Horner and Nickel (7) also examined the products of the reaction of I and N,N-dimethyl-p-toluidine (eqn. (12)). Structures assigned as XII, XIII, and XIV are tentative.
salts of tertiary anilines does not occur; and although transfer of benzenesulfonyl group does occur as in eqns. (12) and (13), there is virtually no evidence which suggests that a similar mechanism to that for tertiary alkylamines is taking place. Instead, for tertiary N-methylanilines in aqueous media oxidative cleavage of the methyl group occurs to provide formaldehyde--a reaction product not reported from alkyl-N-methylamines. Aromatic substitution arises as a second complication of reaction of I and those amines which are conjugated to an aromatic ring. Finally one-electron transfer as in the formation of XVI may he an important clue to future mechanistic explanations of these differences in behavior. Decreased nucleophilicity and base strength as well as increased steric bulk for anilines may play vital roles. In summary, product studies imply that there are basically two reaction types which occur when I is mixed with tertiary amines-one is characteristic of alkylamines, the other of anilines. A Caveat for the Synthetic Organic Chemist
It is appropriate to point out here that benzenesulfonyl chloride is often added to impure tertiary amines to remove primary and secondary amines by forming their respective benzenesulfonamides. The basic idea is that tertiary amines do not react! The above examples should clearly illustrate this fallacy and serve to warn preparative experimentalists that substantial amounts of tertiary amine may be lost in such "purifications." The Undergraduate Laboratory and the Hinsberg Test
a
xm
Reaction of I with N,N,N,N-tetramethyl-p-phenylenediamine (XV) was also included in the study by Horner and Nickel (7). In polar solvents a blue color developed rapidly. Although not recorded in the Experimental, it is stated in the Discussion that the color spectrum matched that of Wurster's Blue, the radical cation of N,N,N,N-tetramethyl-p-phenylenediamine (XVI). The dihydrochloride of XV and obenzenesulfonyl-N,N,N,N-tetramethyl-p-phenylenediamine (75%) were the products isolated (eqn. (13)).
0
+ zcr
(13)
The above examples illustrate striking departures in the behavior of tertiary anilines and I from the pattern set by reactions of tertiary alkylamines and I. Adduct formation-so evident with tertiary alkylamines-is completely absent. Thus alkylation to quaternary
The third area where the Hinsberg test is practiced is in the undergraduate organic laboratory for classification of amines as 'Lunknowns." In 85% of the current laboratory manuals the test is used and relies on the following three reaction sequences
+
HO -
H*
CIHrSOICl RsN + "No Rx" -4 RINH+
(16)
HIO
Obviously primary sulfonamides are soluble in bases, and then insoluble in acids (eqn. (14)). Secondary sulfonamides are insoluble in bases and remain so upon acidification (eqn. (15)). Tertiary amines are insoluble in basic solution and then dissolve when acidified (eqn. (16)). In light of the above discussion and ample proof that tertiary amines DO react with benzenesulfonyl chloride, one may ask, "Why does the test work? Why has there apparently been no serious problem before now?" The answer is perhaps twofold. First of all two of three amine types (primary and secondary) usually give satisfactory results. (However, see below for further discussion.) Because tertiary amines supposedly do not react, they may be less often given to students as unknowns. A negative or "no reaction" experiment is viewed by many as a less desirable laboratory experience than a L'positive" experiment where a Volume 49, Number 4, April 1972
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reaction occurs and a new product is obtained. Thus, statistically fewer tertiary amines may be given out as unknowns. Secondly, there are good chemical reasons which can he advanced to explain why tertiary amines give "correct" results (i.e., appear not to react) in this test. Thus with tertiary alkyl amines-reaction with I should form an adduct, XVII, such as described earlier by Vorlander (8, 5) and others (3, 6). I n the presence of base (as in the Hinsherg test), rapid displacement of the amine from XVII hy hydroxide ion results, with formation of benzenesulfonic acid (eqn. (17)). 0 0
CsH5SOaH+ NR,
(17)
XVII
Thus the tertiary amine effectively catalyzes hydrolysis of I, and the test gives "correct" results in that the amine may be recovered unchanged and sulfonamide does not form, although "reaction" has occurred. Tertiary anilines are mainly insoluble in the basic media of the Hinsherg test. Their reaction with I may be slow due to their low nucleophilicity and steric bulk; thus hydrolysis of I by hydroxide ion may effectively compete with the amine for I. If rapid reaction of I with the amine does occur, a relatively stable radical cation, XVIII, may form in a reversible one-electron transfer reaction (eqn. (18)). CeH&hCl
+ CJIsNRz
+ HO-
CsHsS02CL
+ C ~ H $ R ~+ C1-
CsHjSO~. XVIII -+
+ CI-
C6HjSOsH
(18) (19)
The hydroxide ion of the basic media may still hydrolyze I reversing the equilibrium before large amounts of XVIII react further to give products. Again the test gives "correct" results in that the amine may be recovered essentially unchanged. Obviously the speed of secondary reactions may be vitally important as to whether new products are obtained upon mixing I with a tertiary amine. Having rationalized the apparent success of the test, a second problem area arises-the failures encountered by the student in carrying out the test. All too often a student complains bitterly that his observations were correctly reported even though he did not get the "correct" answer for the class of his amine unknown. Such failures have been noted in the literature. For example Ritter (14) has stated that Hinsberg's original directions (15) are "unsatisfactory in the hands of the average student" and proposed a new procedure in which hydroxide bases are not used and ethanol is the solvent. I n his method I and the amine are allowed to react and acid is addcd to precipitate any sulfonamide which has formed. Tertiary amines, supposedly unreacted, are soluble. Upon separating any precipitate, aqueous base is added to it to dissolve primary sulfonamides. Secondary sulfonamides will remain insoluble. I n response to this new method Gennaro (16) noted that Ritter's procedure minimizes imide formation (excess amine is present during the test) but is severely limited for analysis of polyamines. The additional amine group causes solubility in both acidic and basic media. 290
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Journal o f Chemical Edumtion
Fanta and Wqng (17) have summarized a problem that occurs frequently-large and cyclic primary sulfonamides may be insoluble in aqueous base-and added that solubilities are greater in aqueous KOH than in aqueous NaOH. Stickler (18) has cautioned that insoluble imides may form from primary amines, although conditions were not specified. However, when one surveys current laboratory manuals such a wide variation is noted in the directions given for the test that this may well be the major culprit in student dissatisfaction with the test. A few of these manuals do include most of the previously published precautions as well as explicit directions; but many are so brief that frequently a student must engage in a bit of research in order to solve his unknown. Research as such is certainly useful as a teaching aid, but research without "notice or warning" and withont "direction or discussion" of how it should be carried out (i.e., the student is completely on his own) is frequently discouraging rather than rewarding. Thus, the instructor should set up the area as a miniature research problem and discuss meaningful approaches with the student, or give adequate directions in carrying out the test. To this latter end the following test description and discussion, gleaned from all available sources, is put forth. Test Description
To one equivalent of the amine and four equivalents of aq. 10% KOH is added 1.5 equivalents of benzenesulfonyl chloride. The stoppered mixture is shaken and cooled if necessary until the odor of benzenesulfonyl chloride is gone. At this point the mixture should still be strongly basic. If not, small amounts of base are added until this is so: If the mixture has formed two layers, they are separated and the solubility of the organic phase in aq. 5% HCl determined. A tertiary amine will be soluble at this point.. A secondary amine will have farmed a. benzenesulfonamide which is insoluble. Larger or cyclic primary smines form benzenesulfonamides that have low solubility in the basic medium and thus are partially insoluble. They remain insoluble in the aq. 5y0 HCI and thus may give approximately the same visual results as the eompletely insoluble secondary bensenesulfonamides. In order to differentiate between these two possibilities, the separated aqueous phase is brought to pH 4. A precipitate indicates that s primary benzenesulfonamide exists. If the original mixture does not form two layers, a. soluble primary benzenesulfonamide is present. This can be further substantiated by adjusting the pH to 4. A primary sulfonamide will precipitate. Discussion
1) An excess of either the amine or I will cause secondary reactions and confuse the result. 2) The reaction time for the test should be short. Many tertiary amines slowly give precipitates when mixed with I under the above test conditions and allowed to stand. 3) Reagent grade amines should he used. Practical grades often contain such large amounts of impurities that results are not clear. For example, tertiary amines often contain significant quantities of secondary amines. Thus trace precipitates should not be counted as "true" results. 4) Many hindered secondary amines require heating with I before they form secondary sulfonamides rapidly (19). Thus they should not be issued as "unknowns" since most tertiary aryl amines also react with I when heated. (For example N,N-dimethylaniline gives a
deep purple dye when the above procedure is followed and the basic mixture is boiled for 2 min.) .i) Primary sulfonnmidrs arr morr soluble in a q u c nus KOH .-. - - - than in anurous S a O H . 6) When acidifying, excess acid is to he avoided, as a precipitate may appear due to the excess acid. Summary
The literature reports that tertiary amines react with benzenesulfonyl chloride under a variety of conditions. Preparative chemists are cautioned that use of benzenesulfonyl chloride to purify tertiary amines may result in substantial loss of product. Thus the Hinsherg test for amines is valid only when reaction speed, concentration, temperature, and solubility are taken into account. A revised test procedure is presented. Authors of textbooks and laboratory manuals may wish to include these observations in future editions. Acknowledgment
The authors acknowledge discussion with Klaus Fischer, who found results similar to Horner and Nickel (7) with trimethylamine, and stimulating discussions with W. L. Meyer and R. P. Quirk. This work has
been partially supported by a pre-doctoral fellowship (GM 43623) to C. Gambill from the National Institute of General Medical Sciences, U. S. Public Health Service. Literature Cited (1) HEIN, G.. I. CXEM. EDUC., 40, 181 (1963): SMITH. P. A. 8.. A N D LOEPPKT,R. N., J . Amw. Chcm. Soc., 89, 1147 (1967).and referenoes
"..=."....
.L-.&"
(2) VORLANDER,D..A N D KAUI.FMANN, M.. Bar.. 43, 2735 (1910); VonG A N D E ~ ,D., &No NOLTE, O., B e . , 46, 3212 (1913). ~ zL.. , AND DEHN,W. M., J. Amw. Chem. Soc.. 39, 2444 (3) S o ~ w ~ n G. 11411) ~....,. (4) WAAIEN, H. F.,AND JONES, L. w., J . A~IICI.Ch~m.SOC.,47, 1353 (1925). D., Ber., 64, 1736 (1931). (5) VORL&NDER, (6) S c ~ ~ e o F.. ~ f Be?., i . 64, 1739 (1931). (7) HORNER, L.,AND NICKEL, H..Ann., 597, 20 (1955). (8) P*nsons, T. F.. B o o a M m , J. D.. P m n a o ~ ,D. E.. A N D F m n , L.. J . O w . Chem., 30, 1923 (1965). (9) HASENOAMP.H.. Be?.. 12, 1275 (1879). (10) M m x ~ a n W. . . m o M s r s n , H.. Bar.. 12, 1791 (1879). F.,A N D DORINQ,H.,Be?., 61, 844 (1928). (11) BERGEL, (12) G e ~ A u ~ n - F n m eE m ..A N D Scxra~nz.P., Ber.. 61, 1307 (1928). (13) Whn& A,, Rev.gin. md. color. 32, 176 (1928). F. 0.. J. CXEM. EDUC.. 29, 506 (1952). (14) RLTTER, 0.. Be?., 23, 2962 (1890). (15) HINBBERO. , R..J. C x e ~ . Eouc., 42, 48 (1965). (16) G m n ~ n oA. 41, 280 (1984). (17) FANTA,P.E..A N D WANE,C. S., J. CXEM. EDUO., , C.,J. CHEM. EDUC..41, 515 (1964). (18) S T I C K L ~ RW. E ~L.. , F u s o ~ R. . C.. a m C u n ~ r ~D.. Y., "The Systematic (19) S H ~ N R. Identification of Organic Compounds'' (4th Ed.), John Wiley 61 Sons, Ino.. New York, 1956, p. 104.
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