Chem.

Educator 2004, 9, 12

(web)1

Preparation of Azo Dyes from Sulfanilamide

Kathleen Alfare, David Lee, Eric Scharrer, and Scott A. Van Arman*,
Department of Chemistry, Franklin and Marshall College, Lancaster, PA 17604-3003, scott.vanarman@fandm.edu and Department of Chemistry, University of Puget Sound, Tacoma, WA 98416 Received January 8, 2004. Accepted March 2, 2004.

Abstract: A synthesis of a library of potential antibiotic azo dyes is described starting ultimately from aniline and directly from sulfanilamide. The procedure is analogous to that for the preparation of the historically important antibiotic azo dye, Prontosil.

Introduction Many instructors find it interesting and pedagogically advantageous to diversify the products synthesized by a group of students in the laboratory such that each student prepares a unique compound. We have adapted a method for the preparation of the antibiotic azo dye Prontosil to be used for a combinatorial synthesis of a library of potential antibiotic azo dyes. The experiment described here has been used as the last laboratory project for the second semester of the introductory organic chemistry sequence but could easily be extended to include additional study. Two suggestions are provided below. The multistep synthesis of sulfanilamide from aniline or nitrobenzene is a common project undertaken in the later part of a course in organic chemistry [1]. In many laboratory texts the historical importance of sulfanilamide synthesis is outlined in some detail. After isolation of the sulfanilamide, many projects continue to analyze its biological activity as an antibiotic or enzyme inhibitor [1d, e]. The colorful history of sulfanilamides discovery as an antibiotic via Prontosil is treated as an interesting side note but is all but ignored synthetically [2]. This is an unfortunate omission given the common scheduling of the laboratory near the end of the organic chemistry course. Diazotization and diazo coupling (a special example of electrophilic aromatic substitution) usually appear in a text chapter on amines following electrophilic aromatic substitution and nucleophilic acyl substitution chapters. Thus, extending the multistep synthesis of sulfanilamide to Prontosil or other diazo derivatives parallels the order and timing of these major synthetic reactions in later portions of many organic chemistry texts. Interestingly, it is common for laboratory texts to include diazotization and diazo coupling projects [1a, b, c]. To our knowledge, none of these laboratory texts explicitly have students make use of the sulfanilamide that may have been prepared previously using a procedure from the same text. Indeed, the synthetic scheme described herein provides a simple summary package in the laboratory that clearly ties these projects together.

Experimental Sulfanilamide (0.29g, 1.7 mmol) was placed in a 25-mL Erlenmeyer flask. Approximately 5 mL of distilled water and 2 mL of concentrated HCl were added. The mixture was swirled until all of the sulfanilamide dissolved. A salt/ice-water bath was prepared and the solution was cooled to < 0 C. In a separate flask, a solution of sodium nitrite (0.14 g, 2.0 mmol) in about 2 mL of water was prepared. The sodium nitrite solution was also cooled in the ice/ salt-water bath. The sodium nitrite solution was added in two portions to the icecold sulfanilamide solution as the flask was swirled intermittently to keep it cold. A brief, slight darkening of the solution may be observed. After about 5 min, 1 equivalent (relative to the sulfanilamide) of the electron-rich aromatic compound previously dissolved in a minimum amount of water/acetone or water/methanol was added to the solution containing the diazotized sulfanilamide. Upon addition, product began to precipitate. After swirling, until it appeared no more product was precipitating, 5 mL of saturated sodium acetate solution was added. The solid was collected by filtration, dried, and weighed. Typical yields are reported in Table 1. If desired, the product may be recrystallized from ethanol or ethanol/water. Results and Discussion We have applied a method for the diazotization and coupling sequence starting from sulfanilamide (Scheme 1) that allows the use of a variety of activated aromatics without significant modification of conditions (Table 1) [3]. Although
Ar

NH 2
several steps

NH 2
1) NaNO 2 , HCl, H2 O, 0C
2) Ar-H

S O NH 2

S O NH 2

Address correspondence to this author. Franklin and Marshall College University of Puget Sound

Scheme 1 the yield of solid product is not always ideal, there are advantages in pedagogy. The technique allows each student to prepare his or her own unique product in the class. The project

2004 The Chemical Educator, S1430-4171(04)0xxxx-x, Published on Web 3/9/2004, 10.1333/s00897040774a, xxxxxxaa.pdf

Chem. Educator, Vol. 9, No. X, 2004

Van Arman et al.

Table 1. Compounds Synthesized, Typical Yields, and Compounds Color

Electron rich aromatic compound (Ar-H) resorcinol monobenzoate 1,5-dihydroxynaphthalene 2-methoxy-4-nitroaniline 2,6-diethylaniline 4-amino-1-naphthalenesulfonic acid, sodium salt hydrate 6,7-dihydroxy-2-naphthalenesulfonic acid, sodium salt hemihydrate 1-naphthol 3,5-diaminobenzoic acid resorcinol a Reported yields are the average of four replicate runs. Typical % yielda 52 72 65 30 60 30 50 53 90 Product color light orange deep brown/red gold/orange red purple red orange/red deep red bright orange

introduces the topic of combinatorial chemistry at an appropriate juncture, late in the course. The products are also aesthetically pleasing and it is fun to generate dyes of different colors. The diazotization/diazo coupling takes less than two hours excluding a recrystallization of the product. The project could easily be extended to include the analysis of the various products as antibiotics. Students could also vary parameters of the synthesis to optimize the yield of individual products. Supporting Material. Detailed instructions for students, including safety warnings, and instructors notes, which include suggestions for recrystallization of the products, are available in a Zip file as supporting material (http://dx.doi.org/10.1333/s00897040774a).

References and Notes

1. Fieser, L. F.; Williamson, K. L. Organic Experiments, 8th ed.; Houghton Mifflin Co.: Boston, 1998; (b) Bell, C.; Clark, A. K.; Taber, D. F.; Rodig, O. R. Organic Chemistry Laboratory, 2nd ed.; Saunders College Publishing: Orlando, 1997; (c) Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Engel, R. G. Introduction to Organic Laboratory Techniques: A Microscale Approach, 2nd ed.; Saunders College Publishing: Orlando, 1995; (d) Krantz, A.; Jesaitis, R. G. J. Chem. Educ. 1973, 50 (1), 7678; (e) Hurdis, E. C.; Yang, J. W. J. Chem. Educ. 1969, 460 (10), 697698. Manalang, M. G.; Bundy, H. F. J. Chem. Educ. 1989, 66 (7), 609 611. Reference 2 describes the synthesis of Prontosil and 4hydroxyazobenzene-4-sulfonamide using conditions tailored to each product, and it reports correspondingly higher yields.

2. 3.

2004 The Chemical Educator, S1430-4171(04)0xxxx-x, Published on Web 3/9/2004, 10.1333/s00897040774a, xxxxxxaa.pdf