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In a chemoselective reaction, one of the functional groups inthe reactant molecule is selectively attacked by a reagent. Thepresent article describes this principle by demonstrating thatcareful alkaline hydrolysis of N1,N4-diacetylsulfanilamide (7)removesonly the N4-acetylgroup fromit leaving the N1-acetylgroup intact to yield N1-acetylsulfanilamide (8).

Background

It is an eternal dream of synthetic chemists to prepare a targetmolecule with the best yield and highest purity without beingencumbered by side products. That is, the chosen synthetic routeshould be able to selectively deliver a single compound. This isalso an important principle of Green Chemistry. Selectivity canbe achieved by choosing suitable starting materials, reagents,solvents, reaction conditions, and most importantly catalysts.This saves starting materials, reagents, energy, solvents, time andeffort, and results in the reduction of production cost and environ-mental pollution. Selectivity aspects are hardly dealt with whileteaching our undergraduate chemistry students, though manyreactions that involve selectivity are dealt with in teaching naturalproducts synthesis, reagents in organic synthesis, synthesis ofdrugs, etc. This omission is even more conspicuous in the labora-tory curriculum as no experiment is specifically designed todemonstrate selectivity aspects.

Three types of selectivity, namely chemoselectivity, regio-selec-tivity, and stereoselectivity including enantioselectivity, are rec-ognized as important. This article describes the first type, whichis given the least attention in our undergraduate teaching. For thispurpose I have chosen the example of the preparation of sulfona-

KeywordsChemoselectivity, sulfa drugs,sulfonamides, amide hydrolysis.

An Elegant Example of Chemoselective ReactionThe Preparation of Sulfonamide Drugs

Gopalpur Nagendrappa

G Nagendrappa, afterretiring from Bangalore

University, is now teachingat the Department of

Medicinal Chemistry, SriRamachandra University,

Porur, Chennai. Hisresearch interests are in

the area of siliconchemistry, mechanisticorganic and synthetic

chemistry.

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mide drugs, which made a great impact on health care by control-ling bacterial diseases prior to the advent of antibiotics, and arestill in use, though in a limited way.

The Sulfonamides

The discovery and development of sulfonamides as medicinalcompounds in the 1930s was a significant milestone in the historyof treating diseases and of modern pharmaceutical industry.Because of their wide spectrum antibacterial activity, sulfona-mides were used to treat a variety of illnesses caused by bothGram-positive and Gram-negative bacteria. Though their impor-tance declined after the introduction of antibiotics and otherdrugs from 1950s, they continue to be used for treatment of somespecific diseases.

The discovery of medicinal property of sulfonamides can becategorized as serendipitous, because it came about as an off-shoot of dyes industry in Germany.

Sulfonamides are derivatives of 4-aminobenzenesulfonamide (1),also called sulfanilamide, with one of the two amide hydrogensbeing substituted by a variety of substituents that enhance ormodify, in desirable ways, the drug action of 1, which is thepharmacophore of the class of sulfonamide drugs1.

Sulfonamides are relatively easy to prepare, and most of them areprepared, with very few exceptions, by a general method given inScheme 1.

R in Scheme 1 is usually a heterocyclic group with a few excep-tions such as sulfacetamide (8) in which R is an acetyl (-COCH3)group. Sulfacetamide is prepared in a slightly different way,(Scheme 2).

Why is there Selectivity?

The mechanistically interesting part of this synthetic sequence(Scheme 2) is the selective removal of N4-acetyl group by alkalinehydrolysis. In principle, both carboxamides and sulfonamides

1 A pharmacophore is definedas a set of structural features ina molecule that is recognized ata receptor site and is respon-sible for that molecules biologi-cal activity.

The discovery anddevelopment of

sulfonamides asmedicinal

compounds in the1930s was a

significant milestonein the history of

treating diseasesand of modern

pharmaceuticalindustry.

The mechanisticallyinteresting part of thissynthetic sequence isthe selective removalof N4-acetyl group by

alkaline hydrolysis.

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NHCOCH3 NHCOCH3 NHCOCH3 NH2

+ HSO3Cl

SO2Cl SO2NHR SO2NHR

RNH2 aq. NaOH

23 4 5

R =N

S

NO

ON

CH3H3C

H3C

: sulfathiazole

sulfisoxazole

sulfamethoxazole

:

:

N

NN

sulfadiazine:

sulfapyridine:

Scheme 1

H2N S NH2O

O

1

1

234

5 6

14

NH2

SO2NH2

NHCOCH3

SO2NH2

NHCOCH3

SO2NHCOCH3

NH2

SO2NHCOCH3

or(CH3CO)2O aq. NaOH

1 6 7 8Scheme 2

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can undergo hydrolysis under alkaline conditions to ultimatelygive 4- aminobenzenesulfonic acid, as its sodium salt (Scheme 3).

However, if hydrolysis is carried out for a shorter period, only theN4-acetamide group is hydrolysed as shown in the last step ofScheme 1. Such preferential reaction of a reagent with onefunctional group in the presence of similar functional groups isknown as chemoselectivity. In the case of diacetamide 7, the laststep is even more interesting, because between the two acetylgroups, it is still the N4-acetyl group that is removed whereas theN1-acetyl group is left untouched.

What is the reason for the distinctly different behaviour of thesame functional (CH3-CO-NH-) group but in two different posi-tions in the molecule? To understand this variation in the reactionof similar or same functional groups towards a single reagent, wehave to look at the electronic effects around the reaction sites.The hydrolysis starts with the attack of the nucleophilic OH atthe carbonyl carbon of carboxamide or sulfur of sulfonamide, therespective electrophilic centre, and proceeds further as shown inScheme 4.

When both functional groups are present in the same molecule as

SO2NHR

NHCOCH3

+ NaOH

SO3Na

NH2

longreaction time

Scheme 3

R CO

NHR1 + OH - H3C CO-

OHNHR1 H3C C

OOH

R SO

NHR1

H3C CO

O-

R SO

OH +

+

OR1NH-

R1NH2

9 10

O+ OH - H3C S

O

O -HO

NHR1

+ R1NH-

H3C SO

O- + R1NH2O

Scheme 4

Preferentialreaction of a

reagent with onefunctional group in

the presence ofsimilar functionalgroups is known

aschemoselectivity.

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in 4, we would expect the OH- to attack sulfur of sulfonamide asit is more electron deficient than carbonyl carbon. However,sulfone (-SO2-) moiety is a powerful electron withdrawing group,which makes the sulfonamide hydrogen slightly acidic. As aresult, when NaOH solution is added the first thing that happensis the loss of proton at N1 position to form amide anion 12(Scheme 5), or 14 (Scheme 6). The negative charge so formed onN1 is shared by the adjacent sulfur by resonance, which repels theattack by OH ion.

There are two more possible reasons for slower hydrolysis ofsulfonamide, which are noted below. When OH adds to sulfur in4 or 6 the tetrasubstituted sulfur has to expand its valency to fiveand become pentasubstituted. This increases valence shell elec-

R SO

HN

OOH-R1 R S

ON

OR1+

- R S NO

R1O-

12 13-H2O

Scheme 5

HN

O2S

CO

CH3

NH CO

CH3

+ OH-

HN

S

CO

CH3

N CO

CH3

HN

S

CO

CH3

N CO

CH3O

O-

OO -

HN

S

CO

CH3

NO-

OO

CCH3

HN

S

CO-

CH3

NO-

OO

CCH3

OH

NH-

S NO -

OO

CCH3

+CH3COOH

14 15 16

+CH3COO-

OH-

Scheme 6

NH2

O2S NH CO

CH3

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trons as well as the steric crowding around sulfur, both of whichare unfavourable to OH attack. For acetyl carbonyl carbon, onthe other hand, the attachment of OH brings about a change fromtrisubstitution (sp2-planar) to tetrasubstitution (sp3-tetrahedral),but no change in the number of valence electrons. These changesdo not hinder the OH attack on carbonyl carbon and takes placefar more easily than that on sulfonamide sulfur.

In the case of 7, as compared to other sulfonamides, the N1-hydrogen is even more acidic as it is flanked by two electronwithdrawing groups (-SO2- and -CO-). In fact, 7 is more acidicthan most other sulfonamide medicinal compounds, and has a pKa= 5.4, which is almost the lowest among them. The anion formedon N1 after the loss of its proton is shared by the neighbouringcarbonyl group as well as by -SO2- group by resonance effect(Scheme 6). As this carbonyl group acquires negative charge(16), it will prevent the attack of hydroxide anion. In comparison,the N4-carbonyl is not hampered by this restriction, and hence itundergoes hydrolysis much faster to lose acetyl group, while N1-acetyl remains intact, (Scheme 6). Thus, we witness a smoothchemoselective hydrolysis of one carboxamide in preference tothe other carboxamide as well as sulfonamide.

The sodium salt of sulfacetamide is neutral and is used as anointment or drops in the treatment of eye infections, for topicalapplication for skin infections, and other similar situations.

A brief procedure for the preparation of sulfacetamide is givenbelow. It is a simple experiment and can be included in MScpracticals as an example of chemoselective reaction, and todiscuss mechanistic aspects of amide hydrolysis.

Preparation of Sulfacetamide

First Step Preparation of N1,N4-Diacetylsulfanilamide (7)

To 8.6 g of 4-aminobenzenesulfonamide (1) in a 250 ml roundbottomed flask are added 40 ml of acetic anhydride carefully.Initially the solid dissolves, but within minutes a solid forms with

When OH adds tosulfur in 4 or 6 the

tetrasubstitutedsulfur has to expand

its valency to fiveand become

pentasubstituted.This increases

valence shellelectrons as well asthe steric crowding

around sulfur.

In the case of 7, ascompared to other

sulfonamides, the N1-hydrogen is even

more acidic as it isflanked by two

electron withdrawinggroups (-SO2- and-CO-). In fact, 7 is

more acidic than mostother sulfonamide

medicinal compounds.

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evolution of heat which is controlled by holding the flask undertap water. The mixture is then refluxed on a heating mantle (or aBunsen burner) for 2-3 h, cooled to room temperature and pouredinto ice-water (30-40 ml with crushed ice pieces). The solidN1,N4-diacetylsulfanilamide (7) formed is filtered and washedwith cold water (3-4 times); the yield is about 70-75%. A smallamount of this is recrystallized from isopropyl alcohol (3-4 ml)containing a few drops of methanol for checking mp (found,253 oC; literature [1] mp 254 oC).

IR (neat, cm1): 3575 (NH), 3469 (NH), 1703 (CO), 1668 (CO),1638, 1589, 1538, 1469, 1374, 1325 (sym. SO2), 1233, 1155(asym. SO2), 1089, 1002, 842, 715, 635, 611, 540.

1H NMR (DMSO-D6, 400 MHz): 1.89 (s, 3H), 2.07 (s, 3H), 7.73(d, J = 8.80 Hz, 2H), 7.82 (d, J = 8.96 Hz, 2H), 10.37 (s, 1H), 11.95(s, 1H).

Figure 1a. FT-IR spectrumof diacetyl sulfonamide 7.

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13C NMR (DMSO-D6, 400 MHz): 23.17, 24.13, 118.35, 128.85,132.68, 143.77, 168.63, 169.10.

Second Step Hydrolysis of 7 to Sulfacetamide (N1-Acetylsul-fanilamide, 8)

The crude product 7 (9.2 g) is treated with a solution of 3.59 g ofNaOH in 40 ml of water. The mixture is boiled for 1.5 h on aheating mantle, cooled, and neutralized to pH 8 with 4N HCl. Thesolution on cooling and standing deposits a little sulfanilide (1)

Figure1b. 1HNMR(400MHz,DMSO-D6 ) spectrum ofdiacetyl sulfonamide 7.

ppm

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which is removed by filtration. The filtrate is further treated with4N HCl till its pH is 4 and kept in a refrigerator for 24 h, whensulfacetamide separates out as a white solid. It is collected byfiltration and recrystallized from hot water. The yield is 2.3 g(30%) and the m.p. is 180 oC (literature [1] m.p. 181 oC).

IR (neat, cm1): 3468 (NH), 3376 (NH), 1682 (CO), 1638, 1590,

Figure 1c. 13C NMR (400MHz, DMSO-D6 ) spectrumof diacetyl sulfonamide 7.

ppm

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Figure 2a. FTIR spectrumof sulfacetamide 8.

1464, 1316 (sym. SO2), 1243, 1144 (asym. SO2), 1084, 991, 853,823, 676, 626, 589, 532.

1H NMR (Methanol-D4, 400 MHz): 1.93 (s, 3H), 6.66 (d, J =8.76 Hz, 2H), 7.64 (d, J = 8.76 Hz, 2H). (NH protons areexchanged for deuterium in CD3OD; therefore, no NH2 protonsignals are seen).

13C NMR (Methanol-D4, 400 MHz): 23.23, 113.87, 125.88,131.28, 155.19, 170.97.

Conclusion

The experiment shows that an amide functional group behaveschemically differently when it is present in slightly different

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Figure2b. 1HNMR(400MHz,CD3OD)spectrumofsulfac-etamide 8.Figure 2c. 13C NMR (400MHz, CD3OD) spectrum ofsulfacetamide 8.

chemical environments. Here one acetamide group finds itself tobe hydrolyzing faster than the other one, in spite of being the samefunctional group, only because the chemical environments aroundthe two groups are different. Such selectivity is a very commonphenomenon and is observed for many other functional groups ina wide variety of transformations (see, Ref [4]).

Acknowledgment

The author thanks R Senthil Kumar for preparing the compounds7 and 8.

ppm

ppm2b 2c

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Suggested Reading

[1] M L Crossley, E H Northey and M E Hultquist, J. Am. Chem. Soc.,Vol.61, pp.29502955, 1939. (Preparation of sulfonamides)

[2] J March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons,pp.440-911, 1992. (Chemoselectivity)

[3] M A Weidner-Wells and M J Macielag, Kirk-Othmer Encyclopedia ofChemical Technology, Fifth Edition, Vol.23, pp.493513, 2007. (Sulfadrugs description)

[4] D J Abraham (Ed.) Burgers Medicinal Chemistry & Drug Discovery, 6thEdition, Vol.1, pp.2523, 2007. (Pharmacophore definition)

[5] Bentley and Drivers Text book of Pharmaceutical Chemistry, 8th Edi-tion, Oxford University Press 20th impression, pp.688693, 2003. (Sulfadrugs general)

[6] R T Morrison and R N Boyd, Organic Chemistry, 6th Edition, PrenticeHall of India, pp.585860, 2007. (Sulfonamide hydrolysis, mechanism)

[7] M Dohrn and P Diedrich, US patent No. 2, 411, 495 (1946, applied, 1939)(Preparation of sulfonamides)

Address for CorrespondenceG Nagendrappa

Department of MedicinalChemistry

Sri Ramachandra UniversityPorur, Chennai 600 116

Email:gnagendrappa@gmail.com

This happened during the time of my doctoral work. One ofmy fellow doctoral colleagues was working in the area ofinorganic complexes. The work involved the preparationand characterization of new complexes, which requiredelemental analysis data in addition to other pieces of infor-mation. On one occasion his research guide, finding somediscrepancy between the analysis data calculated for anassumed molecular formula and the experimentally foundvalues, asked him to add a molecule of water in calculatingthe percentage values to match the experimental values.My friend took some compound in a test tube and asked hisguide how he might add one molecule of water to it! I do notremember what the guides reaction was, but this is one ofthe memorable episodes of my PhD days that lingers on.

G Nagendrappa

How to Add a Molecule of Water toMolecular Formula?