CHAPTER lectrophilic Aromatic substitution something chemically remarkable happens when three conjugated double bonds See more on are incorporated into a six-membered ring to produce a so-called aromatic com- se nota pound. In sharp contrast othe adiition reactions that typily akenes (Secs. 10.4 pon 2 and Ghap. 12) and alkynes (See. 11.3), the chemistry of aromatic mole a characterized by substitutions, that i, transformations in which a proton o” Svs na is replaced by some other atom or functional group. Welll be exPionog those types of fascinating and very useful reactions in this chanter. You wit News the opportunity not ony to execute reactions in which functional revs re intro duced onto the aromatic ring but also to study both qualitatively and quantitatively aac igcts that substituents on the ing have on rates at which these substitutions ane et ervege experiments will help you to understand the remarkable chemist of aromatic compounds. 45.1 INTRODUCTION lectrophilic aromatic substitution is an important reaction that allows Hhe O° aoe af many different functional groups onto an aromatic ring, A general orm aera rc ection is given by Equation 15.1, where Ar-H is an aromatic compound, an stone, and represents an electrophile that replaces an Hon the ring. This edva- seers, oversimplified because the electzophile is usually generated during the reac tion, and a Lewis base assists in the removal of H™ ArH + BY —— AcE + HT asap An An substituted rene electrophile ene The rates of electrophilic aromatic substitutions are generally second-order over aul, being first order in both the aromatic component and the electrophile (E915 2). ‘a general mechanism that is consistent with this kinetic expression is depicted in Equations 153-155. Rate = ky [Ar—HI(E*) as) 451gga. Experimental Orgone Chonery ier and Matin i ‘Step 1: Formation of electrophile: ete SES te No (a3) ste 2 Recon wih elt , i non erate la ] ca } E. 4 Step 3: Lass of proton tv give prod led) 8 ee aed (455) Ne} ) “The electrophile is usually produced by the reaction between a catalyst an ¢ compound containing @ poten electrophile (Eq. 15.3) The second-order NNT of com Poon arises fom te sep shown in Equation 15.4 in which one molecule each ae ene and elecrophile react to give a positively charged intermediate, The Forme of eet faseation is the rate-determining step (rds) inthe overall reaction; the 60>" ‘ Scquent deprotonation ofthe cation (Eq 15.) fat. The bimoleculss nary ‘of the sa ae tare forte rate-limiting sep and the fact that an electrophile is involved seavtaahing the aromatic substrate Casifes the reaction as S_2 (Substitution Fee ophlic Bimolecular- Experiments involving four diferent such reactions a 21700 sr hss chapter: Friedel-Crafts alkylation and acylation nitration, and bromination-502 Experimental Orgeie Chemisty aber and Martin 15.4 NITRATION O F BROMOBENZENE ‘Reaction of an aromatic compound Retfarc and ritrc acids introduces a nitro SOV suc sibtitution (Sec. 15.1) as depicted species i the nitronium ion, NO3, acei s produced by reaction of sulfuric acid spepeteric acid (Eq 15:5) note that tric 360 he weaker of these two strong min wa avids is serving asa base rather than a5 7. ‘acd in this equilibrium. such as benzene with a mixture of concentrate of electrophilic HNO: ne 45.14) Benzene Nirbenzene Zeson HA sot HA HO-NO. =—— S641no; ——= #0 +°NO2 515) H Nitec acid ‘Nitronium on “The rate-determining step (rds) in the nitzakon’ reaction involves nucleophilic attack ofthe aromatic ing, a Lewis base, oF he nitronium ion, a Lewis acid, to form ate Ee 51 In a ci ir canls treme eam es 5? a NO, NO: A yO Cee oh oe Ch asa6) n o-Conplex Or 7 toy oo fe + 140 asa) ” “The mechanism of the reaction ofa nitronsumy 0% with a substituted benzene sachs bromobenzene (18), the arene wsed in experiment, ssiias to that with Pater Now, however, thre different products cox now be formed because of he presence of the bromine atom on the ring (Eq. 15.18). The activation, energies for attack at the positions ‘ortho and para to the substituent are Jower than that for at Br Br Br Br NO; 10N05 Cy ae +> as. 1380 A ~NO? NOz 1" 1» 20 a rometenzene 2Bromo- Brome Brome slcbenzene sitobeneene asobenene27 aR secrophilc Aromatic Substision 503 chaps ts because the o-complexes 22 and 23, which are the P= at the yo tre ortho and para products 19 and 2), respectively, are more stable than correo 24, which gives the meta compound 7 "The increased stability of 22 and Serarive to 24 is associated with the partisPacs ‘of nonbonding, electrons on the tromine atom in delocalizing the positive Charge the complexes 22 and 23. Thus, Like an alkyl group, a bromine atom is an. ‘example of an ortho-para director, since a dove forenation ofthese isomers over the mea Soret For this nitration reaction the preference is found to be about 1007 at the meta position. This br L_NO2 H No: 2 2B “The op ratio itself is of interest because isolating PE disubstituted products requires separation ofthese isomers. ASSETS that attack of the electrophile at the ea positions occurs on a purely statistical DAS this ratio is predicted to be 2:1, feo Posithere are two ortho carbon atoms and only 05° Ta ‘carbon atom in bro- bese ene, This prediction neglects the possibility that the steric bulk and the aasverive electronwitharawing effect ofthe bromine HO ‘might inhibit approach ine electrnphile to the orth relative tothe para Posito® By determining the rela See ounts of 19 and 20 produced, you will be sble fs evaluate this hypothesis. srmother product may result if further nitration of 1 © 120 occurs. Considering, the directing effects ofthe bromo and nitro ubsstuets Jeads to the prediction that the major product from both isomers would Pe 2 ‘promo-2,4-dinitrobenzene (25), a8 wre rn Equation 15.19. The possible formation of 1 ‘promo-?,6-dinitrobenzene (26) sro ig less likely because of the steric and induce effects of the bromo arspatituent. Fortunately itis relatively easy to TAiSy dinitration by performing sanction at temperatures below 60°C. Controling the temperature suppresses tration because the strongly deactivating nitro substituent in 19 and 20 raises inst pe energy for their utration above that of 18. Anctner factor decreasing ‘Re ainutration of 20s its precipitation during the course ‘of the reaction, thereby removing it from the nitrating medium Br x05 cr ves Ee C+ as) NOx 25 1-Bromo-24-initrobenzene Br Om NOH LA 26 1-Brome-26-dinitobenzenesos Experimental Organi Choisy Giber and Marin sased on the preceding discussion, the major obstacle 40 HEA Ee peed Sipensere Gs sepaating from 2bromoritebenzene O°) ‘The strat- iy for ding this eis on the greater polarity of 19-700 ‘makes this isomer more oe in pela solvents than 20. Ths difference is drama¥coy demonstrated by sole Fa aolublitie in ethanol. At room temperature, he 0719 Sot 191 wary soluble, whereas the para somer i slightly so} dissolving to the extent of Wad) 12/100 mL. Ths lage difference in solubilities a!" separation ofthe iso ay Bane technique of fractional crystallization. The Tralst of products mer Fram nitration of bromobenzene is dissolved in hot Ss ethanol, and the ea allowed to cool. The les soluble pra somer selectively crystallizes from schation it holed by Siaon. Concentration ofthe trate allows ena? of a second crop of 20. cor oral crstlizaton itis comuonly possible o induce ysGNoaE oe sabe component, x this case the orto isomer 19, ones TN Toe solu of he mor fas been mostly removed. However, the lov melting Pot} °° Corey ole if isomers difficult to crystallize inthe presence ofimpuses Consequently, aang ts inomer involves column chromatography (See-63) pee EXPERIMENTAL PROCEDURES Nitration of Bromobenzene Purpose To demonstrate nitration by electrophilic aromatic substitution and to test the direct effects of a bromo substituent pecause concentrated sulturic and nitric aside may eause Severe chemical Cams, do not allow them to contact your skin. Wear latex glove ‘when handling carne scgents. Wipe off any drips and runs on the outside surtace of reagent tstles and graduated cylinders before picking them up. Wash i atfected area aovcsiately and thoroughly with cold water, and apply 5% sodlum bicarbonate solution. A = NITRATION Miniscale Procedure Preparation Answer the Pre-Lab Exercises om page PL. 92: Read 1 MSDSs for” ereicale used or produced in this procedure. Review Sections 410, 2.14, Aon Cee dyer produced in this procedure. Review Sections 2.9, 2 0, 2 Exercises and MSDSs : . 5 Apparatus A 25-ml.round-bottom flask, Claisen adapter, he mometer, Wate aetied condenser, ice-water bath, apparatus for magnetic stir heating. Setting Up Prepare a solution of 4.0 mL of concentrated nile acid and 40 mL. Seng ated sulfuric acid in the rouncd-bottom flask and cool itto 100m temperatul‘Apparatus for brominating sae Microscale Procedures Chapter 15 m Elecropilc Aromatic Su wth a water bath, Equip the flask wih a sitar and a Claison adapter fited wih ine wa oneer and a thermometer that extends into the flask (Fig, 16.18) reaction and Work-Up In portions of approximately 0.6 ml. add 45 Mi of bro roctpzene tothe sired mixture through the top of the condenser ove! period ooaerat 10 min, Do not allow the temperature of the reaction mixture exceed oe tc during the addition. Control the temperature by allowing more toe Soe sine aJution of auccessive partons of bromobenzene and by cooling tne reaction flask with an ice-water bath ‘tar the adtion is complete and the exothermic reaction has subsided, Nest the stired mitre for 18 min, Keeping Is temperature below 60°C * Cool the reac- are ture to room temperature, and then pour it carefully and with string jlo 40 mL of cold water contained in a beaker, Isolation and Puriication Isolate the mixture of crude bromonioberseare by vacuum itration. Wash the fiter cake thoroughly with cold watt until the oy ce are neutral to pHydrion paper; allow the solid to drain under vacuum until nearly dey. * eor tne fiter cake to an Erlenmeyer flask and recrystalize the crude pros uct om 95% ethanol. Alow the residual solution to cool slowly to room tet\pet dae en coo! it to °C in an ice-water bath. Isolate the crystalline product by tem titration. Wash the product witha itl ice-cold 95% ethano|, alowita Ne yaetnee to dra into the fier flask withthe mother liquors. Transfer the product 10 ‘a watchglass or a piece of fiter paper for air-cryin Conxentrate the mother liquors to a volume of about 10 mL by simple distile tion, Perform this operation in a hood to prevent release of vapors into the labewe tory. Alternatively, use rotary evaporation or other techniques, to effect 1Ory ntfation. low the residual solution fo cool to room temperature to prodre censcond crop of &-bromonitrobenzene. Isolate it by vacuum fitration and, ater air-drying, put it in a separate val from the first crop. Ae Peoncentrate the mother liquors from the second erop 10 @ volume of 43-4 mL The resulting oll contains crude 2-bromonitrobenzene. Separate the of com the two-phase mixture by means of a Pasteur pipet and weigh and reserve it for chromatographic analysis (Parts 8 and C) “Analysis Weigh both crops of product and calculate the yield, Measure the melt ing points of both erops, Obtain IR and NMR spectra of your starting material © paauct and vompare thom with these of authentic samples (Figs. 691 48.19-15.22). Apparatus A 3-mL conical vial, water-cooled fatus for magnetic stirring, vacuum and Craig heating ndenser, ice-water bath, appa ibe filtration, and flameless Setting Up Prepare a solution of 0.5 mL and 0.5 mL of aengentrated sulfuric acid in the vial, and coo! it to room temperature with a water {ath Equip the vial wth a spinvane and the condonser‘Reaction and Work-Up In portions of approximately 0.1 mL, add 0.5 mL. of bro- mobenzene to the stirred mixture through the top of the condenser over a period of about § min, Although the temperature of the reaction mixture may become warmto the touch, do not allow the reaction mixture to become hot to the touch Guring the addition. Control the temperature by allowing more time between the Sddition of successive portions of bromobenzene and by cooling the vial with an ice-water bath if necessary. “After the addition is complete and the exothermic reaction has subsided, heat the stirred reaction mixture for 15 min, keeping the bath temperature below 70 °C.* Cool the vial to room temperature, and then pour the reaction mixture carefully and with stirring into 5 mL of cold water contained in a beaker. Isolation and Purification Isolate the rinture of crude bromonitrobenzenes by vac tum filtration. Wash the filter cake with small portions of cold water until the washes fare neutral, and allow the solid to drain under vacuum until nearly dry.* “Transfer the filter cake to a Craig tube and recrystalize the crude product from 195% ethanol. Allow the solution to cool slowly to room temperature; then cool itto 0°C jn an ice-water bath. Isolate the crystaline product by vacuum or Graig tube fitrationPost-Lab Questions 1) 2) 3) 4) Explain why 4-bromonitrobenzene is less polar than 2-bromonotrobenzene. Explain why the melting point of the 4-bromonitrobenzene is higher than 2- bromonotrobenzene. Which of the two isomers would have a higher Re value on a silica (polar) TLC plate? Why? The ratio of the two isomers is usually found to be 38:62, with the 4- bromonitrobenzene being the major product. Use this ratio and the amount of 4- bromonitrobenzene actually isolated to estimate the experimental yield of mononitration in this reaction. What errors are there in using this method to calculate the extent of mononitration?