374

CHAPTER 6

MicroscaleOrganic Laboratory Experiments

Common names:2-nitrophenol, o-nitrophenol CA number:[88-75-5] CA name as indexed:phenol,2-nitroCommon names:4-nitrophenol,p-nitrophenol CA number: [100-02-7] CA name as indexed:phenol,4-nitroPurpose. Aromaticnitrationis an important syntheticreaction. This experiment explores two methodsusedfor placinga nitro groupon an aromatic ring systemvia an electrophilic aromaticsubstitution reaction. ExperiIn ments l29Al,I29Bl, and [29C] anhydrousnitric acid is used as the nitrating agent.InExperiment usinga SiO2. HN03 [29D],nitrationis accomplished reagent. PriorReading Technique SimpleDistillationat the Semimicroscale 2; Level (pp. 61,-6a) Tccluique Crystallization 5: Use of the Hirsch Funnel (pp. 88-89) (pp. 89-91) CraigTubeCrystallization Tbchnique Chromatography 6; Column Chromatography(pp. 92-95) Thin-LayerChromatogaphy(pp. 97-99) (pp.101-104) Concentration Solutions of Chapter Mixture Melting Points(pp.52-54) 4:

InI flue are the the dirr the

mil SiC

Per ma, pht unl use the tha

GENERAL REACTION
+ HNo3 O" activator > O*"2 + Hro

Drscuss roN
The nitration reactionsdescribedin this experiment all demonstrate one of the classicelectrophilic aromatic substitution reactions. Nitration has been used extensivelyin organic synthesissince a nitro group on an aromatic ring maybe readily reducedto an amino group. Once introduced onto the aromatic ring, the electron-withdrawing nitro goup deactivatesthe ring toward further reactionswith electrophiles.For example, bromination of nitrobenzene leads only to z-nitrobromobenzene; no dibromonitrobenzene is readily formed. However, when activating groups (rr-electron donors) are present on the ring it is possible to nitrate the ring fwice. This phenomenon can be illustrated by comparing the results of the nitration of 1,4-dichlorobenzene @xperiment l29Al) with that of {N'-diacetyl(Experiment[298]).Because the presenceof the acti1,4-phenylenediamine of vating acetamido (CH3CONH-) groups, the dinitro derivative forms readily.

5r

Ax

EXPERIMENT Nitration: 29 2,5-Dichloronitrobenzene; N,N'-Diacetyl-2,3-dinitro-1 375 ,4-phenylenediamine InExperiment[29C) (the preparation of 5-nitrosalirylic acid),the directing influences the 1-CO2H and 2-OH substituents the entering-NOz goup of on are illustrated.In this example,these two groups compliment each other since theyboth direct the entering nitro groLrp thc 5 position.The5 position and to the position are both electrorricallyfavored since tl-re-Co2H group is rneta 3 directing; -OH group is ortho-para directing.The nitro group ends up at the the position, and not at the 3 position, clueto steric effects. 5 The use of a silica gel-basedreagentto accomplishnitration under fairly mildconditions is illustrated in Experiment [29D]. The nitrating reap;ent, sio2' HNo3 is preparedby treatment of silicagel with nitric acid.In the experiment, phenol is nitrated to producea mixture of prroducts .Tltin-laqer chromatograplry usec-l analyzc.the mixture, and the ortho anc-l is to para nitrated phenols separatedby colurnnchromatography are using a silica gel column. If unreacted phenol is detectedin the TLC analysis,an extractiontechnique is used separate from the para isomer. to it This separation techniqueis bascdor-r the that a nitratc.dphenol is more acidicthan plrenol itself. fact Itis generallyacceptedthat the nitronium ion (No2*; is the electrophile that addsto the aromaticring. The ovcrall mechanismfor nitration follows:
HONO, + HONO2 HzO\l-NO2 + HONO, H2O-NO2 + NO3

H1O' + NO"- + NOI

-Yt)
CI )'-."
HONO2 + HOSO?H
+

CI

z\I
(/-

+ HNO]

NO,

CI

This mechanism illustrates two HNO. molecules reacting to generatc the nitronium as when using the anhydror.rs ion nitric acid reagent.Sulfuricacid is often useclto enhancethe production of NC)2+as shown hcre:
H2O -NO'

+ HSO;

Hr6;No,

H2o + fio"

Thus commonly used nitrating reaient a mixture of concentraied a is sulfuric and nitric acids.

S E MM I C R O S C A L E P R E P A R A T I O N I OF ANHYDROUS NITRIC ACID

Anhydrous nitric acid (HNo.) is prepared by the following procedure.
CAUTION: The reagentsand the product of this preparation are highly corrosive. The distillation must be conductedirr a hood. Appropriatt gloves are strongly suggestec-l. Prevent contact with eyes, skin, and clothing. Any spill should be neutralized using soiid sodium carbonate or bicarbonate,

HOOD

376

CHAPTER 6

MicroscaleOrganic Laboratory Experiments

EXPERIMENTAL PROCEDURE
Estimated time of preparation: h. 0.5 nitric acid immediately the nitration experiments NOTE. Usethis anhydrous for giuenbelow, amount The obtained thescale at used hereis sufficient theprepafor ration of two of the nitro compounds described this experiment. in
of Reactantsand Product Compound
Concd nitric acid (68%) Concd sulfuric acid (96-98%) Anhvdrous nitric acid 63.01

F
lr

ti tl'
L:

MW

Amount
0.7 mL 1.0 mL

bp ('C)
120.5 338 83

d
7.41 1..84 1..40

R
(r

1(

Reagents and Equipment. Using two clean, dry 1.0-mL graduated pipets, suladd 0.7 mL of concentratednitric acid,followed by 1.0 mL of concentrated furic acid,to a 10-mL round-bottom flask containinga boiling stone.Swirlthe flask gently to mix the reagents.Attach the flask to a Hickman still fitted with a n a i r c o n d e n s e(rr ) . to NOTE: It is useful to inuert a 10-mL beakerouer the air condenser help contain the acid aapors.
H Concd N03,0.7 L m + c o n c dH 2 S O 41 . 0 m L ,

P p ir k

CAUTION: Sulfuric acid can cause severe burns. Nitric acid is a strong oxidizing agent. Prevent contact with eyes, skin, and clothing. A spill can be neutralized using sodium carbonate or bicarbonate.

ul rl

verygentlywith a microburnet, Reaction Conilitions. Heatthe acidsolution keeping microburner constant in motion,until approximately mL ofan0.2 the hydrousnitric acidhasbeencollected distillate the collarof the still. as in Purification and Characterization. Use the anhydrousnitric acid ascollected.No further purificationis required. liquid, bp NOTE.Anhydrous nitric acid (white fuming nitric acid)is a colorless that in is B3"CIt is estimated the nitric acid obtained this preparation nt least 99.5-100% pure.If it is necessary storethedistillate, to remlr)e acidfromthe the collarof the still (Pasteur pipet)and placeit in a 1.0-mLconical fittedwtth uial a glass stopper, mny benecessary slightlybendtheendof thepipetin aflame It to not so that it canreach collarof a still that does haaea sideport.Thennhythe drousnitric acidis colorless faintlvvellow, or

P n e1

el

cl ri R

II

pl

2,5-Dich loronitrobenzene REACTION

oJ E S

.'+cr
1,4-Dichlorobenzene

+ + HNo3 crQcr
Not
2,S-Dichloronitrobenzene

t( o ti o

Experiment Nitration: 29 2,5-Dichloronitrobenzene; N,N'-Diacetyl-2,3-dinitro-1 381 ,4-phenylenediamine Weigh the crystalsand calculatethe percent yield. Determine the melting pointand compare your value to that listed in the literature. Obtain an IR spectrum the material and compare it with that recorded in the literature. of

2-and 4-Nitrophenol
INSTRUCTOR PREPARATION. a 250-mLErlenmeyer containing magIn a llask netic stiruing weighand place bar, 20.0g of silicagel (70-230mesh; remoaal the is of Now t'ines not necessary). add 50 mL of 7.5M nitric acidand stir themixture 3 h at roomtemperature. Remoue nitrated the silicagel by graaity t'or filtra(do tion not rinse), placeit on a clay plate,and allow it to air dry in a hood HOOD oaernight. theproduct an airtightcontainer. Store in Determine nitric acidcontent thesilicagel by titrationof a watersusthe of pensionthegelwith a 0.1M NaOH solution.The content thegelshould of acid of in be therange 16*20%by weight. of Nitration of Phenol

R E A C TO N I
OH

A
\)

sio.HNo, A-No'
\,)

-\
+

Ir-l

EXPERIMENTAL PROCEDURE
Estimated time to completethe experiment:2.0 h. PhysicalProperties of Reactants Compound Phenol SiO2'HNO.
Methvlene chloride

MW 94.77

Amount 240mg 1 . 0g
5 mL

mmol 2.55

mp ("C) 40.5-41.5

bp ('C) 182 40

Reagents and Equipment, Weigh and add 240 mg (2.55 mmol) of phenoi toa 10-mL round-bottom flask containing a stir bar. Now add 5 mL of methylenechloride. To this solution, weigh and add 1.0 g of nitrated silica gel (-16%HNO3). Attach the flask to an air condenser(+). CAUTION: Phenol is highly toxic and corrosive.Prevent contact with eyes and skin. It is best dispensed by warming the container of phenol in a warm water bath and then using an automatic delivery pipet. This should be done in the hood.

Roomtemp thermometer

HOOD
A 1 0 - m LR B f l a s k

382

CHAPTER6

MicroscaleOrganic Laboratory Experiments

Reaction Conditions.

Stir the resulting mixture at room temperature for 5 mrn.

TLI Cra

HOOD

Isolation of Proilucf. Separatethe silica gel from the reaction mixtureby gavity filtration through a filter funnel containing a small plug of giasswooi. Collect the filtrate in a L0-ml Erlenmeyer flask containing a boiling stone, Wash the collectedsilica gel with two 0.5-mL portions of methylene chloride, and collect these washings in the same Erlenmeyer flask. Concentrate the filtrate to a volume of about 1.0 mL using a warm sand bath under a slow stream of nitrogen in the hood. Use thin-layer chromatogaphy to obtain an analysis of the product mixture (seePrior Reading).Use methylene chloride as the elution solvent,silica gel (with a fluorescent indicator) as the stationary phase,and W light forr,rsualization. TypicalRlvalues are 0.04 for 4-nitrophenol, 0.15 for phenol,and for 2-nitrophenol. 0.58 NOTE. 2,4-Dinitrophenolhas a typical R1ualue of 0.33 under the chromntography conditionsaboue;it is not usuallyformed under thesereactionconditions. Characterization and Purification, Column chromatogaphy is now used to separatethe mixture of products. Pack (dry) a 1.0-cm-diametcr buret column with 7.5 g of activatedsilica gel. Place the above product solution on the column using a Pasteur pipet and then elute the column with 25 mL of 60:40 methylene chloride/pentanesolvent. Collect the first 20 mL of eluate in a tared 25-mL Erlenmeyerflask. Concentratethis fraction to drymess a warm sand in bath under a slow steam of nitrogen to isolate the 2-nitrophenol. Weighthe product. Now elute the column with about 30 mL of 1:1 ethyl acetate/methylene chloride solvent. Collect the first 20 mL of eluate in a tared 25-mL Erlenmeyer flask containing a boiling stone. Concentratethis fraction as above to a volume of about 2 mL. Use thin-layer chromatography to determine the purity of the product (seeconditionsoutlined above). The main constituentof this fraction is 4-nitrophenol. However, the presence of unreacted phenol or possibly quinone is often detected.Now concentratethe product solution to d4mess and weigh the 4-nitrophenol isolated. If the TLC analysis indicates impurity, 4-nitrophenol may be purifiedas follows. Dissolve the solid residue in 7 mL of saturated sodium bicarbonare solution and transfer the resulting solution to a 15-mL centrifuge tube. Extract this solution twice with 2-mL portions of methylene chloride (aVortexmixer may be used to good advantagehere). Remove the methylene chloride layers using a Pasteurpipet and savethem (together) in a small Erlenmeyerflaskuntil you have isolated and characterizedthe product. Cool the resultingaqueoussolution in an ice bath and add 6 M HCl drop wise, with mixing (glass rod or Vortex mixer), until it becomes neutral or slightly acidic toward litmus or pH paper. Do this stepcarefully.Tbo aigorous n reactionmay result in lossof product.Now extract the resulting solution with three 2-mL portions of methylene chloride. Following each extraction,remove the methylene chloride using a Pasteurfilter pipet and transfer it to a 10-mL Erlenmeyer flask. Dry the wet solution over anhydrous sodium sulfate and then transfer it by Pasteurfilter pipet to a tared 10-mL Erlenmeyerflask containing a boiling stone. Concentrate this solution using a warm sandbath under a slow stream of nitrogen gas to yield the 4-nitrophenol product. Weigh the product. The purity of the material may be checked again, using

anc the

ch

tor for soi mit the ter

5-l 5--t

6-1

6-'1

Experiment29

Nitration: 2,5-Dichloronitrobenzene; N,N'-Diacetyl-2,3-dinitro-1 ,4-phenylenediamine383

TLC outlined above.It may also be recrystallized as from water using the tube,if necessary. Craig Tocharacterize 2- and 4-nitrophenols, the determine their meltingpoints and obtaintheir infraredspectra. Compareyour resultsto thosereportedin (The literature the AldrichLibraryof IR Spectra and/orSciFinder Scholar). ChemicalTests, Chemical classification (see tests Chapter arealsoof value 9) toestablish identity of thesecompounds. the Performthe ferricchloridetest forphenols.Is a positive result obtained for each compound?Does the fusion test detectthe presence nitrogen? sodium of The test for nitro groups alsobe performed. might The phenyl- or cr-naphthylurethane derivatives of phenols may be prepared further establish the to their identity (seeChapter9, Preparation Derivatives). of

OU ESTIONS
Predict the most likely mononitration product from each of the following compounds. Explain the reasonsfor 6-186. your choice.

CF"

l'

{a) ll
\/

/,t\

(b)

f"'
CH.

CH3)z

NO"

>,
H,C

( c) cH/\

a.-\ ll | cu,,

t-

Br

( d)

(f)

CHs

d",
(r
\,

r,,\ tgrll I \, .,t2

N

CHs

5-187.Write equations to show how nitronium ions might be formed using a mixture of nitric and sulfuric acids. 5-188.\tVhich ring of phenyl benzoate would you expect to undergo nitration more readily? Explain.

'o' il. ,z/-c-Qh

\,

Phenylbenzoate 5-189.Arrange the following compounds in order of increasingreactivity toward nitration. Explain. (a) Acetanilide (b) Acetophenone (c) Bromobenzene (d) Toluene 5-190. Offer a reasonableexplanation of why nitration of 1,4-dichlorobenzeneyields the mononitro derivative while N,M -diacetyl-1,4-phenylenediamine forms the dinitro compound. 5-19L. Explain why p-nitrophenol is a stronger acid than phenol itself.Would p-methoxyphenol be a stronger or weaker acid than phenol? Explain.