Organic Chemistry FIFTHEDITION MarcLoudon Purdue University ROBERTSADCOMPAYPUBLISHERS Greenwood Village.Colorado Contents Preface Reviewers andconsultants About the Author CHEMICAL BONDING AND CHEMICAL STRUCTURE 1.1Introduction A.What IsOrganic Chemistry? B.Emergence of Organic Chemistry C.Why Study Organic Chemistry? 1.2Classical Theories of Chemical Bonding A.Electrons inAtoms B.The Ionic Bond C.The Covalent Bond D.The Polar Covalent Bond 1.3Structures of covalent Compounds A.Methods forDetermining Molecular Geometry B.Prediction of Molecular Geometry 1.4Resonance Structures 1.5wave Nature of the Electron 1.6Electronic structure of the Hydrogen Atom A.Orbitals, Quantum Numbers. andEnergy B.Spatial Characteristics of Orbitals C.Summary: Atomic Orbitals of Hydrogen 1.7Electronic Structures of More complex Atoms 1.8Another Look at the covalent Bond: Molecular Orbitals A.Molecular Orbital Theory B.Molecular Orbital Theory and the Lewis Structure of~1.9Hybrid Orbitals A.Bonding inMethane B.Bonding inAmmonia xxxi xxxvi xxxix 1 1 1 2 3 3 3 5 9 13 13 14 20 22 23 23 25 28 29 32 32 36 37 37 40 vii ViiiCONTENTS Key Ideas inChapter 1 Additional Problems 42 43 ALKANES46 2.1Hydrocarbons 2.2Unbranched Alkanes 2.3conformations of Alkanes A. Conformation of Ethane B.Conformations of Butane 2.4Constitutional Isomers and Nomenclature A. Isomers B.Organicomcndature C.Sub!.titutivcomenclarure of D.Highl) Conden:,edStructures E.Classification of Carbon Substitution 46 48 50 50 53 57 57 58 59 64 66 2.5cycloalkanes and Skeletal structures67 2.6Physical Properties of Alkanes70 A.Boiling Points70 B.Melting 73 C.Other Phy!>icalProperties74 2.7combustion76 2.8Occurrence and Use of Alkanes78 2.9Functional Groups, compound Classes, and the "R" Notation81 A.Functional and Compound Cla\scs8 1 B. "R"Notation82 KeyIdeas inChapter 283 Additional Problems83 ACIDS AND BASES. THECURVED-ARROWNOTATION87 3.1Lewis Acid-Base Association Reactions A. Elcctron-Dclicicnt Compounds B. Reacti ons of Electron-Defici ent Compounds withLewisBases C.The Curved-ArrowNotationfor Lewis Acid- BaseAssociation and Di ssociati onReactions 87 87 88 89 3.2Electron-Pair Displacement Reactions A.Donation of Electrons to Atom!> ThatAreotElectron-Deficient B.The Curved-ArrowNotationfor Electron-Pair Reactions 3.3Review of the Curved-Arrow Notation A.Usc of the Curved-Arrow Notationto RepresentB.U:.c of the Curved-ArrowotationtoDeriveResonance3.4Bronsted- Lowry Acids and Bases A.Definition of BronstedAcid., and B.uclcophilc!..Electrophiles. andLeaving Groups C.Strength.., of BronstedD.Strength-; of BrV)nstedE.Equilibria in Acid-Base Reactions 3.5Free Energy and Chemical Equilibrium 3.6Relationship of Structure to Acidity A. The ElementEffect B.The Charge Effect C.ThePolar Effect Key Ideas in Chapter 3 Additional Problems INTRODUCTION TOALKENES. STRUCTUREAND REACTIVITY 4.1Structure and Bonding in Alkenes A. CarbonHyhridization in Alkenes B.The7T(Pi) Bond C.Double-Bond Stereoisomer!. 4.2Nomenclature of Alkenes A.I UPAC Substitut iveNomenclature B.Nomenclature of Double-Bond Stcreoisomers: The .24.3Unsaturation Number 4.4Physical Properties of Alkenes 4.5Relative Stabilities of Alkene Isomers A. Heatsof Formation B.Relative Stabil ities of Alkene 4.6Addition Reactions of Alkenes 4.7Addition of Hydrogen Halides to Alkenes A. Regio:..electivity of Hydrogenllalidc Addition B. Carbocation inHydrogen Halide Addition CONTENTSix 90 90 91 94 94 9-l 96 96 98 101 103 104 106 108 lOR 110 Ill 116 117 122 122 123 125 128 131 131 134 139 140 141 141 144 147 147 148 149 XCONTENTS C. Structure andStability of Carbocationo; D. CarbocationRearrangement inHydrogenHalide Addition 4.8Reaction Rates A. The Transition State B. The EnergyBarrier C. Multistep Reactions and the Rate-Limiting Step D. Hammonds Postulate 4.9catalysis A. Catalytic Hydrogenation of Alkenes B.Hydration of Alkenes C.Enzyme Catalysis Key Ideas in Chapter 4 Additional Problems ADDITIONREACTIONS OF ALKENES 5.1An overview of Electrophilic Addition Reactions 5.2Reactions of Alkenes with Halogens A.Addition of Chlorine andBromine B.Halohydrins 5.3Writing Organic Reactions 5.4Conversion of Alkenes into Alcohols A. Oxymercuration- Reduction of Alkenes B. Hydroboration-Oxidation of Alkenes C.Compari!>Onof Methods forthe Synthesis of Alcoholsfrom Alkenes 5.5ozonolysis of Alkenes 5.6Free-Radical Addition of Hydrogen Bromide to Alkenes A.ThePeroxide Effect B.Free Radicals andthe "Fishhook"Notation C.Free-RadicalChain Reactions D.Explanation of the Peroxide Effect E.BondDissociation Energies 5.7Polymers: Free-Radical Polymerization of Alkenes 5.8Alkenes in the Chemical Industry Key Ideas in Chapters Additional Problems 151 154 157 158 160 162 164 166 168 169 172 172 174 178 178 181 181 183 186 187 187 190 194 196 200 200 201 202 207 211 214 216 219 220 PRINCIPLES OFSTEREOCHEMISTRY 6.1Enantiomers, Chirality, and symmetry A.Enantiomers andChirality B.Asymmetric Carbon and Stereocenters C.Chirality andSymmetry 6.2Nomenclature of Enantiomers: The R,S system 6.3Physical Properties of Enantiomers: Optical Activity A.Polari;cd Light B.OpticalActivity C.Optical Activities of Enantiomcrs 6.4Racemates 6.5stereochemical correlation 6.6Diastereomers 6.7Meso compounds 6.8Enantiomeric Resolution 6.9Chlral Molecules without Asymmetric Atoms 6.10Conformational Stereoisomers A. Stcrcoisorners lnterconvened byInternalRotations B. Asymmetric Nitrogen:Amine Inversion 6.11Drawing Structures That Contain Three-Dimensional Information 6.12The Postulation of Tetrahedral carbon Key Ideas in Chapter 6 Additional Problems CYCLICCOMPOUNDS. STEREOCHEMISTRY OFREACTIONS 7.1Relative Stabilities of the Monocyclic Alkanes 7.2Conformations of cyclohexane A.The Chair Conformation B.lntcrconversion of Chair Conformations C.Boat and Twist-Boat Conformations CONTENTSxi 226 226 226 229 229 231 234 235 235 238 239 241 242 246 249 251 253 253 255 257 259 263 263 268 268 269 269 273 274 XiiCONTENTS 1.3Monosubstituted cyclohexanes. Conformational Analysis277 1.4Disubstituted cyclohexanes281 A. Ci'>-Trans1-.omerim in Disubstituted B.Conformational Analysis C.U'>eof Planar Structurefor Cyclic Compound'> D.Stereochemical Con ...equences of the Chair lntercomer,ion 7.5cyclopentane, cyclobutane, and Cyclopropane A. Cyclopcntane B.Cyclobutane andCyclopropane 7.6Blcyclic and Polycyclic compounds A. Classifi cati onandNomenclature B.Cis and TransRing Fusion C.Trans-Cycloalkenes andBredt'sRule D.Steroids 7.7Relative Reactivities of Stereoisomers A.Relative Reactivities of Enantiomers B.Relative Reactivities of Diastereomers 7.8Reactions That Form Stereoisomers A.Reactions of Achiral Compounds That Gi\'e Enantiomeric Product' B.Reaction' That Give Diastereomeric Products 7.9Stereochemistry of Chemical Reactions A. Stereochemistry of Addition Reactions B.Stereochcmitl)of Substitution Reactions C.Stereochemi'>Lry of Bromine Addition D. of Hydroboration- Oxidation E.Stereo 8.2Structures 8.3Effect of Molecular Polarity and Hydrogen Bonding on Physical Properties A.Boiling of Ethers andAlkyl 281 283 28-f 285 288 288 289 290 290 292 294 296 298 298 300 301 301 30-f 305 305 306 308 312 313 314 316 323 324 32-f 326 330 332 333 333 B.Boiling Points of Alcohol\ C.H)drogenBonding 8.4Solvents in Organic Chemistry A. Cla ... sification of Solvents B. Solubility 8.5Applications of Solubility and Solvation Pri nciples A. CellMembranes andDrug Solubility B. Cation-Binding Molecules 8.6Acidity of Alcohols and Thiols A. Formation of Alkoxidcs andMcrcaptidcs B.Polar Effects onAlcoholAcidity C.Role of theSolventin Alcohol Acidity 8.7Basicity of Alcohols and Ethers 8.8Grignard and Organolithium Reagents A. Formation of Grignard andOrganolithium Reagl:nt-; B.of Grignard andOrganolithiumReagent!--8.9Industrial Preparation and use of Alkyl Halides, Alcohols, and Ethers A. Free-RadicalHalogenation of Alkane' B.Useof Alcohols with Thionyl Chloride andPho!>phorll' ..Tribromide 10.4Conversion of Alcohols into Alkyl Halides: Summary 400 400 400 402 402 404 406 407 41I 412 412 414 416 418 420 420 424 424 426 428 429 436 436 440 443 443 447 448 449 450 10.5Oxidation and Reduction in Organic Chemistry A.Half-Reactions and Oxidation Numbers B.Oxidizing and Reducing Agents 10.6Oxidation of Alcohols A. Oxidation roAldehydes and Ketones B.Oxidation to Carboxylic Acids 10.7Biological Oxidation of Ethanol 10.8Chemical and Stereochemical Group Relationships A. Chemical Equivalence andNonequivalence B. Stereochemjstry of the AlcoholDehydrogenase Reaction 10.9Oxidation of Thiols 10.10synthesis of Alcohols 10.11Design of Organic synthesis Key Ideas in Chapter 10 Additional Problems THECHEMISTRY OFETHERS,EPOXIDES, GLYCOLS, AND SULFIDES 11.1synthesis of Ethers and sulfides A.Williamson Ether Synthesis B.Alkoxymercurarion-Reducrion of Alkenes C.Ethers fromAlcoholDehydration and Alkene Addition 11.2synthesis of Epoxides A.Oxidation of Alkenes with Peroxycarboxylic Acids B.Cyclization of Halohydrins 11.3Cleavage of Ethers 11.4Nucleophilic Substitution Reactions of Epoxides A. Ring-Opening Reactions under Basic Conditions B.Ring-OpeningReactions under Acidic Conditions C. Reaction of Epoxides withOrganometallic Reagents 11.5Preparation and Oxidative Cleavage of Glycols A.Preparation of Glycols B. Oxidative Cleavage of Glycols 11.6oxonium and Sulfonium Salts A.Reactions of Oxonium and Sulfonium Salts B.S-Adenosylmelhionine: Nature' s Methylating Agent CONTENTSXV 452 452 456 459 459 461 462 465 465 469 471 474 474 476 477 482 482 482 484 485 488 488 491 492 495 495 497 500 503 503 506 508 508 509 XViCONTENTS 11.7Intramolecular Reactions and the Proximity Effect A. Neighboring-Group Participati on B.The Proximity Effect andEffective Molarity C.StereochemicalConsequences of Neighboring-Group Pm1icipation 11.8oxidation of Ethers and sulfides 510 510 513 516 518 11.9The Three Fundamental operations of Organic synthesis520 11.10Synthesis of Enantiomerically Pure compounds: Asymmetric Epoxidation522 Key Ideas in Chapter 11527 Additional Problems528 INTRODUCTION TOSPECTROSCOPY. INFRARED SPECTROSCOPY ANDMASS SPECTROMETRY536 12.1Introduction to Spectroscopy A.Electromagneti c Radiation B.AbsorptionSpectroscopy 12.2Infrared Spectroscopy A. The Infrared Spectrum B.PhysicalBasis of IR Spectroscopy 12.3Infrared Absorption and Chemical Structure A. Factors That Determine IR Absorption Position B. Factors That Determine IR AbsorptionIntensity 12.4Functional-Group Infrared Absorptions A. IR Spectraof Alkanes B.IR Spectraof AlkylHalides C.!R Spectra of Alkene!> D.TRSpectra of Alcohols andEther. 12.5Obtaining an Infrared Spectrum 12.6Introduction to Mass Spectrometry A. Electron-Impact MassSpectra B.IsotopicPeaks C.Fragmentation D. The Molecular Ion.Chemical-Ionization Mass Spectra E.The Mass Spectrometer Key Ideas in Chapter 12 Additional Problems 536 ~ 6 ~ 8540 540 542 544 545 5-l8 552 552 552 553 556 557 558 558 560 563 566 569 571 571 CONTENTSxvii 13NUCLEAR MAGNETIC RESONANCESPECTROSCOPY578 13.1Anoverview of Proton NMR Spectroscopy578 13.2Physical Basis of NMR Spectroscopy581 13.3The NMRspectrum: Chemical Shift and Integral583 A. Chemical Shift5H3 B.ChemicalShift Scales585 C.Relation,hip of ChemicalShift to Structure586 D. Theumber of Ab,orption\ in an 1MR Spectrum589 E.Couming Protonswith theIntegral591 F.Using the Chemical ShiftandIntegraltoDetermine Unknown Structure:- 593 13.4The NMR spectrum: Spin- Spin Splitting595 A. The 11+ISplitling Rule596 8. Why Spliuing Occur\599 C.Solving Un!..nownwith;MR Spectralnvoh ing Spliuing601 13.5complex NMR spectra603 A. Multiplicative Splitting603 8.Breakdown of the 11+IRuh;607 13.6use of Deuterium in Proton NMR611 13.7Characteristic Functional-Group NMR Absorptions612 A. NMR Spectra of611 B.NMR Spectra of Alkanei>and614 C.NMR Spectra of Alkyl andEthers616 D.MR Spectra of Alcohob616 13.8NMR spectroscopy of Dynamic systems619 13.9carbon NMR622 13.10Solving Structure Problems with Spectroscopy629 13.11The NMR Spectrometer632 13.12Other uses of NMR634 Key Ideas in Chapter 13635 Additional Problems636 14THECHEMISTRY OF ALKYNES644 14.1Nomenclature of Alkynes644 14.2Structure and Bonding in Alkynes646 XViiiCONTENTS 14.3Physical Properties of Alkynes A.Boiling Points and Solubilities B. lR Spectroscopy of Alkyne C.MR Spectroscopy of Alkynes 14.4Introduction to Addition Reactions of the Triple Bond 14.5conversion of Alkynes into Aldehydes and Ketones A.Hydration of Alkynes B. Hydroborati on-Oxidation of Alkynes 14.6Reduction of Alkynes A. Catalytic Hydrogenation of Alkyne:-. B.Reduction of Alk) ne!>with Sodium inLiquid Ammonia 14.7Acidity of 1-Aikynes A. Acctylenic Anion!> B. Acetylenic Anion-. 14.8organic synthesis Using Alkynes 14.9Pheromones 14.10Occurrence and Use of Alkynes Key Ideas in Chapter 14 Additional Problems DIENES,RESONANCE, AND AROMATICITY 15.1Structure and Stability of Dienes A. Stability of ConjugatedDienes.Molecular Orbital., B.tructure of ConjugatedDienes C.Struct ure and Stability of Cumulated Di enes 15.2Ultraviolet-Visible spectroscopy A. The UV- ViSpectrum B. Phy!.icalBacope of theexperimentali st.Thelogic of thetime seemsto havebeenthatlife not understandable: organic compound:. !->pringfromlife:therefore. or-ganic compound., are not undeNandable. 1 2CHAPTER1CHEMICAL BONDING AND CHEMICAL STRUCTURE The barrier between organic (living) andinorganic (nonli ving) began to crumble in1828 becau!>e of a serendipitous(accidental)discoveryby Friedri chWohler ( 1800-1882). a German analyst originally trained inmedicine. When Wohl er heated ammonium cyanate, an inorgani c compound, he isolatedurea, a knownurinary excreti on productof mammals. ammonium cyanate (CH4N40) aninorganic compound heat urea

anorganic compound (1.1) Wohler rccognited that he had symhesized this biological material .. ,\ ithouttheof kidneys. nor ananimal.beitmanor dog...otlongthereafter followedthe synthesiof aceticacidb) HermannKolbein1845 andthe preparation of acetyleneandmethane byMarcell inBerthelot inthe period1856-1863. Although "vi talism"wasnot so mucha widely acceptedformalthe-oryasan intuitiveideathatsomethingmightbespecialandbeyondhumangraspaboutthe chemistry of living things.Wohler didnot identify his urea synthesiswith the demi se of the vi-talisticidea:rather. hi s work signaled the startof aperiodinwhi ch the synthesisof !'o-called organi c compounds wasno longer regarded asoutside the province of laboratory in-vestigation. Orgunic chemists now investigate not only molecules of biological importance. but alsointriguingmoleculeof bizarrestructureandpurelytheoreticalintcrc-.t.Thus.organic chemistry deals with compounds of carbon regardless of their origin. Wohler o,eemsto have an-ticipatedthese developmentwhenhe\\rotetohismentor...Organic chemistry ap-pearsto belikea primeval tropicalforest.fullof themost remarkable thingUb!>talllialfractionof themodemchemicalindustryandthereforecontributestotheeconomic.ofmanynations. Third, many who take organic nowadays are planninginthe biologi-cal sciences or inalliedhealth disciplines. !>uchasmedici11eor pharmacy. Organic chemistry is immensely important as a foundationtofields.andits importanceis sure to increae. One needonl y open moderntextbooks or journals of biochemistry or biologyto appreciate the so-phisticatedorganic chemistrythatis centralto theseureas.Finally.even for those who donot plan a career inany of the sciences, a study or organic chemistryisimportant.We live ina tech-nol ogical agethat ismade possible inlargepartby applications of organi c chemi stry to indus-tries as diverse as plastics. textiles. communications, transportation.food.andclothing.In addi-tion. problem!. of pollution and depletion of resources are allaroundIf organic chemistry has played a partincreating these problem. itwi llsurely have a role intheir solutions. a science. organic chemistryat the interface of the physicaland biological sciences. Reearchinorganic chemistry is amixtureof sophisticatedlogicandempiricalobservation. Atitsbest.ittakesonartisticdimensiom.Youcan use the study of organicchemistry to de-velop andapply basic skills inproblem solvi ng and. at tJ1e same time. to learn a subject of im-mensepracticalvalue. Thus, to develop as a chemist.to remaininthemainstream of a health profession,orto bea well -informedcitizenina technologicalage,you wil l findvalueinthe study of organi c chemi stry. Inthi s textwehave severalobjectives.We' llpresentthe nuts andbolt!> .. - lhcnomencla-ture, classi lication. structure, andof organic compounds.We' IIalso cover the prin-cipalreactionand the syntheses of organicmolecules.But,more thanthis, we'll develop un-derlying principles that allow us to understand, andto predict, reactions rather than -; 1.2 1.2CLASSICAL THEORIESOFCHEMICAL BONDING3 ).imply mernori;ing them. We'll con).ider . orne of the organicthatis industrially im-portanl.Finally. we'll examineof the beautiful applications of organic chemitry inbi-ology, suchashow nature does organic chemistry andhow the biological world has inspired a great dealof the researchin organic chemistry. CLASSICAL THEORIES OFCHEMICAL BONDING To under..,tand organic chemistry. it is necessaryto haveorne understanding of the chemi cal bond- theforce!.tharhold atom!>together within molecules.FiN. we'll review some of the older. or ..classical:ideas of chemicalbonding-ideas that, despite their age.remainueful today. Then. in thelast part ofthi!-. chapter. we'll consider more modem ways of describing the chemical bond. A.Electrons in Atoms Chemi.1try happens because of the he!ral'ior ofelecmms in atoms and molecules. The basis of this behavior isthearrangement of electronswithin atom. anarrangement suggestedby the periodic table.Consequently. let'-; lir"t review the organization of the periodic table (see page facingin'>idcback cover). Tht'>haded art'M greak'timportam:ctnorganic chem-t:-try;knowingtheir atomic number" andrclati1e positionwill bevaluablelater on.For the moment. however. consider thefoliO\\ ing details of the periodic tablebecausetheywere im-portantin the development of the concept!> of bonding. Aneutralatomof eachelement contnins a number of bothprotons andelectrons equal10 its atomic number.Theperiodic aspector the table- its organizationinto groups of elements withsimi larchemicalpropert ies- ledtotheideathat elect ronsresideinlayers,orshells, about thenucleus.The-;hell111'c:lectronsin anatomits valente shell1 'and theelectronsinthis shellarecallcpvalencl' ell'ctrons.Thenu111berofl ' clencc:electron.\ .f(Jr any nemral atom in(,111A Kroup n( the perio(/ic' t(tble (except he I ium) equal.\its group number. lithium. sodium. and(GroupI A) have one valence electron, whereas carbon (Group -lA) hasfour.thehalogenc;(Group7 A) haveseven.andthenoble gases(except he-lium) have cigh1.Helium hastwo 'valence electrons. Walter Kosscl( 1888-1956) notedin1916 that fl>rmion' they(endto g1lin or losevalenceclectrom.:0lo havethe '>amcnumb...:r of electrons asthenoble gas of closes atomil.!number.Thus, potassium,with onevalence electron(aJlcl19total electrons),tendsto loseanelectrontobecomeK+.the ion.whichhasthe samenumber of electrons ( 18) as the nearest noble(argon). Chlorine. with seven valence electrons (and17 total elec-trons) t...:ndsto accept anelectron to become the18-electron chloride ion, Cl-. which also has thesamenumber of electronasargon.Becausethenoble gaseshaveanoctetof electrons (that i ....eight electrons) in their \alence the tcndenc)of atom' ro gain or los-e-valence electron'> to form ions wi(h thenoble-tws conligurarion has been called the oct etrule. B.The Ionic Bond AchemicalcompoundinwhichthecQmponentatomsexistasionscalledanioniccorn-]JOund. Potassium chl ori de.KCI. is a common ionic compound. The electronic configurations of thepotassiumand chloride ions obeytheoctetrule. The structure of crystalline KCIis shown in Fig.1.1on p.4. In theKCI structure. which is typical of many ionic compound ....eachionissurrounded by negative ions. and each ncgatilc ion i. The ionic bond i'>the '>amein all direc-tionneighboring negative ions. and a negative ion ha'>the same attraction for each of it\ neighboring po'>itiveion). However, chemists have adopted a useful and important procedure for electronic book-keepingthatassignsa chargetospecificatoms.Thechargeoneacha1omthusassignedis calledits formalcharge. The sumofformal chargeontheindividualatom!>must equal tho.: lotal ..:hargc onthelon. STUDY GUIDELINK 1.1 Formal Charge 1.2CLASSICAL THEORIESOF CHEMICAL BONDING7 Computation of formalchargeon anatominvol vesdivi dingthetotalnumber of val ence electrons betweenthe atom andi tsbonding partners.Eachatomrecei vesall of itsunshared electrons and ha((of its bonding electrons. To ;\:ahydrogenandanother carbon.oticethatthetriple bond (a'>well as a double bond in other compounds) i.considered as one bondfor purposes of YSEPRtht:ory.becauseallrhreeconnt:ctthesametwo atoms. with180bond angles arc tohave linear geometry. Thus. acetylene is a fi11earmolct:ulc. HH acetylene 18CHAPTER1CHEMICAL BONDINGAND CHEMICAL STRUCTURE ow let's consider how unsharedvalenceelectron pairs aretreatedbyVSEPRtheory. An unshared l'alence electron pair is treared as if it were a bond \t'itlwut aat one end.For example.inVSEPRtheory.thenitrogeninammonia.:NH3.issurroundeobyfour "bonds": three N- 1-1 bonds andtheunsharedvalence electron pair. These''bonds" are directedto the verticesofa tetrahedronsothatthehydrogens occupythree of thefour tetrahedralvertices. This geometry is called trigonal pyramidal becau!-ethe three N-Hlie along the edges of a pyramid. VSEPRtheoryalsopotulatesthatunsharedl'alenceelectronpairsoccupymorespace than an ordinary bond.It'as if the electron pair ''spreads out'' becauseit il>n 't contrained by a secondnucleus.As a resuh. thebond angle betweenthe pair andtheother bonds are somewhat larger than tetrahedral. and ther- H bond angles aresmaller. In fact.theH-N-H bond angle in ammonia is107.3. H ammoni a an unshared electron pair occupies more space than a bonding electronpair 11 Estimate each bond angle inthe followingmolecule. and order thebonds according tolength. be-ginning with 1he shortest. 5 0 I!JII6 H-C===C-C-CI ,, d SolutionBecause carbon-2is bound to two groups (H and C).itsgeometry islinear. Similarly. carbon-3also haslinear geometry. The remaining carbon (carbon-4) is boundto three groups (C, 0, and Cl); therefore. ithas approximately trigonal planar geometry. Toarrange the bonds ih order of length. recallthe order of importance of tl1ebond-length rules. The major influence on lengthi!>the row inthe periodic table fromwhich the bonded atoms arc taken. Hence, the H-C bond is shorter than all carbon-ing1c line.E>.plainthese 2J.I\JAniline a UV spectrum withpeaks atA11,.,=230 nm( - 8600) and 280nm(E =1-130). Inthe pres-ence of dilute HCI.the'pectrum of aniline change:. dramatically: Ama,=203 ( =7500} and25-1 (E=160). This ),pectrumisnearlyidentk:alto the UV spectrum of ben;.enc.Accountfor the effect of acidonthe UY spectrum of aniline. 23.6-tImaginethat you ha'c -.am pies of thefollowingfour a mines.butyoudon "tknow "hich iswhich. Explai n howyou couldu'c protonNMRto distinguish among them. NH, I-PhCH2CHCH3 A NH, I-

c PhCH!N(CH,h 8 PhCH1CH1NIICH3 f) lal+ HN02-""cbht"dl -(c) _......,CI c A -:Po cc II ClCl exces-s ld)o-!JOH+HCI+NaN02 IJ ll -;-. ,,QH, II ,O he.u (Ghc the stcrcochcmislf)' as ,,ell asthe structure of the product. ) !jl H,C= C-CH, Br+l:.tNH_, - ( a compound with 5 c.Jrbons) - I-Br Pdf< Figure P2359 heal -(an ofbcntene) H"il)"Cu:-\0 ADDITIONAL PROBLEMS1163 23.65Inthe warehou\e of the company Tuman)Amine\. Inc .. two unidemificd compound' ha\e been found. The idem of the Cun.,table inaqueou\ acid andthefollowing N\IR 'pectra: ProtonMR:5 :uo C6H.,): 5 2ASC2//. d.J=6 Hzl:5.127 (6H. s):8 4.50 I I H. t. J= 6 Ht ) 1'C NMR:546.3. 853.:!. 568.8. 5 102.4 :23.67CalPropo\c a structurefor anamineI CC,H,,N).which liberate' awhentr..:atcdwit h NaN02 andHCI. The 1 'CM R spectrum of Aa.,follows. wi th at-tached proton!.inparentheses:5 14(2). 5 34.3(2). 550.0(1). I hi Propo-.e a '>tructurefor an amine B which doc;, twtliberate a ga..,whenwithNa ;UldHCI. and ha\ IR at 9 17 t:m-1. 990 em -. and1640 em- . a'>wella\- IIat 3300 em-. The 11C\IMR spectrum of B i'folio''':536.0. 554.4. 5115.8.5 136.7. 23.68Give a curved-arrow mechanismfor each of there-arrangement rcactiom given inFig.P23.68 . .2.'.69Pro' ide a cur\ed-arro\\mcchani\mfor thee\ample of theBmlifr- Hilman reaction'>hewninFig. P23.69.Be wre that the role of thetriethylamine cawlyst i' clearly ta l00 III

(b)0 ( C) GN-B' KOII() FigureP23.68 bcnlt.'IH,' indicrued. (/lint:Therole of the catalyst i..,110/ lo re-mon: thea-proton of the c'-lcr:thil>protonio,not acidic.Wh) ?J 70Achemi'>l.Madatreated ammonia withpen-tanalin the presence of hydrogenand a cataly!>l in the expectation of obtaining1-pentanaminc by n.:ductivc amination.In additionto1-pentanamine. ho\\C\Cr. also obtamed dipent) I amine and tripent) Iamine t'ee Fig.P23.70). Explainhouthe by-product\ arc formed. 2J.71Around19 12.RichardWilhtlittcr (who a,.,.ardedtheI915obclPri1e in Chemi'>tl)) treated diaminc A "ith meth) I iodide. and thenwithAg:O andheat. ,.,.hereupon a hydrocarbon B. C, Hx.diMilledfromthereact ion mixture. Compound 8reactedrapidlywi thunder mild condition\. Treatment of compoundC inthe wa)ga,c a h)-drocarbon D. "h1ch did not react "llhA 0 Q"'" c 0 II OH0 I MeCH-C- C-OEt II Figure P23.69 Figure P2370 luemify the two hyurm:arbons 8and /). and explaintheir Ycry different bclm ior toward(Wilhtiiuer con-cluded fromthc..c Oh'l:n at iOn\ LhatCOilliX>UndD could not be an alkene. ) 23.72ExplaintheshowninFig.P23.72by 'howing rele,ant intermediates. prm iding analogic' to n reaction\. and. \\here appropriate. gi' ing cun,cd-arnmmechani,nh 23.73!:>.plain thefactthattheamine'inFig.PD.7.'\. dc,pitc their \imilaritic' in\tructurc. have considerably differentba,icitic,. (/lim: a modelof compounc..l (a) IIthe f1orbitals of the bcntcne ring.) 23.7-1!Sec Fig. P23. 7-1. I Amide A. 8-\'alcrulactam. at) pi-cal amide witha conJugate-acid p/\. ol 0.8. The t\\O cyclic tertiary IJand C also hmc typical conjugate-acidpK,, \ ' a lues.IncontraM.the conjugatc-acitlpK. of amide f) i' unusuall)highfor anamide. and11h) drol} 1e' much morerapid!)thanother Dra''the \tructure of the conjugate aciu of amidc IJ.andsuggc\t a reasonf'or bothpK,, andit' rapid(b) CJ-1\theformula C12(H20)11 or andbothglucoseandfructose(sugar.,pre\'alentinhoney)havetheformula C6(H20)6 or C6H 1201,.This hydrate-of-carbonpatterni:,morethananapparent relationship. Anyonefamiliar withthe of table&ugarinto carbonbyconcentrated (or anyone who has madecaramel a lessextreme exampl e of the samephenomenon) has witnessedin practice the dehydration ofA quarter pound of nice white Jump \ugar putinto acup" iththe\mallest po\\iblc dasb of boiling water andthentheaddition of plenty of oilof' itriol i a trulywonderful\pectacle. andmon:instructivethanmuch reading.to see thewhite sugar turnblack,thenboil\IX>ntaneously. andnow.rising outof the cupinblack. itheaves andthrobs astheoilof vitriolcontinues its workin thelower part of the cup. cmiuingof.... (J.W.Pepper. Sciemijic Am11.1ements .for )'owrgPeople.I 8631 As theresultof a more modern understanding or their structures. carbohydr atesare now defined asaldehydesandketonescontaining a number of hydroxy groups on an unbranched carbon chain. aswellastheir chemical derivatives. Tim common carbohydrate structure.\: O=CI I -CH -CH -CH -CH -CIJ,OH IIII-HOCH,-C-CI I -CH-CJ I -CH20H - IIIII OHOHOHOH0OHOHOH 24.1 24.1CLASSIFICATION AND PROPERTIESOFCARBOHYDRATES1167 Lessprecisely.butmore descriptively, carbohydrate chemistry canberegardedthe chem-istry ofugars andtheir deri\'atives. Carbohydrates are among the most abundant organic compoundon the earth.ln polymer-i.wd formcellulose. carbohydrates accountfor 50-80% of the dry weight of plants. Carbo-hydrates area major source of food;sucrose(table sugar)andlat.: tose (mi lk are exam-ples.Even the shel ls of arthropods such aslobsters consist largely of carbohydrate. The study of carbohydrates relies heavily onthe of !>tereochcmistry (Chapter 6) andontheconformationalaspectsof cyclohcxanerings(Chapter 7).Therefore.molecular models should bevery helpful youstud)the materialin this chapter. CLASSIFICATION AND PROPERTIES OFCARBOHYDRATES Carbohydrates can be classified in several way!.. Certain classitications that arc based ontrue-lUre areillustrated by the following examples. HOCH, -CH -CH -CH -CJ-i -CH = 0 - IIII OHOHOHOH analdose (aldehyde Ci\-carboncarbohydrateiscalleda hexose,anda five-carbon carbohydrate i!-.called a pentose. Thesetwo canbe combined:analdohexose an aldose containing six carbon atoms. and a ketopentose is a containing five carbon atoms.Aketose can alsobeindi catedwi th thettlose:thus.a 11ve-carbonketoseisalso calleda pcntul ose. Another type of classification schemeiba!tedonthehydroly'>i:-. of certainto'>impler carbohydrates. Monosaccharides cannot be convertedinto simpler carbohydrate by hydrolysis. Glucose andfructose are examplei. of monosaccharides.however. is a disaccharide-a compoundthat canbe convenedbyinto twomonosaccharides. a disaccharide Likewise. trisaccharidescanbe hydrolyzed to three mono!>accharides. oligosaccharides to a few"monosaccharides.andpolysaccharidestoaverylargenumberof monosaccharide'>. Because of their man)hydrox)groups. carbohydrates areveryoluble inwater.The ea'>c with which a large amount of table sugar disl>olvesin water to make syrup anexample from common experience of carbohydrate solubility.Carbohydratesarcvi rtually insoluble in non-polar solvents. 1168CHAPTER 24CARBOHYDRATES FISCHERPROJECTIONS Almost all of theare chiralmolecule!>. andmo!-thave more thanone a-..ymmeuic carbon.Manycarboh)drate-..ha'e\C\cralcontiguou'>a'>ymmetriccarbon"inanunbranched chain. For example.the ha\Cfour '>Uchcarbon.,.\\ hich are indicated tl'-tCJ;-.k-.in the following.. *" HOCH, -CI I - CH-CH-CI I -CH=O - IIII 01101-1OH011 four ,hymmctric carbon' ( ) To !>how the stereochemistry of suchmolecules.we could usc line-and-wedge structures. How-ever. a simpler system of showing :..tcrcochemistry wa.; developed by the German chemist Emil Fi-.cher.who'>clandmark work onthe structure of gluco'>ewe "IItake up inSec.24.1 0.Fischer developed a way to representthree-dimcn,ional structure-. on a two-dimensional -..urface (paper or blackboard) that doc-. not require the U'>Cof and da-..hctl \\edge'>. Such -.tructures are calledFischerprojections.We 11u-.cFi,cherprojection-. cxtcn\i,ely inthi-,chapter.In !-.Cction.you"lllearn howto draw andmanipulate Fischer projections. To the process of drawing a Fischer projection. we 11use the 11?::\R enantiomcr of erythrose. anwith two carbons (Fig.24. 1).Yrmshould jiJihm- I his dis-cussion wilh a mo!tnt!ar model. To molecule in a Fischer projection. arrange the moleculeinanall-eclipsed COI!{omuuionabouttheC2-C3bond-the bondconnectingthe two asymmetric Vie\\themolecule ashown b)thee) e in Fig.2-t.l a.' e\1.impo-..e a referenceplane containingthe C2-C3 bond onthe molecule. (This plane'' illultimatel)be the plane of the page.) The plane should be oriented sothat the other two carboncarbon are receding behind I his plane,andthe bonds to the OHandH groups are e/llel"!:illXin from of I his plane.Theview seenby the eyei sin Fig. 24.1 b.Finally.we project thil- structure onto rheplane- thatis.flattenit into thepage-to give theFi!-cher projection.The asymmel-ric carbons t!temse/\'e.s are not drall'/1.but areto be located at theinter-.ections of \'er-/rcf.:rcncc plan c.....::>I H....../CH=O II0 -.:::: C"./ I H""C 1-10C:II 20H vic\\rd br the Fi!.chcr cmwl'ntion ( a) t'.th.l (1!=0 = HX OH H.OH = CHOH '' ha Ithe ere(b) CII=O t1 t'r1n OH I II Q IIOH thetj,,hcr projection (d Figure24.1How to derive a Fischer projection for an aldotetrose. (a) The eclipsed conformation used to derive the projection, with the reference plane perpendicular to the page. (b) The view of the conformation in (a) as seen by the eye. The reference plane is now the plane of the page. The groups behind the plane are shown in gray. (c) TheFischer projection. Theasymmetric carbons arelocated at the intersection of verticalandhorizontal lines. 24.2FISCHERPROJECTIONS1169 ticalandhorizontalbonds ( Fig.24.1 c).(As onestudent pointedout,theFischer projectionb the way thatthe molecule wouldlookif we were to put it on thenoor and step onit !) Thefollowingfiverulessummarizetheconventionsusedintheconstructionof Fischer projections. I .AFischer projectionisbased on aneclipsed molecular conformat i on. 2.The bonds connect ingthe asymmetricare arrangedi n averticalline. 3.The asymmetric carbons arelocated at the intersection!. of vert icalandhor izontal bonds andarenot drawn explici tly. 4.Verticalbondstotheasymmetric carbonsrecedebehindthepage,awayfromtheob-server in thethree-dimensionalmodel. 5.Horizontal bonds to the asymmetricemerge from the page. towardthe observer in thethree-dimensionalmodel. In other words,in order for a flatFi scher projection to conveythree-dimensionalinformation requires a specificviewing mode ( rulesIand2) and a strict adherenceto a convent ion about the relationship of the horizontalandvert icalbondstothe plane or thepage(rules 4and5). Rule 3 alerts us tothefact thatwe are (or might be) dealing with a Fischer projection andnot an""ordinary Lewis structure. To derive theFi scherprojection of amoleculewithmore thantwo asymmetric carbons.a molecule i s first placed (or imagined) in anecl ipsed conformation in which the chain of asym-metric carbonsi s vertical andcurving awayfromthe observer. asif this chai n were drawn on a convexsurface such asa paper cylinder. This conformat ion i s il lustratedfor the naturally oc-curring enantiomer of glucose. analdohexose,in Fig. 24.2a.The horizomalbondsproject LO-wardtheobserverfromthissu1i'ace.Allbond!>arethenprojectedontothi ssurface(Fig. 24.2b). Mentally cutting the cyl inder andflattening i t gives the Fischer projecti on (Fig. 24.2c). The use of anecl ipsedconformation to derive a Fi scher projecti ondocsnot meanthatthe molecule actuallyhas sucha conformat ion.As you've learned.most moleculesactually exist in staggeredconformations (Sec.2.3).Fischer projections convey noinformation about mol-ecular conformations. Their only purpose i s to show the absolwe of each asym-melric carbon. CHO H--1--0H H0--1--1-1 H--1--01-1 H- -1--0H ( a)(b) Figure24.2HowtoderiveaFischerprojectionforoglucose,thenaturallyoccurringenantiomer.(a)The eclipsedconformation is viewed with t he chainof carbonsoriented vertical ly and curvingawayfromthe ob-server, andthe horizontal bonds projectingtowardsthe observer. (b) Thisview isprojected onto animaginary curved cylinder. (c) Mentally cutting the cylinder and flattening it gives the Fischer projection. 1170CHAPTER2dCARBOHYDRATES To derive a three-dimensionalmodel of a molecule from its Fischer projection, reverse the process just described. Always remember that the vert icalbonds inthe Fischer projection ex-tend away fromthe observer. and the horizontalbonds extendIOIVardthe observer. t H=O viewing direction HO ~ ~ tf , ...../ OHuppacarhon inthr c:> 1c- C\/11\cher proJl'rlion (24.2) H- C- OH I H- C- OH HOCH2 CH=O Fischer projectionthe corresponding line-and-wedge structures For anygivenmolecule, several valid Fischer projecrions canbe drawn.It isuseful to be able to draw the different Fischer projections of a molecule without going back andfotthto a three-dimensional model. For this purpose. some rules for manipulation of Fischer projections are helpful. Be sure to use models to convince yourself of the validity of these rules. l.A Fischer projecrion may be runzed 180 inthe plane of the paper: Bythisrule.the following two Fischer projections represent the same stereoisomer. 180 HO+:H HOTH CH=O (24.3) This manipulationisallowed because it leaveshorizontalbondshorizontalandvertical bondsvertical: therefore.it doesnot alter themeaning of the Fischer projection. 2.A Fischer projection may not be wrned 90 in the plane of the page. lll!WIIllll:\ HH HOCH,*CH==O OHOH (24.4) This manipulationviolates theFischer conventionthatallasymmetriccarbonsshould be aligned verticall y.When we attempt this operation on a Ficher projection containing ai n ~ l e asymmetri c carbon. a further problem becomes evident: enantiomers I H HOCH2+CH=O OH O=CH \.... H c I"'oH HOCH2 lf (24.5) 242FISCHERPROJECTIONS1171 The 90rotationexchanges horizontalantivenical groups and.intheproce. :-.. imercon-\'ert5 The original sTrucTure into its ena111iome1:i., because the whole idea of Ficherprojections is to conve)stereochemical informa1ion. Thefollowing rule has a simi lar rationale. 3.AFi.\Cher projection may not be lifted from the plane of the paper and Turned me1: . !b I H+:H110+7 H-l--OHHO-l--H (24.6) CH20HCH20H ! tL___--1.----,-----.,1---'1 - enantiomcrsI. 4.Thethree groups aTeither end of aFischer projection may be i111erchanged in acyclic permutation. That is.all three groups can be IIIOI'ed mthe same time in aclosed loop so that each occupies an adjacent position. \lltl\\ I1 (24. 7) *CH10\ HOH \II< l\\ tl > HOCH2 OH H OH HOCH,:+H (24.8) IIOCI-12 OH H Fischer projections of the samemolecule This operationisequivalent toaninternalrotation.Thispointshouldbecomeclearif youconven any one of the structures inEq.24.8 into a model. Leaving themodelin an eclipsedconformation.carryoutaninternalrotationof120 aboutthecentral carbon-carbonbondasshownby the coloredarrowsinEq.24.8. andthenforma new Fi!.cher projection from the resulting structure. Each120internal rotation is equivalent to one cyclic permutation described by rule 4. A different Ficher projection of the same molecule resultsfrom eachdifferent cclip-,ed conformation. 5.An imerchange of any rwoof the group!>bound to an asymmetric carbon changes the configuraTion of that carbon. (Verify this rule with models.) Thi!. rule applies not only to Fischer projection . . but also tothree-dimensionalmodels aswell.Itfollowsthata pair of interchangesleavesthe configuration of the carbon unaffected: thelirst interchange changesthe configuration. andthesecondinterchange changesthe configurationbacktotheoriginal. In fact.the cyclic permutationin rule 4 is equivalent to a pair of interchanges. 1172CHAPTER24CARBOHYDRATES IIi'>particularly easy torecogni1e enantiorners andmeso compound'>fromthe appropriate Fi!.cherprojections.becauseplane!>of intheactualmoleculesreducetolinesof symmetry intheir projections. llliiTOIlint: CH=O HO_j_H : rH:: CO!H ,ameso compound inc uf S\ mm, tr. !2-l.9) The R.S 'iy!>temcanbe appliedto a projectionwithoutw. inga mode l.If the group of priority i' ineither of the twoverticalpositions. simply applytheR.S prioritytotheremaining three groups. H , H 0 f---f-1--l olS\ mmetn, ,arbon b1'1 on ,xamin,d , 1,,, k\\I'< 1lrdtr of dc,(cnJi ng pri in each of the following pair'> are enantiomers. diastereomers. or identicalmolecules. lalOH H02C+CH3 H3C+C0 2H OH CH3 H02C+OH HO+C02H CHJ Which of the following are of a compound? CH=OCH20HH HOHHOHHOCll1011HO HOHHOHHOHH HOHHOHHOHHOCH2 CHPHCHPHCI120H A8c H CH20H OH H OH D STRUCTURES OF THEMONOSACCHARIDES A.stereochemistry andconfiguration We'l l consider thestereochemistryof carbohydrmesbyfoL:usinglargely onthe aldoseswith or fewer carbons. The aldohexoses havefour a),ymmclric carbons anomcrs Similar!). there aretwo enantiomeric !>CI'>of four (eight -.tercoi..,omerstotal) in the aldopentose '>eries. Each diastereomer i' a carbollydrme "ith dWerem properties. by a d(lferellf 11ame.The aldo'c' with '>ixor fewer carbonarc given in Fig. 2-L3 on p. I 174a-,Fi'>cher projections. CH=OCH=O OHHOH CH=OCH=OCH=OCH=OCH=OCH=O I H1-1-l---OHH0-1--- HH-1---H-l---01-lH01-iHO_j__H1-10-l---HH--1-H-1---0H H-1---0H1-1 --+--0H H-l---01-1H0-1---H-l---OHH--+--01-1H_j__ OHHO OHH HHO OHH HH OHHO=tH OHHOHHOH H1-10 HHO+ H 0 1-1HOHHOH CH20H o-( + )-aUose CH20H 0-(+ )-alt(OSC CH20HCH20HCH20HCH20HCH20HCH20H o-(+)-glucoseo-(+)-mannoseo-(-)-guJoseo-(-)-idoseD- (+)-galactoseo-(+)- talose CH=O H-l---OJ-1 H-1---0H H-l---01-1 CH20H o-(-)-ribose /"" '/ CH=O H+OH H+OH CH20H o-(-)-erythrose CH= OCH= OCH= O H0-1--- H H_j__OHHO_j__H HO=tHHO=tH HOHHOI-l H-1---0H H-1---0ll CI-1201-1CH20I-I o-(-)-arabinose ..>r CH20H o-( +)-xylose D-{-)-lyxose '-./ -CH=O H+ OH CH20H D-( +)-glyceraldehyde HO+ HO H+OH CH20H D-(-)-threose Figure24.3The o family of aldoses. Each compoundshown here has an enantiomer inthe L family. The blue arrows show howthe aldoses arerelatedby the Kiliani- Fischer synthesis(Sec. 24.9). 24.3STRUCTURESOFTHEMONOSACCHARIDES1175 Eachof themonosaccharidesinFig. 24.3hasanenantiomer.For example. thetwo enan-tiomers of glucose have the following structures: CH= OCII = O HOHHOII HOHHOH HOHHOH HOHHOH CH20HCH20H cnantiomers of glucose IIis imponant to specify the enanti omers ofin a simple way.Suppose you have a model of one of these glucose in your L1and:howwould you explaintosome-onewho cannot seethemodel(for example,over thetelephone)whichenantiomer you are holding?Youcould usetheR.Ssystemtodescribetheconfigurationof oneor moreof the asymmetric carbon atoms. A different system. however.in usclong before the R.S system wa!- etablished.TheD, Lsystem, which camefrommadein1906 by a New York Universi ty chemjst. M.A. Rosanoff. is still usedtodayfor this purpose. As thisystemi .ap-plied to carbohydrates,the configuration of a carbohydrate enantiomer is specified by apply-ing thefollowing convemions: I.The configuration of the naturally occurring ( + )-glyceraldehyde i.designated as D.andthe configuration of its enantiomer. ()-glyceraldehyde.is designated asL.The OH group in the o- tereoisomer is ontherightwhenthe CH=O group is in the upper verticalposition and theCHPH group in thelower vertical position. CH= O H+OH CH20 ll o-( +)-glyceraldehydeL-(-)-glyccraldchydc The basis for the use of theletters D andL wasthefactthat the D s1ereoisomer of glyceraldehyde is dextrorotatory andthe 1J stereoisomer islevorOtatory.As withtheR.S tpredominantlycyclic hemi-acetals. ( 24.12a) ( 24.12b) Thearne true of aldoses and Although monosaccharides are often written by con-vention asacylic carbonylthey exist predominantly ae:a fi\'e-mcmbered cyclic hemiacetalfom1 of o-mannose calledo-mannofumno. e. Although the cyclic structurel- of aldoses were originally proved by chemical thesecyclic strUlances. yetthereis a doublet ato5.2 corre-.ponding to a proton a to two O'- diastereomers of o-glucopyranose. CH=O H HOHH HOHHO HOHH IIOHH one additional asymmetric carbon (the anomeric carbon) HO H +HO H H a -.111omer13-anomcr anomers of D-glucopyranose (24.14) (TheringsintheFischerprojectionsof theecycliccompoundsareclosedwitharather long bond.We'lllearnhow to draw more conventi onal representations of thesecyclicstructures.)Bothof thesecompoundsareformsor andin fact.glucose inolution asa mixture of both. They are dia!>tereomers and arc therefore '>eparable compounds with different propertie:..Whentwo cyclic forms of a carbohydrate dif-ferinconfigurationonly artheir hemiacetalcarbon:..the)aresaidtobeanomcrs.In other word:.. anomers are cyclic forms of carbohydratesthat are epimeric at the hemiacetal carbon. Thus.thetwoforms of D-glucopyranose are anomers of glucose. The hemiacetalcarbon(car-bon- 1 of an aldose)is sometimes called lhe anomeric carbon. A'>thepreceding structures illustrate. anomer.,arenamedv. iththe Greeklcttcrl- aand{3. Thb nomenclature referto the Fil>cher project ion of the cyclic form or a carbohydrate. written with all carbon atoms in atraight vertical line. /11the a-anomer the llemiacetai - OH group i.\ on1he same side of theFischer projection as the oxygen at 1heCOI(fif?umtional carbon. (The configurational carbon is the one usedfor specifying the 0.1.)''>tematicmanner for thep) ranoses. Convert the Fischer projection of fl-o-glucopyranose into a chair conformation. SolutionFirst redraw the Fischer projection for inan equivalent projection inthe ring oxygen is in a down position. Thi' i' done by using a cyclic permuta-tion of the groups on carbon-5. anallowed manipulation of Fi\cher projection\ (Eq.24.8, p.1171 ). 110H C)dll HOH rcrmutalo '" 110H IIOH HOCI11 H 0--' Recallthat the carbon backbone of \uch aFi$cher projection isimagined to be foldedaround a barrel or dnm (Fig.24.2b. p.1169).Such aninterpretation of the Fischer projection of /3-D-glu-copyranose the followinginwhich the ring he:.in aplane that emerge' fromthe page. (The ring hydrogens are notshown.) /ring oxygenisinthe rightrear position _____ anomeric carbon llt) Haworth projection 24.3STRUCTURESOF THEMONOSACCHARIDES11 8 1 Whenthe plane of theringturned 90 so that the wwmeric carlum i1on the right and the ring o.1ygen is in the rear.the group' in up positions arcthose that arc on theleftinthe Fi!>cher projec-tion:the in down po\itions are thoe thatare onthe right inthe Fischer projection. Apla-nar structure l>f thi!>sort i!.called a Haworth projection.In a Haworthprojection. the ringis drawn ina plane atright to the page andthepositions of the substituents arc with up or downbonds. The shadedareinfront of the page.andthe others arcinback. AHa'' orthprojection doesnotindicate the conformation of the ring. Six-membered carbohy-drate ringsre.,embletituted cyclohexanes.and, likeC)'clohexanes. the)exist in ch.II a-worthreceivedtheobelPritc inChcrniwy in1937 andwa!>kni ghtedin1947. 1182CHAPTER24CARBOHYDRATES AlthoughtheprocedureinStudyProblem24.2can beusedforanycarbohydrate.insome ca.,es itis sometimes simpler to derive a cyclic structure fromiL'>relationship to another cyclic structure. Firt.noticethatthe structure of /3-D-glucopyranose toremember because. in themorestable chair conformation,allringare equatorial(StudyProblem24.2). Suppose,now,thatwewanttodrawtheconformationof,8-D-galactopyranose.Because o-galactose ando-glucose areepimcrs at carbon-4. the conformational representati onof /3-D-galactopyrano. e can be quickly deri,ed by interchanging the-Hand -OH group'>at carbon-4 of ,8-D-glucop) rano-;c. 111\Crl{I c:> (24.17) /3-D-glucopyranose/3-o-galactopyranose Likewise.becausemannoseandglucoseareepimericatcarbon-2.the ofa canbe . imply deri,ed byinterchanging the - II and -OH group!. at car-bon-2 of the corre!.ponding o-glucopyranose strucwre. Sometimes itbecomes necessary to drawthe conformati on of a carbohydrat ethat either is a mixture of anomcrsor isof uncertainanomeric composition.Inrotationfoundto be+112 degrees mL g 1 dm 1With time. howc,er.the specific rotation of theolution decreaes. ulti-mate!)reaching a '>table value of + 52.7 degreemL g-1 dm-1Whenpure {3-D-glucopyranose is dissolved in water. it has a specific rotation of+ 18.7 degreesmL g-1 dm-1 The specific ro-tationof increaseswithtime,alsoto+ 52.7 degreesmL g-1 dm-1This change of opticalrotationwithtimeiscall edmutarotation(mula.meani ngchanKe).Mutarotation also occurs whenpureanomers of other carbohydrates are dissolved insol ution. Themutarotationof glucoseiscausedbytheconversionof thea- and,8-glucopyranose anomerinto anequilibriummixture of both.The sameequilibrium mixture i'>fonned, asit must be. from either pure a-D-glucopyranose or {3-D-glucopyranose. Mutarotation is catalyzed by both acidandbase,but it also occurslowly in purewater. HOCII lO OH 011 n -anomer lalo = + 11 2 degreesmL g-1 dm 1 acid or base IIOCH!O OH t3-anomer Oil +18.7 degrees m L g 1 dm 1 J111 (2-1.18) Mutarotationis characteriMic of the cyclic hemiacetal formsof glucose: analdehyde can-not undergo mutarotation.analdehyde carbon i' not an asymmetric carbon. Mutaro-tationwasoneof thephenomenathatsuggetedto early carbohydrate chemi1't:-.thataldose. might exista!>cyclichemiacerals. Mutarotati on occurs,fi rst, by openi ng of the pyranose r ing to thefreealdehyde form.This nothing more thanthe revere of hemiacetal formation (Sec.I 9. I OA). Then a 180rotation aboutthe carbon-carbon bond to the carbonyl group permits reclosure of thehemiacetalring by thereactionof the hydroxy group at the opposite faceof the carbonyl carbon. O HOH OH a -anomer OH 180 internal rotation OH HO....:::::O OH H O HO011 011 II {3-anomer (24.19) 1184CHAPTER 24CARBOHYDRATES Themutarotation of gluco!>eduealmost entirel yto theintcn:onversionoftwo pyra-no"cforms.Other carbohydrateundergomore complexAnexample ofbeha' ior ispro' idcdbyD-fructo\C.a 1-ketohe\Ol>C. The of thecyclichemiacetal fonmofo-fructol>ccanbederi,edfromit'carbonyl(ketone)formusingthemethod.., de!>cribedin Sec.24.38 (see also Problem24.6d): CH, QII I-C=O II 0 \ \ \ 11-lf--011: I H--+--OH/ ,,'' CH20 H - thhj, imolv.:d o-fructose in pyr,uw't: lorm,uion CH,OH I-C=O H-+--011: / H --+--0 11- - thi, oxygen 1sin form.Hion o-fructose It happen' thatthe cry..,talline form of o-fructo of funmocequi librianeednotMopatcarbon-2. For example,D-fructose at carbon-3onprolongedtreatmentwithbae.(Why?) Severaltransformationsor thi stype areimportantinmetabolism.Onesuchreaction.the conversion or D-gl ucose-6-phosphate into o-fructose-6-phosphate, occurs inthe breakdown of o-glucosc (glycolysis). the or reactions by which D-glucose isutilited a1- a food source. Because biochemical reactionoccur ncar pH7, too little hydroxide ionprcl-ent to catalyze thereaction.ln!>lead.thereactioncatalyzedbyancntyme. ipond-ing reactionof anordinary aldeh)dC under the 'ame condition< Glycoside formation: .tcid HOCH1 O +11 ,0(24.26a) one alcohol - OR group." hereai.,anotherrea.,onthatearl ycarbohydrate chemists suspectedthataldoseix-mcmbered.Theterm.furanolide isusedfor afive-memberedring. Glyco!-ideformation.likeacetalformal ion. iscatalytcdbyacidandan a-alkoxy carboca1ionintermediate CSec.19.6). IICI HOCH, - () : + OH OH\...../-Cl-STUDY GUIDE LINK 241 Acid Catalysis of carbohydrate Reactions ana-.tlkoxy carbocation HOC!( ,OI I ------:. rl + 110 lh OH H carboein analk) lmed carbohydrate becauseitispart of the glyco... idic linkage.Becauseiti'> anacetal. it canbe hydrolyzed in aqueous acid under mild conditionterified. HOCH2O OH o-glucopyranose .l(ctic p1ridinc Ac0CH2 O OAc I ,2,3,4,6-penta-0-acetyl-o-gl ucopyra nose (83"o yield ) (24.32) derivati vesof carbohydrate:-. canbesaponi fiedin base or removed by transestcrilication with analkoxide '>uchac and ( +)-man noe i' the f.ame asthat at carbon-3 of ( - )-arabinose (stepI). atthi-.pointFi'>chcr could deduce the complete si tuationwaslikethat of a young woman who has just met two brother:,.but she docsn , know their names.So she ask:;. a friend: 'What are their namesT The friendsay:,. "Oh. they arcMannose and Glucose: only I don't know whichis which! .. Just becau. e the woman know!> both names doesn't mean thathe can associate eachnamewith each face.Similarly, althoughFischer knew thetructuresasso-ciated withboth (+)-glucose and ( + )-man nose.he didnotyetknow how to correlate each al-dose with each structure. Thilastproblemwa!>solved inStep -L Another aldose, (+)-gulose, can be oxidizedwithHN03 to the same aldaric acid as ( + )-glucose. How does this fact differentiate between ( + )-gluco'>c and ( + )-mannoe'? Two differ-ent aldoses can give the same aldaric acidonly if their - CH=O and -CHP H groupare at opposite ends of an othemise identical molecule (Problem 24.20). Of the two !>tructuresin Eq. 24.49. only in structure Adoes aninterchange of the - CHp H and -CH=O groupre-sult ina differentaldohexose. Fischer actually interconverted the!>etwo group!> chemically on (+ )-glucose(byaseriesof reactions inFurtherExploration24.2intheStudy Guide)andobtaineda different sugar,whichhenamed( + )-gulo!.e. t11-0CIIUll C02H 1-1OHH01-1 IIOH HOH several HO reactions H HOJ-1 IINO, (24.50) HOHHOH HOH IIOH HOH IIOH I )I I IIII C02H (+)-glucose (+)-gulose oxidation of di fferent aldohexoses ei ther aldohexose gives the same product To be sure that the CH20H and CH=Ohadgoneas expected.Fischer veri-fiedthat both (..,..)-glucose and (+)gulose were oxidi;--edtothe o;arne aldaric acid.as . hownin Eq.24.50. The inescapablethen.isthat the wucture of (+ )-glucose inEq.19.49 is/\. 24.10PROOFOFGLUCOSESTEREOCHEMISTRY120 3 Completionoftheproofrequiresthatthesameinlcrconversions,whencarriedouton structure B. givethe same aldohexose. (Verify this point byrotating either structure180 inthe plane of the page. ) (11 = 0CH011 HOHHOH interconvert HOH CHzOH HOH and CH=O (24.51 ) HOHHOH HOHHOH (II UttCl(-{l the same aldohexose, and therefore, ( + )-mannose Therefore. 8cannotbe( -t- )-glucose.Becauarbitrary assignment of the absolute configurationof ( + )-glucose was correct- thatis. whether the - OHat carbon-Sof (+)-glucosewasrca II y on the rightinitsFischerprojection(asassumed)or on theleft.Thegroundworkforsolvingthis problem waslaidwhen the configurati on of (+)-glucosewas correlatedtothat or (-)-tartaric 1204 2 CHAPTER24CARBOHYDRATES CH=O IIOH HOH HOH HOH CH20H (+)-glucose acid. (Stereochemi cal coJTelation was introduced in Sec.6.5.) Thi s correlati on carried out in thefollowing way. (+)-Glucose wa-.convertedinto (- )-arabino'>e by a reaction called the Ruff degr adation. reaction !-.etjuence. analdo:.eoxidized to aldonic acid (Sec.24.8). and the calcium salt of the aldonic acidtreated with ferric ion andhydrogenperoxide. This treatmentdecar-boxylates the calcium salt and:.imultaneously carbon-:!to analdehyde. CH=O IIOil HOH I lBr!/H!O 110II Fe(OAch 30'o 2HOH+(2.t.52) HOH HOH HOil CJ120H CH10II1 (- )-arabinose calcium gluconate (41 ovidd) In other words. analdoseis degradedto another aldosewith onefewer carbonatom. irs srere-ochemisfiJ otherll'ise remainin,t.:the same. Becausethe relati on:-.hip between( + )-glucose and ( - )-arabinosewasalreadyknownfromtheKili ani-Ficher synthesi..,(StepIof theFischer proof in the pre' -.,ection). thi'> reaction ser\ed to establi!.h the cour D-( + )-Glyceraldehyde.intum.wasrelatedto D-( - )-erythroseby a !-.ynthesis: CII =O H+OH CH20H o-( + )-glyceraldehyde (absoluJc configuration assumed b)cotl\'ention) Kihani-Fi\cher CH=O H+OH H--t-OH CH20 H o-(-)-erythroseo-( - )-threose at carbon-.> assumed by convention) (24.54) Thissequenceofreactionsshowedthat(+)-glucose.( - )-erythrose.( - )-threose.and (+)-glyceraldehyde were all of thesame stereochemical serie-,:theD-;erie!-..Oxidation of D-(- )-threose with dilute HNOJ ga\e D-( - )-tartaric acid. In1950.theab!lolute configuration of naturally occurring ( -r )-tartaric acid(a' it'>pota'-!'ium rubidium doublewas determined by a specialtechnique of X-ray crylltullography call edanoma/ou.1 dispersion.determinationwasmadeby J.M.Bijvoet.A.F.Peerdc-man.andA. J. vanBommel, Dutch chemitswho worked. appropriately enough, at thevan 't Hoff laboratoryinUtrechr. If Fi'>chcr hadmadetheright choicefor the configuration at car-bon-Sof ( +wenow calltheo configuration-the assumed structureforo-( - )-tartari c acid andthe experimentally determined !>lruct ure or ( t)-tartari c acid determined 24. 11OISACCHARIDESANDPOLYSACCHARIDES1205 by theDutchwould be enantiomer'>.If Fi.,chcr had incorrectly. the '>tructurefor (-)-tartaric acid wouldbethe... ame a\ the experimental!)determined of ( + )-tartaric acid.andwouldha'c tobe To quoteBijvoet andhi' col-league\:""There.wlr isthlllEmil Fischer.\COIII't' lltioll!forthen conliguration]appean to C/11.\ wer to realitY... CH=O HO+H II+OH CH20H o-(- )-threose H0-+111 H+OII CO, H H+OH IIO+ H C02H D(- )-tartaric acidL-( + )-tartari c acid (by X-ril}'Cf')'Stallography) (2-1.551 IQ,f,]:ib#J ,,.- 24.28Given the structure of o-glyceraldehydc. howwould you assign a structure to each of the two 24.11 aldoses obtained fromitbyEq. 24.54. as11umingthat these compounds were previously un-known? 24.29Imaginethat ascientistthe cryMallographic workthatel>tablishedtheabolute configuration of (+)tartaric acid and findl>that the structure of compound is the mirror imageof theone giveninEq.24.55.What changeswouldhavetobemadeinFischer's structure of D-( +)-glucose? DISACCHARIDES ANDPOLYSACCHARIDES A.Disaccharides Oisaccharidesconsistoftwo connectedbyuglycosidiclinkage. ( + )-Lactose i1-.anexample of adisaccharide.({ + )-Lactosei:-.pre!-cnttotheextent of about 4.5'.0incow's milk and 6-7% inhumanmil k.) f3 bond HOCH,OHI. Cll z0I I0 OH011 galactose unit glucoseunit (+)-lactose or 4-0-(,B-o-galactopyranosyl)-o-glucopyranose In< + )-lacto:-.c.ao-glucopyranoC. in the !>ensethat a methyl glycoside can be hydrolyzed to give methanol and a carbohydrate. Compare: HOOCH3 0 1-1 OH o-galactosc - nH I,\fttCI CH,OH - 0 OH o-glucose ( 2-l.56a) +11 -01-1 IMtlCI+I()CIJ3 (24.56b) t)l! 01-1 Equation24.56a demontratesthe o;tructuralba.'i"for thedefinition of disaccharidepre-\Cntedin Sec.2-t.l: Adi!>accharidei!. a carboh}dratc that can behydroly:ted to two monoac-charide\. 1-l ydrolyioccur!>at the glycosidic bond betweenthe two residues. The \tereochemitry of the glyco idic bond in ( + )-lactose i'> {3.That is. thestereochcmistr) of the oxygenlinking the two monosaccharide reidueallows tO act a sourceof glu-cose.a-Gl ycosides of galactoseareiner1 to the action of this cn;,yme.(Peoplewho suffer from lactoseintolerancemusttake a form of this ent..yme orallyto digest lactose-containing foods.) Becausecarbon-!of thegalactoseresidue in( + )- lactoseis invol vedina gl ycosidic link-age,itcannotbeoxidi zed.However,carbon- !of the glucoseresidueis part of a hemiacetal group.which.like thehemiacetalgroup of monosaccharides,is in equilibriumwiththe f ree aldehydeandcanundergo characteristicaldehydereacti on1-..Thus,treatmentof(+)-lactose with bromine water (Sec.27.7A) effectl- oxidation of the glucoseresidue: 24. 11DISACCHARIDE$ AND POLYSACCHARIDES1207 Carbohydrates suchas (+)-lactose that canbe oxidized i nwayare call edreducing sug-ars, bccaue,in being oxidited. theyreduce the oxidizing agent\. The glucm,e isaid to be at the reducing end of the disaccharide. and the galactocof its hemiacetalgroup. ( + )-lacto.cabomany other react ions of aldose hemiacetals. suchm.mutarotation. ( + )-Sucrose, or table sugar.i:- another import ant disaccharide.More than120 mi Ilion tons of -.ucroseproduced annuallyintheworld. con:.bl'> of a D-glucopyranosereiduc and a D-fructofuranoe residue connected by glyco. idic bond!> (color) at the anomeric carbon-. of lwth. OH- -- agi)COIOilbonJ ,11gh,ose HOCH2 O 0 {3gl\'1.0\ld ll honJ Jl Ildl'c Cll zOH OH (+)-sucrose(a -D-glucopyranosyl-(j-o-fructofuranosidc) The glyco!>idicbondin( +)-'>ucroeidifferentfromtheonein On I)one of I he rc. iduesof lactose- thegalactoseanacetal(glycosidic)carbon.Incon-trast. both of ( + have anacetalcarbon. The gl ycosidic bond i n (+)-sucrose bridgescarbon-2or thefructofuranoseresidueandcarbon- Iof thegl ucopyranoseresidue. Thes.e are the carbonyl carbon'>in thenoncyclic forms of the individualmonm.accharide; re-memberthatthecarbonylcarbon-.becometheacetalorhemiacetalcarbonsinthecyclic form:-. I C-1 ofC- 2 of fructose Thu:-.neither thefructose nor the glucose pan ofhas a free hemiacetal group.Hence. (+)-sucrosecannotbeoxidited b)bromine water.nor itundergo mutarotation.Carbo-hydratessuchal.(+)-sucrosethatcannotbeoxidizedbybrominewaterareclassifieda-. nonreducing sugars. Like other gl ycosides. ( + )-sucrose can be hydrolyzedtoit!->componentmonosaccharides. Sucroseis hydroly.-:cd by aqueous acid or by enLymes (called inl'(!t'/ases) to an cquimolar mix-tun: of o-glucose ando-fructose.Thismixtureis'>ometime!lcalledimert JIIKar because.a-. hydrolysi.of has a greater magnitude thanthepositive rotation ( + 52.7 degrees mL g-1 dm-1)of glu-cose( '>ometimescalleddexTrme).Fructose.whichi!lthesweetestof thecommonsugar., (abouttwicea'>.,,,eetaucrosc).accountsfortheintense!-.Weetnessof honey.whichi'> mostlyinvert sugar. 1208CHAPTER2.:1CARBOHYDRATES 24.30What products are expected from each of the followingreactions? (a) lactobionic acid (Eq. 24.57)+ IM aqueou\ HCI-(b) C++ dimethyl ' aOH-(c) product of part (b)+IMaqueousH2SO,-24.31Consider the structure of cellobiol>e.a di saccharide obtainedfrom theof the poly-saccharide cellulose. Jnto what il>cellobiose hydrolyzed by aqueous HCI? cellobiose Tales of serindipitous sweet Discovery: Artificialsweeteners Artificial sweeteners are synthetic substitutes for sucrose and other natural sweeteners. Such com-pounds are in high demand because they allow consumers to enjoy a sweet taste without the calo-ries of natural sweeteners. The annual worldwide market in artificial sweeteners is more than SSbil-lion. It has been estimatedthat well over100 million Americansuseartificial sweeteners. Artificial sweeteners have been sought since the ancient Romans, who used lead acetate ("lead sugar") as an alternative to sugar, and many Romans suffered severe lead toxicity as a result. To qualify as an artificial sweetener, a compound must have sweetness many times that of sugar so that very little sweetener has to be used to achieve the desired effect. Because so little is used, al-most no calories are consumed. However, fi nding sweet compounds isnot the major hurdle to the development of an artificial sweetener. Rather, a candidate compound must undergo rigorous test-ing to be sure that it isnot toxic and does not have undesired side effects. Almost every sweetener that has been introduced has attracted its share of public suspicion despite the large amount of bi-ological testing involved in getting it to market. The most widely used sweeteners in modern times have been sodium saccharin, sodium cyclamate, aspartame, and, most recently, sucralose. sodium saccharin(1879) 300 times as sweet as sucrose aspartame(1965) 180 times as sweet as sucrose sodium cyclamate(1937) 30- 50 times as sweet as sucrose sucralose(1989) 600 times as sweet as sucrose 24. 11DISACCHARIDE$ANDPOLYSACCHARIDES1209 The discoveries of all of these sweeteners were serendipitous, and all resulted from the tasting of laboratory samples by the researchers involved. Tasting new compounds was actually once a com-mon laboratory practice, and the tastes of new compounds were routinely reported in the chemical literature. However, tasting new compounds is no longer condonedas asafelaboratory practice. Sodium saccharin was discovered accidentally in 1879 by ConstantinFahlberg, a student in the laboratory of Prof. Ira Remsen at The Johns Hopkins University. At dinner, Fahlberg noticed a sweet taste on his fingers and concluded that it must have come from a compound he was working with. A "taste test of many of his compounds led to sodium saccharin asthe culprit. Fahlbergbecame wealthy from commercialization of the discovery, and when Prof. Remsen did not receive any finan-cial benefit. he became quite bitter toward his former student. Aspartame was discoveredaccidentally in1965by JimSchlatter, a chemist at G. D. Searle and Company, whilehewas workingonthe discovery of drugs to treat stomachulcers. Henoticeda sweet taste onhis fingers after handling the compound. His supervisor convinced Searlethat the compound was worth development, and the result was the NutraSweet brand of aspartame. The most intriguing story surrounds the discovery of sucralose.Scientists from Tate & lyle, a British sugar company, were workingin1989 withresearcher leslie Houghandhisstudent, Shashikant Phadnis,at QueenElizabethCollege(now part of King'sCollege)inLondon on aproject thatin-volved testing chlorinated sugars as chemical intermediates for the synthesis of other compounds. Hough asked Phadnis to "test sucralose, but Phadnis misunderstood the word "test," thinking that he had been asked to"taste"the compound. The rest is history. B.Polysaccharides In principle. an)number of monosaccharide canbelinJ..edtogether with glycoidic bond-, to form chains. When such chain.., are long. theare called polysaccharides. This -,ectionc;un eys a fewimportantpolysaccharide'>. CelluloseCellulose. theprincipal !>tructural component of i" themostabundant or-ganiccompoundontheearth.Cottonalmostpurewoodi..,cellulosecombined with apolymer calledlignin. About 5XI kg of cellulose isbio:-ynthesized anddegraded annually onthe earth. a regularpolymerof D-glucopyranol'c connectedby(3-1linkages. /rcducingend OH\HOH non reducing end011 ceUulosc general structurr 1210CHAPTER24CARBOHYDRATES Like disaccharide, polysaccharides canbehydrolyzedtotheir constituent monosaccharides. Thus. cellulose can be hydrolyzed too-glucose residues.Mammal" lack the enzymes that cat-aly7ethe hydrolysis of the /3-glycosidiclinkage.of cellulose: thiiswhyhuman.cannot di-ge'>tgrases.whichareprincipallycellulo. e.Cattle.though.canderivenourishmentfrom grases,butthi.isbecause the bacteria intheirrumene, Arnel, and !>Oon. and is used inknitting yarn and decorative householdariicles. cellul ose acetate Cellulose ispotentiallyimportant asanalternative energysource.Recallfromp.369 that biomassislargelycellulose,andcelluloeismerelypolymerizedglucose.The glucose de-rivedfromhydrolysis of celluloe can be fermentedto ethanol. which can be ued as a fuel(as ingasohol): andplants obtain the energy to manufacture cellulose fromthe sun. Thu. the cel-lulose inplants- the mo. t abundant source of carbon on the earth-canbe regarded as a store-houseof solar energy.Animportantresearchproblemihowtoconvertthemoreabundant sources of cellulose.uch awild grases. into glucoe without expending large amount of en-ergy.Aolutiontotniproblemwouldreduceor eliminate theneedtousecultivated crops, uchas corn.as a source of ethanol. StarchStarch, like cellulose, is al. o a polymer of glucose.Infact.starch ia mixture of two differenttype!. of glucose polymer. In one. amylose.the glucose units are connectedby a-1 A-glycosidiclinkage. Conceptually.the onlychemical differencebetween amylose andcellu-loseisthe stereochemistry of the glycosidicbond. ( HOCH2O a - 1, 1 ghlll'idiL 1, ,... 0 amylose 11 ( II .. 400) The other constituent oftarchiamylopectin.a branchedpolysaccharide. Amylopectincon-tainrelativelyshortchainsofglucoeunitsina-1.4-linkages.Inaddition.itcontain branches thatinvolve a- 1.6-glycosidic linkages. Pan of a typical amylopectin molecule might lookac;followhellilinkedto(glycopro-teins) arefoundatthe outerurfaces of cell membrane!.. and some ofarc for blood-group specilicity. Discovery of o-Giucosamine In 1876 Georg Ledderhose was a premedical student working in the laboratory of his uncle, Friedrich Wohler (the same chemist who first synthesized urea; p. 2). One day, Wohler had lobster for lunch, and returned to the laboratory carrying the lobster sheii."Find out what this is." he told his nephew. History does not record Ledderhose's thoughts on receiving the refuse from his uncle's lunch, but he proceeded to do what all chemists did with unknown material-he boiled it in concentrated HCI. After hydrolysis of the shell, crystals of the previously unknown o-glucosamine hydrochloride pre-cipitated from the cooled solution (see Eq. 24.58). PrinciplesofPolysaccharideStructureStudiesof many havere-vealed the following generalizationsabout polyo;accharide structure: I.Poly'>accharide:- aremostly long chain-; with some branches:there arc no highly cross-linJ...ed.three-dimen:-.ionalSome cyclic arckno\\ n. 2.The linkage" between monoaccharidearc in every glyco... idicmonosaccharides canbeliberated from all poly-.accharides b)acid 3.Agivenpoly!>accharidecontain'>onlyoneMereochemicaltypeof glyco!.idclinkage. the gl ycoside linkages incellulose arc all {3:thoseinstarch arcalla. 2-l.32What would be obtained when cellulose is treatedfirst exhaustively with dimethyl sulfate/NaOH, thenwithlM aqueou\ HCI? KEYIDEASIN CHAPTER24 Carbohydratesarealdehydes andketonesthat con-tain a number of hydroxy groups on anunbranched carbon chain, as well astheir chemical derivatives. for any chiral molecule. These are derived by the rules given in Sec. 24.2. A Fischer projection shows the configuration of each asymmetric carbonina chiralmoleculebut implies nothing about its conformation. The structures of chiral compounds canbe drawn in planarrepresentationscalledFischerprojections, whichareespeciallyusefulfordepictingmolecules thatcontaincontiguousasymmetriccarbonsinan unbranchedchain.AFischerprojectionisderived from an eclipsed conformation in which all asymmet-ri c carbons are aligned vertically. Asymmetric carbons arerepresented asthe intersectionpoints of vertical and horizontal lines. Allvertical bonds at eachasym-metric carbon are assumed to be oriented away from the observer and all horizontal bonds toward the ob-server. Several valid Fischer projections canbe drawn The D,Lsystem is an older but widely used method for specifyingcarbohydrateenantiomers.Theoenan-tiomer isthe one inwhich the asymmetric carbon of hi ghestnumber hasthesameconfigurationas(R)-glyceraldehyde (o-glyceraldehyde). Monosaccharides exist in cyclic furanoseor pyranose formsinwhichahydroxygroupandthecarbonyl group of the aldehyde or ketone have reacted to form a cyclic hemiacetal. Thecyclicformsof monosaccharidesareinequilib-rium with small amounts of their respective aldehydes or ketonesandcanthereforeundergoanumber of aldehydeandketonereactions.Theseincludeoxida-tion(brominewateror dilutenitricacid);reduction with sodium borohydride; cyanohydrin format ion (the first step in the Kiliani -Fischer synthesis); and base-cat-alyzedenolizationandenolate-ionformation(the Lobry de Bruyn-Aiberda van Eckenstein reaction). The- OHgroupsof carbohydratesundergomany typicalreactionsofalcoholsandglycols,suchas etherformation, ester formation, and glycol cleavage with periodate. Because the hemiacetal carbons of monosaccharides areasymmetric,thecyclicformsofmonosaccha-ADDITIONAL PROBLEMS121 3 rides exist as diastereomers called anomers. The equi-libration of anomers isthe reason that carbohydrates undergo mutarotation. In a glycoside, the - OHgroupat the anomericcar-bonof acarbohydrateis substitutedwithanether (-OR) group. In disaccharides or polysaccharides, the - ORgroupisderivedfromanothersaccharide residue.The- ORgroupofglycosidescanbere-placedwithan-OHgroupbyhydrolysis.Thus, higher saccharides can be hydrolyzed to their compo-nent monosaccharides in aqueous acid. Disaccharides, trisaccharides,and soon, canbe classi-fiedasreducingornonreducingsugars.Reducing sugarshaveatleastonefreehemiacetalgroup.In nonreducingsugars,allanomericcarbonsarein-volved in glycosidic linkages. REACTIONREVIEW For a\1111/lllllf)' ofcli.\cuS.\('di11thi.\clwpte1:see Sectio11R. CllliJUt!r 24.ill the Stud) Guide and Manual. ADDITIONAL PROBLEMS 24.33Gi'e the productlsl expected "hcnD-mannose (or other compoundindicated) react\" ith each of thefol-Io" ing reagent\. (A..,.,urncthatcyclic manno-.e deri\'a-ti'e' are p) rano\e.... ) !al Ag+(:-.1H,J1 (b) dilute HCl (c) dilute NaOH (tlJBr/ Hp. thenII 10+ (c) CH,OH.HCI (f) aceticanhydride/pyridi ne (g) product of pan (d) +Ca!OII ),.then Fc(OAc),. !h) product of pan (C) 1- PhC111CI(C\cC'>') andNaOH 24.34Gi'e the products e\pectcd "hen D-ribo'>e (or other compound indicated) react\ '' 1th each of the folio'" ing reagent\. (til di lwcfiNO, icdum) CH, OH 1-1 -LocH, 0 II ,C-t-H 24.53or the I) pe l>hnwninFig.P24.53 (p.12 1X)- for example. ethyl or propyl groups): (a) What generalreacti onwhen this s izing agent reacts with cellulo\e at pH7? (b) Why should thistreatmentcause the cellulose to become moretowetting'? ( Inanswering thi s question. think Qf' wetti ngasa solvation phe-nomenon.) (c) Why does treatmentcause the paper to be s lightly alkaline'! That b. what basic group does this treatment introduce? 2-'.57Outline amechanismfor thereactioninFig. P24.57. which an example of the Maillard reaction followedb)the Amadori rearrangemem. Explain '' ith amechanism '' hy treatment of the 2-deoxy-2-amino derivative of o-glucose (D-glu-cosaminc) with aqueousaOH liberates ammonia. O Nll2 o-glucosarninc O HOO OH 0HO 11-2OH Figure P24.53 24.59L-A\corbic acid(\ itarnin C) ha!. thefoll owi ng \tructurc: or 0 II HO-C H+ O IIO+H (a) A!.corbic acidpK,,=4.2 I. andiabout as acidic a!.a typical carboxylic acid.Identify the acidic hydrogenand explain. (b) Thou,ands of annuall y of ascorbic acid arc made commerciallyfromD-glucose.In the synthe- 'hown inFig.P24.59. give the structures of the compound\AC. Figure P24.57 P-glucose NaBI 11 F1gureP24 .59 A o-glucitol (L-sorbitol) biological oxidation ADDITIONAL PROBLEMS1219 24.6HAt 100 oc. o-ido\e exbh mo:.tly (about 86%) as aI ,6-anhydropyrano,c: B Cll I ,6-anhydro D- idopyranosc (a) Dntw the chair conformation of this compound. (b) ExplainwhyD-idoscmore of the anhydroform than t>-gluco1.c.(Under the same conditions. glu-cose onl y 0.2% of the1.6-anhydro form.) HO ll II 011 L-sorbosc ( a acid 25.1 1220 25 TheChemistry of the AromaticHeterocycles Heterocycl ic compounds are compound!> withthai contain more than one clement. The heterocyclic compoundsof greatestintere)..tto organic chemists ha\'e rings contai ning carbon andoneor morehet er oat oms-atoms otherthancarbon.Allhough chemistryof many saturated heterocyclic compound:-.is analogoustothatof their noncycli c counterparts,a sig-nificantnumber ofunmturated heterocycl iccompounds exhibitaromat icbehavior.There-mainder of this chapterfocusesprimarily on the unique chemistry of a few of thesearomatic heterocycles. The principlesthatemergeenableyouto under,tandthechemistry and of other heterocyclic compound' thatyou may encounter. NOMENCLATURE ANDSTRUCTUREOF THE AROMATIC HETEROCYCLES A.Nomenclature The names Cparationof chargei' pre..,entinallbutthefirststructure.thelirst i!. considerabl)more imponant thanthe others. theimportanceof the orher struc-tures isevidentin a compariatu-ratedheterocyclic ether. 1222CHAPTER25THE CHEMISTRY OF THE AROMATIC HETEROCYCLES dipole moment: boiling point: 0 tetrahydrofuran 1.7D 67 C 0 0 furan 0.7 D 3 1.4 C The dipol emomentof tetrahydrofurani s aaributabl e mostl ytothebond dipoles of its polar C-0 singl e bonds. That i s. electrons inthe a- bonds arc pull edtowardthe oxygenbecauseof its electronegati vity. This same effect is present in furan, but in addition there is a second effect: thedclocalitation of the oxygen unshared el ectrons into the ring shown in Eq. 25. 1. Thi s tends to pu'>helectrons a\\ay from oxygeninto the 11"-electron sytem of the ring. [Q '9- J? - etc] "1:::::------:::-:::::::::-:::------:_::t:---:-::-::::: __ :::::::::-t:---dipole moment contribution of c-o ubonds +dipole moment contributi on of 7T-electron delocalization = net dipole moment of furan (25.2) Becausethesetwo effects infurannearl y cancel,furan a verymall dipole moment. The relative boilingpoint s of tetrahydrofuranandfuranrefl ectthe di fference intheir dipol e mo-ments. Pyridine.like bcruene. canbe repre1-.entcdby two e4uival cnt neutral structures. Three addi ti onalpyridine of importance rencctthe relative electronegmivities of nitrogen andcarbon. ... + Q] )o 0 0 (25.3) N - -minor contributors The aromaticity of some heterocycli c compounds was consideredin the discussion of the Huckel4n + 2 rule (Sec.l5.7D). II i s important to understandwhich unshared electron pairs in a heterocyclic compound are part of the 4n+ 2 aromatic7T-clectron system, andwhich are not (Fig. 25.2).Vinylic heteroatom'>.c;ucha'>the nitrogen of pyridine. contribute one 7T elec-tron to the six 7T-elcctron aromatic !.y.,tcm.just like each of the carbonin the7T !.ystem. The orbitalcontaining the unshared electron pair of the pyridine nitrogen is perpendicular to the 2p orbitals of the ring andtherefore not invol vedin1Tbonding.In contra!-t.all ylic het-croatoms, suchasthe nitrogen of pyrrolc, contribute two electrons (an un!>hareclpair)toLhe 4H+ 2 7T-clectron ( a) pyridj ne The pair isvinylic and thus is 1101part of the 4n + 2 7T-dcctron system. 25 1NOMENCLATURE AND STRUCTUREOFTHEAROMATIC HETEROCYCLES1223 411+ 2 7T-clectron system (b) pyrrole The unsharedpair is allylic and thus is put of the 4n + 2 7T-clcctron system. 411+ 2 7T-electronsystem (c) furan One unsharcd pair is allylic and is part of the411+ 27T-clcctron system; the other unsharcd pair isvin)lic and isnot. Figure 25 2The orbital configurations in pyridine, pyrrole, and furan. (a) ln pyridine, the nitrogen 2p orbital, like the carbon 2p orbitals, contributes one electron to the 4n+ 2 7T-electron system, and the nitrogen unshared elec-tron pair occupies an sp2 orbital (blue}, which is not part of the 1T system. (b) In pyrrole, the unshared electron pair occupies a 2p orbital on nitrogen (blue), and it contributes two electrons to the 4n +217'-electron system.(c} Furan has two unshared electron pairs (red). One unshared pair occupies a 2p orbital and contributes two electrons to the 4n + 2 1r-electron system, as in pyrrole.The other unshared pair occupies an sp2 orbital. Like the unshared pair in pyridine, it does not contribute to the 4n+ 2 7Telectron system. aromatic7T-electronystem.Thi'>nitrogenadopts hybridizationandtrigonalplanar geometry!.Othatits unhared electronpair can occupy a 2p orbital. which the optimum shape andorientationto overlap withthecarbon2porbital s andthu!.to bepart of thearo-matic 7i-electron system. Consequently, the hydrogen of pyrrole liein thl.!plane of the ring. The oxygenof furancontributes one unshared electronpair to thearomatic7T-electronsys-tem.andtheotherunsharedelectronpairoccupiel>aposition tothecarbon-hydrogen bond of pyrrole-in the ring plane. perpendicular to the2p orbitals of thering. The empirical resonance ene1xr canbe usedto estimate the additional!.lability of a hete-rocyclic compound dueto itaromaticity.(This conceptwaintroducedinthediscussion of thearornaticity of benzenein Sec.15.7C.) The empirical rc1.onanceenergies of benzene and some heterocyclic compounds arc given in Table 25. 1.To the extent thatresonance energy is ameasureof aromaticcharacter,furanhastheleastaromatic character of theheterocyclic compounds inthe table.The modestresonance energy of furan hassignificant consequences for itreactivity. aswe'lllearn in Sec. 25.38. 1tM1ffjl Empirical Resonance Energies of some Aromatic Compounds Resonance energyResonance energy CompoundkJmol -1 kcal mol _, Compound kJ mol _, kcalmol -1 benzene138- 15133- 36thiophene12129 pyridine96- 11723- 28pyrrole89-9221 - 22 furan6716 1224CHAPTER25THE CHEMISTRY OF THE AROMATIC HETEROCYCLES +ij;il:ihMJ253 25.4 Draw theimportant reonance structures for pyrrole. Cal The dipole momentsof pyrroleandpyrrolidinearc ' imilar inmagnitudebut haveoppo-site directions. Explain. indicatingthe direction of the dipole moment in each compound. (Him:Usetheresult in Problem 25.3.) ![J N 0 N II HH 1.80 D1..1 - 1.57D (b) Explai n why the dipole moments of furan andpyrrole have opposite directions. (c) Shouldthedipolemomentof 3.4-di chl oropyrrolebegreaterthanorlessthanthatof pyrrole? Expl ain. 25.5Each of the following NMR chemi calgoes with a proton at carbon-2 of either pyridine, pyrrolidine, orpyrrole.Match each chemical shiftwiththeappropriateheterocycliccom-pound,and explain your ans wer: 8 8.5 1: 8 6.41 ; and 8 2.82. BASICITY AND ACIDITY OF THENITROGENHETEROCYCLES A.Basicity of the Nitrogen Heterocycles P) ritlinc and quinoline act as ordinary amine .... H3o+ 0+ 1110 I+ I I pi\,,5.2 (25.5) Pyridine and 4uinoline are much less ba\ic than aliphatic tertiary amine.; (Sec. 23.5A> because or the fp1 hybridization of their nitrogen un!.haretl electron pair\. (Recall from Sec.1-L 7 Athat the ba!.icit)of anunshared electron pair dccrca'>C'- '' ithincrea-.ingfcharacter. Bccauo;e pyrrole andindole look like amine!.. it ma) come acrved withfuranandthiophene: 0 ( l lJ0 II Bh 0--II H,C-C- 0- Ul CH3C02H - (II +H3C- C-OH 0 (25. 13) (ah icdci-Crafts reJction)(75-92% yield) NOz 0-r H03fJ-,o,+O+1110 s a(ctit Jnhydride ss (25. 14) (70o/oyield)( Sl?oyield) 1228CHAPTER25THECHEMISTRY OF THE AROMATIC HETEROCYCLES Pyrrole,furan.andthi ophene are allmuch more reacti vethanbenzenein electrophil ic aro-matic substillltion. Although preci se reactivity ratios depend on the particular react ion. the rel-ati ve rates of bromination aretypi cal : pyrrole>furan> 3XlOili6XJQII thiophene> 5X benzene 1 (25.15) Milder reactionconditionsmustbeu. edwi thmorereacti\'e(Reacti on condi -tions that arc too vigorous inmany bring about so many reactions thatpolymerit.ation andtar formation occur.)For example.a les!-.reactive acylating reagent i!> ust.!dinthe acylation offuran thanin the acylation of bent.cnc. (Recall that anhydride-. are less rcacti\ e than acid chlo-pp.1011- 1015.) 0 II 11.\C- C-CI Bt t\d)f t I l\ICIJ H! O 0 o-Il C-CHI+ (971Voyield) 0 I IICI 0 + 0 H3C- C- OI! yield ) (25. 16a) es.t6b> The reactivi tyorder of the heterocycles(Eq.25. 15)is a consequenceor the relat i ve abil i-tiesof theto stabi li;e positive chargeinthe intermediate (asinEq. 25.11 a. for example).Bothpyrrole andfuranhaveheteroatom' fromthe period of the periodic table. nitrogen i-.better thanoxygen atdelocali;ing charge-ni tro-genb less electronegati\'e- p} rrolc more reactivethanfuran.The -,ulfur of thiophene is a third-period element and. althoughitless electronegati vethan oxygen.it!>3p orbital s over-laplessefficientl ywiththe2p orbitalsof the aromati c7T-clcctronsystem(secFig.16.7.p. 771 ).In fact.the react i vityorder ofthe heterocycl e!>inaromatic substitut ion purithenormalcfTectof the heterocyclic atom in directing to theThe following example illustrates 3-thiophenecarboxylic aci d5-bromo-3-t hiophenecarboxylic acid (69% yield; satisfies the di recting effectof boththL'hetcroatom Jnd - COzll ) (not observed; the directing effc:ct()( the:heteroatom onl y) (25.18) 25 3THECHEMISTRYOF FURAN,PYRROLE, AND THIOPHENE1229 In this example. the -C01H group directs the second into a meta ( 1.3) relation-ship;thethiopheneringtend!>toatthe2-position. Theobservedproduct satisfies both ofdirecting effect-.. (Notice thatwe countaroundthe carbonframework of thehet-erocyclic compound. nm throughthe hetcroatom. whenlt',ing thi::.onho.meta.para analog).) In thefolio"' ing example. the chloro group is an ortho. para-directing group.Becau!le thepo-'>ition .. para ..10 the chloro group abo a 2-po-..ition. both the ::,ulfur of thering and the chloro group direct theincoming nitw group to the same O-c1 s 2-chlorothiophcne p.u ..Jnr t ,l) / o1; __f[];:.c, s 2-chloro-5-nitrothiophenc (57% yield) (25.19) Whenthedirectingol' andthe ring compete.it is not to mixture-.. of product\. 2,5-di mcthylfuran 2-nitrothiophcne Hf'\0, 0c 02N-O-N02 + s 2,5-d.initroth iophcne (44u) Q,i'i -'[)_NO, s 2,4-dinit rothiophenc (56"o) (6011urield) Finally.if hoth 2-posi ti on'>arc occupied. 3-sub:,titution takes place. AtOll acetic anhydride (65% yield) B.Addition Reactions of Furan reaction:refer toSec.15.4A if necessai).) CH30MBr HOII +HBr CH30MOCII) HOH +HBr mixture of (72-76% yield) (25.22) Anothermanifestat ionoftheconjugated-dienecharacterof furanisthatitundergoes Oiels- Alder reactions (Sec.15.3) with reactive dienophilc!. suchasmaleic anhydride. + o loccuratthesidechainsof heterocycliccompoundswithoutaffectingthe rings. just as !.Orne reactions occur at the !-ide chain of u ... ubstitutcd benzene (Sec!..17.1-17.5). CH=O 0 s 3-thiophenecarbaldehydc (Sec.19.14) 3-thiophcnccarbox:ylic acid (95-97% yield) (25.24) Aparticularly useful example of a -;ide-chain reactionisremo,al of a carboxy group directly attachedtothering(decarboxylation).This reactionis effectedby strongheating,insome caseswith catalysts. heat !()___ 0 200c { + co{25.25) 2-furancarboxylic acidfuran 25.4THECHEMISTRYOFPYRIDINE 1231 i;i.l:iiif&i25.9Complete each of the following reactions by giving theprincipal organic product(s). 25.4 (alBr n + Ho, 'AcOH s (b)00 f)-cH3 +A cOli (d0 II + H3C-C-Ph 0CH=O NaOH (d)CH3 d+ s 25. 10Write a curved-arrowfor the followingreaction. 0+l\Me2 N-I HErlich's reagent (used for detectingand indoles) THECHEMISTRY OFPYRIDINE A.Electrophilic Aromatic Substitution In general. it is difficult to prepare monosubstituted pyridincs by clectrophili c aromatic substi-tution because pyridine has a very low reactivity; it muchreact ive lhan benzene. An im-portantreasonfor this low reactivityisthatpyridineisprotonatcdunder theveryacidic con-ditions of most electrophi li c aromatic sub!>titlltion (Eq. 25.4, p.1224). The resulting charge on nitrogen makes it difficult to form a carbocation intermediate. which would place a second positive charge within the same ring. Fortunately.anumberof monosub!>titutedpyridine(andothermethylmedarcobtainedfromcoaltar(Sec.16.7}. Another\cryU!-eful derivativeof pyridinei'>nicotinicacid(pyridine-3-carb()\ylic acid).whichis convenientlypreparedin a number of way1..oneof whichis -;ide-chainoxidation of nicotine. analkaloid pre-.cntin tobacco (Fig. :n.-t p.1156). I) Oj '\ HCH NJ oxrda11o11 ncutrJi in nicotine (Nitri c acid in this reactionis asanoxidizing agent.) UO, H -I ni cotinic acid (70C'cntin , cry small concentration. the methyl-,ub!->tituted pyridine' arcnotvery reactive. de- thepre!-.ence of the activating methylA-:.the example inEq.25.27 illustrates..in pyridine generally takes place in the3-positi on.AlthoughthemethylinEq.25.27alsodirectsubstitutiontothe 3-position. the tendency of pyridine to undergo 3-subr-.tillltion general evenin the absence of directing groups.As with other electrophilil.: substi tutions. anunderstanding of this directing effect comesfrom an examinati on of the carbocation intermediate).formed in sub-stitution at different positions. Substitutionin the 3-posit ion givesa carbocation wit h t hree different resonance structures: 3 -Suhsrirur ion: (15.28a) Substitutionatthe4-positionalsoi1wol\eOdiumamide( Ia+-. Eq.14.21.p.663) bring-; aboutthe direct with nucleophiles:notice partic- the electronnow 01110the positi\Cl)chargednitrogen.oticc abo inEq.25.49 thatthe po'>iti\ dy charged nitrogen of the pyridinium ion-.cr\'e'- to '>tahili7e the attached carbanion by resonance.This chemistry has -,ornecloseparallel'>inthebiologicalworld.For example. re-'ie\\ing Sec.10.70 willshowhow thep)ridiniumionofAD+ o;enes a!>an elecrronaccep-tor inbiochemical reduction. (otice particular!)Eq what appears to be a carbanion interme-diate. imine derivative of the cr-amino acid and pyridoxaJ phosphate II a carbanion intermediate" (25.56a) (See also Eq.22.63a. p.1082. for a !>imilar reaction infatty-acid biosynthesi!>.) This. however, isno ordinary carbanion.Most carbanionsaresuch Mrong bases that they cannot existunder physiologicalconditi ons: however.this carbani onamuch weaker becauseit is srabi-li::,ed by resonance: (?;: -C-CH,RC:H -N=C-CH2R I-C02 l ::Jl-N II three of the many resonance for the carbanion intermediate (25.56b) (Only thrt!eof themanypO!.!.iblcre!.onancearc\hown:youshould draw others.) The curved in the middle structure. which resultin the structure on the right, show how the pyridini11111ion swbili::,es negmive charge by accept in!: electrons. I n fact, the red part of the structure onthe ri ght shows that the "carbanion i1.reall ynota carbanion atall - it i s a neutral molecule. (Compare with Eq. 25.49 on p.1240.) The 1-ame type of 'carbanion i s involved in all of the pyridoxal-catalyzed transformations discussedin this secti on. (Sec Problem 25. 18.) Gi venhowimportantthepyridiniumringisfor delocalizingchargeinthereactionsof pyridoxal pho'>phate. a pertinent question is whether pyridoxal phosphate actually exists in the pyridinium-ionform.AtypicalpK. of pyridinjum ion!>i1- about 5 (Eq. 25.4.p.1224 ).Yet the reactions promoted by pyridoxal phosphate take place at physiological pHvalues (about 7.4). I fthe pyridiniumioninpyridoxalphosphatehada pK11near5,mostor it wouldexi st asthe 1244CHAPTER25THE CHEMISTRY OF THE AROMATIC HETEROCYCLES conjugate-ba!->cp) ridine fom1atpH7.4: thatI 'k of itwould exi\tinthe conjugate-acid pyridinium-ionform.(Verifyconclu..,ion.)Itturns outthatthemolecular architecture of pyridoxal pho!>phate ensures a muchhigher concentration of the crucial pyridiniurn-ionform. The key element inthe structure the - OH group inthe 3-position andonho relationship tothe aldt:hyde(secEq.25.57).ortho relationshipmakesthephenolic - OHgroup of pyridoxa l phosphate unusually acidic. (Why? See Problem18.30(c). p.861.) loni.wtion of the phenolic- 0 11group.inturn.thepK.of thepyridiniumionbecausethenegative charge or thephenolate stabilizes the charge of thepyridiniumion(andviceversa). As are\ult.thepredominant formor pyridoxalphophate atphy.,iologicalpi Itheformin whichthephenoliionited and the p) rid inc isprotonated: 0 IICH=O -o- POCJ-I, nOII I- o- I/. NCH I 35% at equilibrium ?!CH= O -o-POCH,uo-1- o- I +/ NCH I II. 65%,llequilibrium two for ms of pyridoxal phosphate (25.57) But that'tabili1ed.Inone well-studied case. (' BH) as needed, provide curved-arrow mechanil.ms for these reactions.Yourmechanbrnshouldshowtheimportantintermediates.Aspm1of your mechanism. explain the significance of the pyridinium ion in the catalysis of this reaction .,equence. (b) U\ing( 8:) and actd\ CBH) as needed. prO\ ide a curved-arrowmechanismforthe convef\ionof thea-aminoacidserineintoformaldehydeandglycine(Eq.25.53.p. 1242). 25.19Isoniazidis anantituberculosis drugthatoperate:.byreacting withpyridoxalphosphate in the causative Mycobacterium.Showhowisonitructures of the nucleicDAand R1A. polymer' that are responsible for the 'loring and transmis'iion of genetic information. This !>ection introduce!> nucleic acid'>. and Sec.25.6 intro-duces