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(BQ) Part 1 book Organic chemistry has contents: Structure and bonding; stereochemistry at tetrahedral centers; an overview of organic reactions, alkenes and alkynes; alcohols, phenols, and thiols; ethers and sulfides; structure determination mass spectrometry, infrared spectroscopy, and ultraviolet spectroscopy,...and other contents.
Structures of Common Coenzymes The reactive parts of the molecules are darkened, while nonreactive parts are ghosted Adenosine triphosphate—ATP (phosphorylation) NH2 N O –O P O– O P N O O P O N OCH2 N O O– O– OH OH Coenzyme A (acyl transfer) NH2 N O O CH3 N O O N HSCH2CH2NHCCH2CH2NHCCHCCH2OPOPOCH2 HO CH3 N O O– O– 2–O PO OH Nicotinamide adenine dinucleotide—NAD+ (oxidation/reduction) (NADP+) NH2 CONH2 N N O O + N CH2OPOPOCH2 N OH HO O N O O– O– OH OH (OPO32–) Flavin adenine dinucleotide—FAD (oxidation/reduction) NH2 N HO OH HO CHCHCHCH2OPOPOCH2 O– O– CH2 H3C N H3C N N N O O OH N O N O O H OH N Tetrahydrofolate (transfer of C1 units) H H2N H N N H N N N CO2– H O H O NHCHCH2CH2C O– 1–5 O S-Adenosylmethionine (methyl transfer) NH2 N N CH3 O –OCCHCH CH 2 +NH S + CH2 N N O OH OH Lipoic acid (acyl transfer) S Pyridoxal phosphate (amino acid metabolism) CH2OPO32– S CHO CH2CH2CH2CH2CO2– + H N OH CH3 Biotin (carboxylation) Thiamin diphosphate (decarboxylation) H S O NH2 + N H N O O –OPOPOCH CH 2 O– O– N N H CH3 N H H H CH3 S CH2CH2CH2CH2CO2– s, even ts in our course en ud st e th Dear Colleague: of t in pure know that mos nces rather than ganic chemistry ie or sc h fe ac li te e th ho in w ily doctors All of us terested primar ochemists, and in bi , e ts ar is s, og or ol aj bi m y re we tu the chemistr hing so many fu questioning why e ac te ar e us ar e of w e or se m the details of ves, more and chemistry Becau h time discussing rsions of oursel uc ve r m ge so un d yo en sp an ogy? Why e rather th nnection to biol e Why w co w le ay tt w li e ve th h t ac ng organisms? continue to te ch chemists bu chemistry of livi interest to resear c of ni e ga ar or at e th th s ng on reacti me discussi t it is d spend more ti aditional way, bu tr e th in y tr don’t we instea is organic chem who want to id for teaching ose instructors sa th r be fo to e h iv at uc rn m l te al gical There is stil istry with Biolo has been no real m e er he C th ic w an no l rg ti O and also true that un spect that more at is why I wrote th su I , nd ce A en y tl in en om er t diff s to gain in pr teach somewha biology continue al ic em ch s A cordingly Applications their teaching ac ng ciple in gi an ch be l my guiding prin ut B y tr is more faculty wil em ch on organic clusively on focus almost ex is still a textbook to is th en : be ke s ta is t m ou saved by e Make no istry The space and what to leav em e ch ud cl al ic in og to t ol bi deciding w every reaction counterpart in use, for almost at have a direct od th go s voted to on t ti pu ac re en e thos of the book is de s has be on % ti 25 ac y re el l at ca im gi lo io addition, ple and approx leaving out nonb nsformations In biological exam a ot bi by r ed ei th ow ll of fo y andard istr discussed is s shorter than st the organic chem ge d pa an es 20 ul ly ec ar ol ne urse entirely to biom l Applications is l two-semester co ca ca gi pi lo ty io a B h in it ok w try the entire bo Organic Chemis faculty to cover r fo le ib text; I believe ss po it from any other t en texts, making er ff di is s l Application y with Biologica tr is m he C ic an Org ts r today’s studen that it is ideal fo Sincerely, John McMurry All royalties from Organic Chemistry with Biological Applications will be donated to the Cystic Fibrosis (CF) Foundation This book and donation are dedicated to the author’s eldest son and to the thousands of others who daily fight this disease To learn more about CF and the programs and services provided by the CF Foundation, please visit http://www.cff.org This page intentionally left blank Organic Chemistry with Biological Applications 2e John McMurry Cornell University Australia • Brazil • Japan • Korea • Mexico • Singapore • Spain • United Kingdom • United States Organic Chemistry with Biological Applications 2e John McMurry Publisher: Mary Finch Senior Acquisitions Editor: Lisa Lockwood Senior Development Editor: Sandra Kiselica Assistant Editor: Elizabeth Woods © 2011, 2007 Brooks/Cole, Cengage Learning ALL RIGHTS RESERVED No part of this work covered by the copyright herein may be reproduced, transmitted, stored, or used in any form or by any means, graphic, electronic, or mechanical, including but not limited to photocopying, recording, scanning, digitizing, taping, Web distribution, information networks, or information storage and retrieval systems, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without the prior written permission of the publisher Senior Media Editor: Lisa Weber Marketing Manager: Amee Mosley Marketing Assistant: Kevin Carroll Marketing Communications Manager: Linda Yip Project Manager, Editorial Production: Teresa L Trego For product information and technology assistance, contact us at Cengage Learning Customer & Sales Support, 1-800-354-9706 For permission to use material from this text or product, submit all requests online at www.cengage.com/permissions Further permissions questions can be e-mailed to permissionrequest@cengage.com Creative Director: Rob Hugel Library of Congress Control Number: 2009928764 Art Director: John Walker Student Edition: Print Buyer: Judy Inouye ISBN-13: 978-0-495-39144-9 Permissions Editor: Robert Kauser ISBN-10: 0-495-39144-1 Production Service: Graphic World Inc Text Designer: Jeanne Calabrese Photo Researcher: John Hill Copy Editor: Graphic World Inc Illustrator: Graphic World Inc., 2064design OWL Producers: Stephen Battisti, Cindy Stein, and David Hart in the Center for Educational Software Development at the University of Massachusetts, Amherst, and Cow Town Productions Brooks/Cole 20 Davis Drive Belmont, CA 94002-3098 USA Cengage Learning is a leading provider of customized learning solutions with office locations around the globe, including Singapore, the United Kingdom, Australia, Mexico, Brazil, and Japan Locate your local office at www.cengage com/global Cover Designer: Jeanne Calabrese Cover Image: Neil Fletcher and Matthew Ward/Getty Images Cengage Learning products are represented in Canada by Nelson Education, Ltd Compositor: Graphic World Inc To learn more about Brooks/Cole, visit www.cengage.com/brookscole We gratefully acknowledge SDBS for providing data for the following figures: 10.12, 10.14, 10.16, 10.17, 13.9, 13.10, 13.7, 14.15, 18.5; and data for the spectra in Problems 10.31, 10.45, 10.46, 13.72, 15.54, and 16.62 (http://riodb01 ibase.aist.go.jp/sdbs/, National Institute of Advanced Industrial Science and Technology, 8/26/05, 2/7/09, 2/13/09, 3/10/09) Printed in Canada 13 12 11 10 09 Purchase any of our products at your local college store or at our preferred online store www.ichapters.com Brief Contents Structure and Bonding Polar Covalent Bonds; Acids and Bases Organic Compounds: Alkanes and Their Stereochemistry Organic Compounds: Cycloalkanes and Their Stereochemistry Stereochemistry at Tetrahedral Centers An Overview of Organic Reactions Alkenes and Alkynes Reactions of Alkenes and Alkynes Aromatic Compounds 10 33 70 105 134 175 212 251 309 Structure Determination: Mass Spectrometry, Infrared Spectroscopy, and Ultraviolet Spectroscopy 11 Structure Determination: Nuclear Magnetic Resonance Spectroscopy 12 Organohalides: Nucleophilic Substitutions and Eliminations 13 Alcohols, Phenols, and Thiols; Ethers and Sulfides Preview of Carbonyl Chemistry 367 404 444 501 555 14 Aldehydes and Ketones: Nucleophilic Addition Reactions 15 Carboxylic Acids and Nitriles 16 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions 17 Carbonyl Alpha-Substitution and Condensation Reactions 18 Amines and Heterocycles 19 Biomolecules: Amino Acids, Peptides, and Proteins 20 Amino Acid Metabolism 21 Biomolecules: Carbohydrates 22 Carbohydrate Metabolism 23 Biomolecules: Lipids and Their Metabolism 24 Biomolecules: Nucleic Acids and Their Metabolism 25 Secondary Metabolites: An Introduction to Natural Products Chemistry 564 610 643 695 749 791 832 862 901 936 987 1015 Key to Sequence of Topics (chapter numbers are color coded as follows): • Traditional foundations of organic chemistry • Organic reactions and their biological counterparts • The organic chemistry of biological molecules and pathways v Detailed Contents Structure and Bonding 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.11 1.12 Atomic Structure: The Nucleus Atomic Structure: Orbitals Atomic Structure: Electron Configurations Development of Chemical Bonding Theory The Nature of Chemical Bonds: Valence Bond Theory 10 sp3 Hybrid Orbitals and the Structure of Methane 12 sp3 Hybrid Orbitals and the Structure of Ethane 13 sp2 Hybrid Orbitals and the Structure of Ethylene 14 sp Hybrid Orbitals and the Structure of Acetylene 17 Hybridization of Nitrogen, Oxygen, Phosphorus, and Sulfur 18 The Nature of Chemical Bonds: Molecular Orbital Theory 20 Drawing Chemical Structures 21 Summary 24 Lagniappe—Chemicals, Toxicity, and Risk 25 Working Problems 26 Exercises 26 Polar Covalent Bonds; Acids and Bases 2.1 2.2 2.3 2.4 2.5 2.6 2.7 vi Polar Covalent Bonds: Electronegativity 33 Polar Covalent Bonds: Dipole Moments 36 Formal Charges 38 Resonance 41 Rules for Resonance Forms 43 Drawing Resonance Forms 45 Acids and Bases: The Brønsted–Lowry Definition 48 33 exercises 13.54 Reaction of (S)-3-methylpentan-2-one with methylmagnesium bromide followed by acidification yields 2,3-dimethylpentan-2-ol What is the stereochemistry of the product? Is the product optically active? O CH3CH2CHCCH3 3-Methylpentan-2-one CH3 13.55 Testosterone is one of the most important male steroid hormones When testosterone is dehydrated by treatment with acid, rearrangement occurs to yield the product shown Propose a mechanism to account for this reaction ■ CH3 OH H CH3 CH3 H3O+ H H CH3 H H H H O O Testosterone 13.56 Dehydration of trans-2-methylcyclopentanol with POCl3 in pyridine yields predominantly 3-methylcyclopentene Is the stereochemistry of this dehydration syn or anti? Can you suggest a reason for formation of the observed product? 13.57 2,3-Dimethylbutane-2,3-diol has the common name pinacol On heating with aqueous acid, pinacol rearranges to pinacolone, 3,3-dimethylbutan-2-one Suggest a mechanism ■ HO H3C H3C OH C C CH3 CH3 Pinacol H3O+ O CH3 C H3C C CH3 CH3 + H2O Pinacolone 13.58 As a rule, axial alcohols oxidize somewhat faster than equatorial alcohols Which would you expect to oxidize faster, cis-4-tert-butylcyclohexanol or trans-4-tert-butylcyclohexanol? Draw the more stable chair conformation of each molecule 13.59 Propose a synthesis of bicyclohexylidene, starting from cyclohexanone as the only source of carbon Bicyclohexylidene Problems assignable in Organic OWL 549 550 chapter 13 alcohols, phenols, and thiols; ethers and sulfides 13.60 Fluoxetine, a heavily prescribed antidepressant marketed under the name Prozac, can be prepared by a route that begins with reaction between a phenol and an alkyl chloride OH CH3 CH3 N N CH3 F3C + CH3 N O KOH DMSO O H CH3 H H F3C F3C Cl Fluoxetine (a) The rate of the reaction depends on both phenol and alkyl halide Is this an SN1 or an SN2 reaction? Show the mechanism (b) The physiologically active enantiomer of fluoxetine has (S) stereochemistry Based on your answer in part (a), draw the structure of the alkyl chloride you would need, showing the correct stereochemistry 13.61 ■ Identify the reagents a–f in the following scheme: OH O a Br b CH2OH c OH CHO d 13.62 e ■ f Identify the reagents a–e in the following scheme: OH O CH3 a c CH3 CH3 b d O e OCH3 CH3 CH3 OH OH H Problems assignable in Organic OWL exercises 13.63 Disparlure, C19H38O, is a sex attractant released by the female gypsy moth, Lymantria dispar The 1H NMR spectrum of disparlure shows a large absorption in the alkane region, to ␦, and a triplet at 2.8 ␦ Reaction of disparlure, first with aqueous acid and then with KMnO4, yields two carboxylic acids identified as undecanoic acid and 6-methylheptanoic acid (KMnO4 cleaves 1,2-diols to yield carboxylic acids.) Neglecting stereochemistry, propose a structure for disparlure The actual compound is a chiral molecule with 7R,8S stereochemistry Draw disparlure, showing the correct stereochemistry 13.64 Galactose, a constituent of the disaccharide lactose found in dairy products, is metabolized by a pathway that includes the isomerization of UDP-galactose to UDP-glucose, where UDP ϭ uridylyl diphosphate The enzyme responsible for the transformation uses NAD؉ as cofactor Propose a mechanism HO CH2OH CH2OH O HO HO O OH O P HO O O O– P O O OH Uridine O O– P O O O– UDP-galactose 13.65 O P O Uridine O– UDP-glucose The red fox (Vulpes vulpes) uses a chemical communication system based on scent marks in urine One component of fox urine is a sulfide Mass spectral analysis of the pure scent-mark component shows M؉ ϭ 116, IR spectroscopy shows an intense band at 890 cm؊1, and 1H NMR spectroscopy reveals the following peaks Propose a structure for the molecule [Note: (CH3)2S absorbs at 2.1 ␦.] ■ 1.74 ␦ (3 H, singlet); 2.11 ␦ (3 H, singlet); 2.27 ␦ (2 H, triplet, J ϭ 4.2 Hz); 2.57 ␦ (2 H, triplet, J ϭ 4.2 Hz); 4.73 ␦ (2 H, broad) 13.66 Anethole, C10H12O, a major constituent of the oil of anise, has the NMR spectrum shown On oxidation with Na2Cr2O7, anethole yields p-methoxybenzoic acid What is the structure of anethole? Assign all peaks in the NMR spectrum, and account for the observed splitting patterns ■ Intensity 1H 10 Chem shift Rel area 1.84 3.76 6.09 6.36 6.82 7.23 3.00 3.00 1.00 1.00 2.00 2.00 TMS Problems assignable in Organic OWL Chemical shift (␦) ppm 551 552 chapter 13 alcohols, phenols, and thiols; ethers and sulfides 13.67 13.68 Propose a structure consistent with the following spectral data for a compound C8H18O2: ■ IR: 3350 cm؊1 1H NMR: 1.24 ␦ (12 H, singlet); 1.56 ␦ (4 H, singlet); 1.95 ␦ (2 H, singlet) The 1H NMR spectrum shown is that of 3-methylbut-3-en-1-ol Assign all the observed resonance peaks to specific protons, and account for the splitting patterns ■ Text not available due to copyright restrictions 13.69 Compound A, C5H10O, is one of the basic building blocks of nature All steroids and many other naturally occurring compounds are built from compound A Spectroscopic analysis of A yields the following information: ■ 3400 cm؊1; 1640 cm؊1 IR: 1H NMR: 1.63 ␦ (3 H, singlet); 1.70 ␦ (3 H, singlet); 3.83 ␦ (1 H, broad singlet); 4.15 ␦ (2 H, doublet, J ϭ Hz); 5.70 ␦ (1 H, triplet, J ϭ Hz) (a) From the IR spectrum, what is the nature of the oxygen-containing functional group? (b) What kinds of protons are responsible for the NMR absorptions listed? (c) Propose a structure for A Problems assignable in Organic OWL exercises 13.70 A compound of unknown structure gave the following spectroscopic data: ■ Mass spectrum: M؉ ϭ 88.1 IR: 3600 cm؊1 1H 1.4 ␦ (2 H, quartet, J ϭ Hz); 1.2 ␦ (6 H, singlet); 1.0 ␦ (1 H, singlet); 0.9 ␦ (3 H, triplet, J ϭ Hz) NMR: 13C 74, 35, 27, 25 ␦ NMR: (a) Assuming that the compound contains C and H but may or may not contain O, give three possible molecular formulas (b) How many protons (H) does the compound contain? (c) What functional group(s) does the compound contain? (d) How many carbons does the compound contain? (e) What is the molecular formula of the compound? (f) What is the structure of the compound? (g) Assign the peaks in the 1H NMR spectrum of the molecule to specific protons The following 1H NMR spectrum is that of an alcohol, C8H10O Propose a structure ■ Intensity 13.71 Chem shift Rel area 2.32 2.43 4.50 7.10 7.17 3.00 1.00 2.00 2.00 2.00 TMS 10 Problems assignable in Organic OWL Chemical shift (␦) ppm 553 chapter 13 alcohols, phenols, and thiols; ethers and sulfides 13.72 ■ Compound A, C H 10O, has the IR and H NMR spectra shown Propose a structure consistent with the observed spectra, and assign each peak in the NMR spectrum Note that the absorption at 5.5 ␦ disappears when D2O is added Transmittance (%) 100 80 60 40 20 4000 3000 2000 1500 1000 500 Wavenumber (cm–1) Intensity 554 Chem shift Rel area 1.16 2.55 5.50 6.74 7.03 3.00 2.00 1.00 2.00 2.00 TMS 10 Chemical shift (␦) ppm 13.73 The reduction of carbonyl compounds by reaction with hydride reagents (H:؊) and the Grignard addition by reaction with organomagnesium halides (R:؊ ؉MgBr) are examples of nucleophilic carbonyl addition reactions What analogous product you think might result from reaction of cyanide ion with a ketone? O CN– H3O+ C ? 13.74 Aldehydes and ketones undergo acid-catalyzed reaction with alcohols to yield hemiacetals, compounds that have one alcohol-like oxygen and one ether-like oxygen bonded to the same carbon Further reaction of a hemiacetal with alcohol then yields an acetal, a compound that has two ether-like oxygens bonded to the same carbon O C OR OR + ROH H+ catalyst C OH A hemiacetal ROH H+ + C OR H2O An acetal (a) Show the structures of the hemiacetal and acetal you would obtain by reaction of cyclohexanone with ethanol (b) Propose a mechanism for the conversion of a hemiacetal into an acetal Problems assignable in Organic OWL Preview of Carbonyl Chemistry Carbonyl compounds are everywhere Most biological molecules contain carbonyl groups, as most pharmaceutical agents and many of the synthetic chemicals that touch our everyday lives Citric acid, found in lemons and oranges; acetaminophen, the active ingredient in many over-the-counter headache remedies; and Dacron, the polyester material used in clothing, all contain different kinds of carbonyl groups H O HO C OH O O N C C HO C C O O HO CH3 OH Citric acid (a carboxylic acid) O O C n O Acetaminophen (an amide) Dacron (a polyester) To a great extent, the chemistry of living organisms is the chemistry of carbonyl compounds Thus, we’ll spend the next four chapters discussing the carbonyl group (pronounced car-bo-neel) There are many different kinds of carbonyl compounds and many different reactions, but there are only a few fundamental principles that tie the entire field together The purpose of this brief preview is not to show details of specific reactions but rather to provide a framework for learning carbonyl-group chemistry Read through this preview now, and return to it on occasion to remind yourself of the larger picture I Kinds of Carbonyl Compounds Table shows some of the many different kinds of carbonyl compounds All contain an acyl group (R–C=O) bonded to another substituent The R of the acyl group can be any practically organic part-structure, and the other substituent to which the acyl group is bonded can be a carbon, hydrogen, oxygen, halogen, nitrogen, or sulfur It’s useful to classify carbonyl compounds into two categories based on the kinds of chemistry they undergo In one category are aldehydes and ketones; in the other are carboxylic acids and their derivatives The acyl group in an aldehyde or ketone is bonded to an atom (H or C, respectively) that can’t stabilize a negative charge and therefore can’t act as a leaving group in a nucleophilic substitution reaction The acyl group in a carboxylic acid or its derivative, however, is bonded to an atom (oxygen, halogen, sulfur, or 555 556 preview of carbonyl chemistry TABLE Types of Carbonyl Compounds Name General formula Name ending General formula Name O O Aldehyde Ester -al C R C R H -oate O Lactone (cyclic ester) -one C R RЈ O O Ketone Name ending RЈ C C O None O Carboxylic acid C R O -oic acid H O Thioester C RЈ -thioate S R O Acid halide O -yl or -oyl halide C R X Amide C R Acyl phosphate O RЈ Lactam (cyclic amide) O– O C R -oic anhydride C O O N O O Acid anhydride -amide C R P O– O C C N None -yl phosphate nitrogen) that can stabilize a negative charge and therefore can act as a leaving group in a nucleophilic substitution reaction O O C C R Ketone O O C C OH Carboxylic acid Amide O C O Acid anhydride SRЈ Thioester O C R R Ester Acid halide O NH2 C ORЈ R X C O C R O R RЈ Aldehyde O R R H The –RЈ and –H in these compounds can’t act as leaving groups in nucleophilic substitution reactions C RЈ R OPO32– Acyl phosphate The –OH, –X, –ORЈ, –SR, –NH2, –OCORЈ, and –OPO32– in these compounds can act as leaving groups in nucleophilic substitution reactions iii general reactions of carbonyl compounds II Nature of the Carbonyl Group The carbon–oxygen double bond of a carbonyl group is similar in many respects to the carbon–carbon double bond of an alkene The carbonyl carbon atom is sp2-hybridized and forms three bonds The fourth valence electron remains in a carbon p orbital and forms a bond to oxygen by overlap with an oxygen p orbital The oxygen atom also has two nonbonding pairs of electrons, which occupy its remaining two orbitals C C O Carbonyl group C Alkene Like alkenes, carbonyl compounds are planar about the double bond and have bond angles of approximately 120° Figure shows the structure of acetaldehyde and indicates its bond lengths and angles As you might expect, the carbon–oxygen double bond is both shorter (122 pm versus 143 pm) and stronger [732 kJ/mol (175 kcal/mol) versus 385 kJ/mol (92 kcal/mol)] than a C–O single bond Electron-rich Bond angle (°) C 118 H C Bond length C C C O 121 C H C O 121 OC O C Electron-poor (pm) 122 O H 150 H H C H C H 109 As indicated by the electrostatic potential map in Figure 1, the carbon– oxygen double bond is strongly polarized because of the high electronegativity of oxygen relative to carbon Thus, the carbonyl carbon atom carries a partial positive charge, is an electrophilic (Lewis acidic) site, and reacts with nucleophiles Conversely, the carbonyl oxygen atom carries a partial negative charge, is a nucleophilic (Lewis basic) site, and reacts with electrophiles We’ll see in the next four chapters that the majority of carbonyl-group reactions can be rationalized by simple polarity arguments III General Reactions of Carbonyl Compounds Both in the laboratory and in living organisms, the reactions of carbonyl compounds take place by one of four general mechanisms: nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl FIGURE Structure of acetaldehyde 557 558 preview of carbonyl chemistry condensation These mechanisms have many variations, just as alkene electrophilic addition reactions and SN2 reactions do, but the variations are much easier to learn when the fundamental features of the mechanisms are made clear Let’s see what the four mechanisms are and what kinds of chemistry carbonyl compounds undergo Nucleophilic Addition Reactions of Aldehydes and Ketones (Chapter 14) The most common reaction of aldehydes and ketones is the nucleophilic addition reaction, in which a nucleophile, :Nu؊, adds to the electrophilic carbon of the carbonyl group Because the nucleophile uses an electron pair to form a new bond to carbon, two electrons from the carbon–oxygen double bond must move toward the electronegative oxygen atom to give an alkoxide anion The carbonyl carbon rehybridizes from sp2 to sp3 during the reaction, and the alkoxide ion product therefore has tetrahedral geometry ␦– O – O ␦+ + C Nu– A carbonyl compound (sp2-hybridized carbon) C Nu A tetrahedral intermediate (sp3-hybridized carbon) Once formed, and depending on the nature of the nucleophile, the tetrahedral alkoxide intermediate can undergo either of two further reactions, as shown in Figure Often, the tetrahedral alkoxide intermediate is simply protonated by water or acid to form an alcohol product Alternatively, the tetrahedral intermediate can be protonated and expel the oxygen to form a new double bond between the carbonyl carbon and the nucleophile We’ll study both processes in detail in Chapter 14 FIGURE The addition reaction of an aldehyde or a ketone with a nucleophile Depending on the nucleophile, either an alcohol or a compound with a C=Nu double bond is formed O Nu– R ؊ OH H C C R Nu Nu RЈ RЈ O A C R RЈ H Aldehyde or ketone Nu O H R C RЈ ؊ OH + Nu H H R C RЈ Nu –H2O Nu H C R RЈ FORMATION OF AN ALCOHOL The simplest reaction of a tetrahedral alkoxide intermediate is protonation to yield an alcohol We’ve already seen two examples of this kind of process during reduction of aldehydes and ketones with hydride reagents, such as NaBH4 or LiAlH4, and during Grignard reactions (Section 13.3) During a reduction, the nucleophile that adds to the carbonyl iii general reactions of carbonyl compounds group is a hydride ion, H:؊, while during a Grignard reaction, the nucleophile is a carbanion, R3C:؊ Reduction O O H– C R RЈ Ketone/ aldehyde – C R OH H3O+ H R C H RЈ RЈ Tetrahedral intermediate Alcohol Grignard reaction O O CH3– +MgBr C R R RЈ Ketone/ aldehyde – OH H3O+ C CH3 RЈ C R RЈ Tetrahedral intermediate CH3 Alcohol FORMATION OF C=NU The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu double bond For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2CUNR′ These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated Instead, it is protonated and then loses water to form an imine, as shown in Figure FIGURE M E C H A N I S M : Formation of an imine, R2CUNR′, by reaction of an amine with an aldehyde or a ketone O + C Addition to the ketone or aldehyde carbonyl group by the neutral amine nucleophile gives a dipolar tetrahedral intermediate R RЈ O – C R RЈ Transfer of a proton from nitrogen to oxygen then yields an amino alcohol intermediate NH2RЉ + NH2RЉ OH C R NHRЉ RЈ N RЉ C R RЈ + H 2O © John McMurry Dehydration of the amino alcohol intermediate gives neutral imine plus water as final products 559 560 preview of carbonyl chemistry Nucleophilic Acyl Substitution Reactions of Carboxylic Acid Derivatives (Chapter 16) The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetrahedral alkoxide intermediate is not isolated Because carboxylic acid derivatives have a leaving group bonded to the carbonyl-group carbon, the tetrahedral intermediate can react further by expelling the leaving group and forming a new carbonyl compound: O O – Nu C R Y Carboxylic acid derivative C R ؊ O + C Nu R Y Y– Nu Tetrahedral intermediate Y = –OR (ester), –Cl (acid chloride), –NH2 (amide), or –OCOR (acid anhydride) The net effect of nucleophilic acyl substitution is the replacement of the leaving group by the entering nucleophile We’ll see in Chapter 16, for instance, that acid chlorides are rapidly converted into esters by treatment with alkoxide ions (Figure 4) FIGURE M E C H A N I S M : The nucleophilic acyl substitution reaction of an acid chloride with an alkoxide ion yields an ester O C R Nucleophilic addition of alkoxide ion to an acid chloride yields a tetrahedral intermediate Cl – ORЈ + O – C R ORЈ Cl An electron pair from oxygen expels chloride ion and yields the substitution product, an ester O + C R Cl– ORЈ Alpha-Substitution Reactions (Chapter 17) The third major reaction of carbonyl compounds, alpha substitution, occurs at the position next to the carbonyl group—the alpha (␣) position This reaction, which takes place with all carbonyl compounds regardless of structure, © John McMurry iii general reactions of carbonyl compounds results in the substitution of an ␣ hydrogen by an electrophile through the formation of an intermediate enol or enolate ion: O ؊ C ␣ position C E+ O O C An enolate ion H C E C C E+ OH A carbonyl compound An ␣-substituted carbonyl compound C C An enol For reasons that we’ll explore in Chapter 17, the presence of a carbonyl group renders the hydrogens on the ␣-carbon acidic Carbonyl compounds therefore react with strong base to yield enolate ions O O O C H Base C C ؊ + C C A carbonyl compound ؊ H + Base C An enolate ion Because they’re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we’ve already studied For example, enolates react with primary alkyl halides in the SN2 reaction The nucleophilic enolate ion displaces halide ion, and a new C–C bond forms: O O C H C A carbonyl compound Base – O RCH2 X C C SN2 reaction C C CH2R + X– An enolate ion The SN2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C–C bonds, thereby building up larger molecules from smaller precursors We’ll study the alkylation of many kinds of carbonyl compounds in Chapter 17 Carbonyl Condensation Reactions (Chapter 17) The fourth and last fundamental reaction of carbonyl groups, carbonyl condensation, takes place when two carbonyl compounds react with each other When acetaldehyde is treated with base, for instance, two molecules 561 562 preview of carbonyl chemistry combine to yield the hydroxy aldehyde product known as aldol (aldehyde ϩ alcohol): O O C H3C H + HO NaOH C H3C O H C H C H 3C C H H Two acetaldehydes H Aldol Although the carbonyl condensation reaction appears different from the three processes already discussed, it’s actually quite similar A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an ␣-substitution step The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of a second acetaldehyde molecule, as shown in Figure HO – O H C C H Base abstracts an acidic alpha hydrogen from one acetaldehyde molecule, yielding a resonancestabilized enolate ion H H O H O C H3C The enolate ion adds as a nucleophile to the carbonyl group of a second acetaldehyde, producing a tetrahedral alkoxide ion H – C C H + H H2O H O O H – O H C C H 3C C H H H Tetrahedral intermediate The tetrahedral intermediate is protonated by solvent to yield the neutral aldol product and regenerate the base catalyst HO O H C C H 3C C H H + OH– H IV Summary To a great extent, the chemistry of living organisms is the chemistry of carbonyl compounds We have not looked at the details of specific carbonyl reactions in this short preview but rather have laid the groundwork for the next four © John McMurry FIGURE M E C H A N I S M : A carbonyl condensation reaction between two molecules of acetaldehyde yields a hydroxy aldehyde product exercises chapters All the carbonyl-group reactions we’ll be studying in Chapters 14 through 17 fall into one of the four fundamental categories discussed in this preview Knowing where we’ll be heading should help you keep matters straight in understanding this most important of all functional groups Exercises Judging from the following electrostatic potential maps, which kind of carbonyl compound has the more electrophilic carbonyl carbon atom, a ketone or an acid chloride? Which has the more nucleophilic carbonyl oxygen atom? Explain Acetone (ketone) Acetyl chloride (acid chloride) Predict the product formed by nucleophilic addition of cyanide ion (CN؊) to the carbonyl group of acetone, followed by protonation to give an alcohol: O CN– C H3C CH3 H3O+ ? Acetone Identify each of the following reactions as a nucleophilic addition, nucleophilic acyl substitution, an ␣ substitution, or a carbonyl condensation: (a) O O NH3 C H3C (b) C Cl H3C O NOH NH2OH C H3C C H H3C (c) NH2 O H NaOH OH O 563 ... of 13 C NMR Spectroscopy 412 DEPT 13 C NMR Spectroscopy 415 Uses of 13 C NMR Spectroscopy 417 detailed contents 11 .8 11 .9 11 .10 11 .11 11 .12 11 .13 1H NMR Spectroscopy and Proton Equivalence 418 Chemical... following figures: 10 .12 , 10 .14 , 10 .16 , 10 .17 , 13 .9, 13 .10 , 13 .7, 14 .15 , 18 .5; and data for the spectra in Problems 10 . 31, 10 .45, 10 .46, 13 .72, 15 .54, and 16 .62 (http://riodb 01 ibase.aist.go.jp/sdbs/,... biological counterparts • The organic chemistry of biological molecules and pathways v Detailed Contents Structure and Bonding 1. 1 1. 2 1. 3 1. 4 1. 5 1. 6 1. 7 1. 8 1. 9 1. 10 1. 11 1 .12 Atomic Structure: