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11 Introduction to Organic Chemistry 2 ed William H. Brown 11-1 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Aldehydes & Ketones Chapter 11 11-2 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 The Carbonyl Group • In this and three following chapters we study the physical and chemical properties of classes of compounds containing the carbonyl group, C=O • • • • aldehydes and ketones (Chapter 11) carboxylic acids (Chapter 12) carboxyl derivatives (Chapter 13) enolate anions (Chapter 14) 11-3 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 The Carbonyl Group • Consists of • one sigma bond formed by overlap of sp2 hybrid orbitals • one pi bond formed by overlap of parallel 2p orbitals electron pairs in C O sp2 hybrid orbitals 11-4 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Structure of Aldehydes • The functional group of an aldehyde is a carbonyl group bonded to a H atom • in methanal, it is bonded to two H atoms • in all other aldehydes, it is bonded to one H and one carbon atom H H C O C O H H3 C Methanal Ethanal (formaldehyde) (acetaldehyde) 11-5 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Structure of Ketones • The functional group of a ketone is a carbonyl groups bonded to two carbon atoms O O CH3 -C- CH3 Propanone (Acetone) Cyclohexanone 11-6 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Nomenclature - Aldehydes • IUPAC names: select as the parent alkane the longest chain of carbon atoms that contains the carbonyl group • because the carbonyl group of the aldehyde must be on carbon 1, there is no need to give it a number • For unsaturated aldehydes, show the presence of the C=C by changing the infix -an- to -en• the location of the suffix determines the numbering pattern 11-7 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Nomenclature - Aldehydes O 5 4 3 2 CH3 1 4 3 2 O 1 CH3 CHCH 2 CH 3-Methylbutanal CH3 CH2 CH2 CH2 CH Pentanal O 3 O 2 1 CH2 = CHCH 2-Propenal (Acrolein) 5 7 3 1 H (2E)-3,7-Dimethyl-2,6-octadienal (Geranial) 8 6 4 2 11-8 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Nomenclature - Aldehydes • For cyclic molecules in which the -CHO group is attached to the ring, the name is derived by adding the suffix -carbaldehyde to the name of the ring 1 CHO CH3 2 CH 3 2,2-Dimethylcyclohexanecarbaldehyde CHO 1 2 3 2-Cyclopentenecarbaldehyde 11-9 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Nomenclature - Ketones • IUPAC names: • select as the parent alkane the longest chain that contains the carbonyl group, • changing the suffix -e to -one • number to give C=O the smaller number O O CH3 CH3 O 1 2 3 4 5 6 CH3 CCH3 CH3 CH2 CCH2 CHCH3 Propanone (Acetone) 5-Methyl-3-hexanone 2-Methylcyclohexanone 11-10 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Nomenclature - Ketones • The IUPAC system retains these names O O CH3 CCH3 CCH3 C- Acetone Acetophenone O Benzophenone 11-11 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Order of Precedence • For compounds that contain more than one functional group indicated by a suffix Functional Group Precedene -CO 2 H -CHO C=O -OH -NH 2 -SH Suffix if Higher Prefix if Lower in Precedence in Precedence -oic acid -al -one -ol -amine -thiol oxooxohydroxyaminomercapto- 11-12 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Physical Properties • Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a C=O group is polar + C O • aldehydes and ketones have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight 11-13 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Reaction Theme • One of the most common reaction themes of the carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound OH R H- Nu C O + R Nu C R R Tetrahedral carbonyl addition compound 11-14 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Add’n of C Nucleophiles • Addition of carbon nucleophiles is one of the most important types of nucleophilic additions to a C=O group • a new carbon-carbon bond is formed in the process • We study addition of carbon nucleophiles called Grignard reagents • Victor Grignard was awarded the Nobel Prize for Chemistry in 1912 for their discovery and application to organic synthesis 11-15 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • Magnesium metal reacts with alkyl and aryl halides to give organomagnesium halides CH 3 CH 2 CH 2 CH 2 Cl + Mg 1-Chlorobutane ether CH 3 CH 2 CH 2 CH 2 MgCl Butylmagnesium chloride 11-16 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • Given the difference in electronegativity between carbon and magnesium (2.5 - 1.3), the C-Mg bond is polar covalent, with C- and Mg+ • a Grignard reagent behaves as a carbanion and as a nucleophile • Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge 11-17 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • Grignard reagents are very strong bases and react with a variety of acids to give alkanes + CH3 CH2 - MgBr + H-OH pKa 15.7 Stronger acid CH3 CH2 -H + Mg(OH)Br pKa 51 Weaker acid 11-18 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • they also react with these acids ( proton donors) to give alkanes R2 NH pKa 38-40 ROH pKa 16-18 Amines Alcohols ArOH pKa 9-10 RSH pKa 8-9 RCO2 H pKa 4-5 Phenols Thiols Carboxylic acids 11-19 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • Grignard reagents provide a way to form new carbon-carbon bonds • a carbanion is a good nucleophile and adds to the carbonyl group of an aldehyde or ketone to form a tetrahedral carbonyl addition compound • the driving force for this reaction is the attraction of the partial negative charge on the carbon of the Grignard reagent for the partial positive carbon of the carbonyl group 11-20 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol O + ether CH3 CH2 -MgBr + H- C-H + Formaldehyde - O [ Mg Br ] + CH3 CH2 -CH2 A magnesium alkoxide OH HCl CH3 CH2 -CH2 + Mg2+ H2 O 1-Propanol (a primary alcohol) 11-21 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • addition to any other RCHO gives a 2° alcohol + O [ Mg Br ] O - + ether Mg Br + CH3 - C-H CHCH3 + A magnesium Acetaldehyde alkoxide (an aldehyde) OH HCl H2 O 2+ + Mg CHCH3 1-Cyclohexylethanol (a secondary alcohol) 11-22 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • addition to a ketone gives a 3° alcohol O - + ether C 6 H5 Mg Br + CH 3 - C-CH3 + Acetone - O [ MgBr] C6 H5 CCH3 CH3 A magnesium alkoxide + OH HCl H2 O C6 H5 CCH3 + Mg2+ CH3 2-Phenyl-2-propanol (a tertiary alcohol) 11-23 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • addition to CO2 gives a carboxylic acid O O - + ether Mg Br + C CO - [ MgBr] + O Carbon dioxide O HCl H2 O COH + Mg 2 + Cyclopentanecarboxylic acid 11-24 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • addition to ethylene oxide gives a 1° alcohol C6 H5 - MgBr + CH2 CH2 O Ethylene oxide - C6 H5 CH2 CH2 O [ MgBr ] + S N2 ether HCl C H CH CH OH 6 5 2 2 H2 O 2-Phenylethanol 11-25 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Grignard Reagents • Problem: 2-phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination OH C-CH2 CH3 CH3 11-26 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Addition of Alcohols • Addition of one molecule of alcohol to the C=O group of an aldehyde or ketone gives a hemiacetal • Hemiacetal: a molecule containing an -OH and an -OR or -OAr bonded to the same carbon O H CH3 CCH3 + OCH2 CH3 OH CH3 COCH2 CH3 CH3 A hemiacetal 11-27 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Addition of Alcohols • Hemiacetals are only minor components of an equilibrium mixture, except where a five- or sixmembered ring can form • (the trans isomer is shown here) O CH3 CHCH 2 CH2 CH OH 4-Hydroxypentanal Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. H3 C O OH A cyclic hemiacetal (major form present at equilibrium) 11-28 11 Addition of Alcohols • Hemiacetals react with alcohols to form acetals • Acetal: a molecule containing two -OR or -OAr groups bonded to the same carbon OH H + CH3 COCH2 CH3 + CH3 CH2 OH CH3 OCH2 CH3 A hemiacetal CH3 COCH2 CH3 + H2 O CH3 A diethyl acetal 11-29 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Addition of Alcohols •• • Steps 1 and 2: proton transfer from the acid catalyst, HA, to the carbonyl oxygen followed by loss of H2O A H ••+ H H •• HO O (2) •• •• (1) R- C-OCH R- C-OCH 3 3 •• •• H H - •• •• R- C •• + OCH3 + H2 O •• + A H An oxonium ion 11-30 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Addition of Alcohols • Steps 3 and 4: reaction of the oxonium ion with ROH followed by proton transfer to A- •• A H •• CH3 -O •• + R- C + OCH3 •• CH3 •• O+ (4) •• R- C-OCH3 •• H •• •• H (3) H O-CH3 •• R- C-OCH3 •• + H- A H An acetal 11-31 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Addition of Alcohols • with a glycol, such as ethylene glycol, the product is a five-membered cyclic acetal O + HOCH2 CH2 OH H + O CH 2 O CH2 + H2 O A cyclic acetal 11-32 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Add’n of N Nucleophiles • Ammonia, 1° aliphatic amines, and 1° aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases) O CH3 CH + H2 N H + CH3 CH=N Aniline Ethanal O + H2 NCH3 Cyclopentanone Methylamine Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. + H2 O An imine (A Schiff base) H + NCH3 An imine (a Schiff base) + H2 O 11-33 11 Add'n of N Nucleophiles • Formation of an imine occurs in two steps • Step 1: formation of a TCAI • Step 2: loss of water •• + H2 N- R C O (1) - C H + N -R •• •• •• O •• •• •• •• O (1) H •• C H •• •• O H TCAI H •• N -R (2) H Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. C •• •• N + R •• C N -R H2 O 11-34 11 Add'n of N Nucleophiles • Rhodopsin (visual purple) is the imine formed between 11-cis-retinal (vitamin A aldehyde) and the protein opsin 2 3 1 6 7 8 4 11 9 12 10 13 5 Rhodopsin (Visual purple) 14 H C=N-OPSIN 15 11-35 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Rhodopsin OPSIN 11-36 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Keto-Enol Tautomerism • A carbon adjacent to a carbonyl group is called an a-carbon, and a hydrogen atom bonded to it is called an a-hydrogen. a- hydrogens O CH 3 - C- CH 2 - CH 3 a- carbons 11-37 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Keto-Enol Tautomerism • A carbonyl compound with an a-hydrogen is in equilibrium with a constitutional isomer called an enol (an alkene + an alcohol) O OH CH3 - C- CH3 Acetone (keto form) CH3 - C= CH2 Acetone (enol form) 11-38 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Keto-Enol Tautomerism • keto-enol equilibria for Keto form simple aldehydes O and ketones CH3 CH lie far O toward the keto form CH3 CCH3 O % Enol at Enol form Equilibrium OH CH2 = CH 6 x 10-5 OH CH3 C= CH2 6 x 10-7 OH 4 x 10-5 11-39 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Keto-Enol Tautomerism • Keto-enol tautomerism is acid catalyzed Step 1: proton transfer from H-A •• •• O H- A CH3 - C-CH3 + the conjugate acid of the ketone •• •• Step 2: proton transfer to A+ •• H O slow CH3 - C-CH2 - H + A - •• OH CH3 - C= CH2 Enol form Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. A- •• CH3 - C-CH3 + keto form fast + •• H O + H- A 11-40 11 Racemization • Racemization at an a-carbon is catalyzed by acid Ph O C C H3 C CH3 H (R)-3-Phenyl-2butanone OH Ph C H3 C Ph O C C CH3 An achiral enol C H CH3 H3 C (S)-3-Phenyl-2butanone 11-41 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Oxidation of Aldehydes • Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents, including chromic acid O CH3 ( CH2 ) 4 CH Hexanal H2 Cr O4 O CH3 ( CH2 ) 4 COH Hexanoic acid 11-42 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Oxidation of Aldehydes • Aldehydes are also oxidized by Ag(I) • in one method, a solution of the aldehyde in aqueous ethanol or THF is shaken with a slurry of silver oxide O CH3 O CH + A g2 O HO Vanillin T HF, H 2 O N aOH HCl H2 O CH3 O O COH + Ag HO Vanillic acid 11-43 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Oxidation of Aldehydes • Tollens’ reagent, another form of Ag(I), is prepared by dissolving silver nitrate in water, adding NaOH to precipitate Ag(I) as Ag2O, and then adding aqueous ammonia to redissolve Ag(I) as a silver-ammonia complex ion + Ag NO3 - + 2 NH3 NH3 , H 2 O Ag(NH 3 ) 2 + NO3 - 11-44 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Oxidation of Aldehydes • Tollens’ reagent oxidizes an aldehyde to a carboxylic anion and silver(1) is reduced to metallic silver • this reaction is used to silver mirrors O RCH + 2 Ag(NH 3 ) 2 + NH3 , H 2 O RCO2 - + 2 Ag + 4 NH3 Precipitates as silver mirror 11-45 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Oxidation of Aldehydes • aldehydes are oxidized by molecular oxygen and by hydrogen peroxide O O 2 CH + O 2 Benzaldehyde 2 COH Benzoic acid • liquid aldehydes are so sensitive to air that they must stored under N2 11-46 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Reduction • An aldehyde can be reduced to a 1° alcohol and a ketone to a 2° alcohol O reduction RCH An aldehyde RCH2 OH A 1° alcohol O reduction RCR' A ketone OH RCHR' A 2° alcohol 11-47 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Catalytic Reduction • Catalytic reductions are generally carried out from 25° to 100°C under 1 to 5 atm H2 O OH + H2 Cyclohexanone Pt 25oC, 2 atm Cyclohexanol 11-48 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Catalytic Reduction • A carbon-carbon double bond may also be reduced under these conditions O CH H C C H3 C H trans-2-Butenal (Crotonaldehyde) 2 H2 Ni CH3 CH2 CH2 CH2 OH 1-Butanol • by careful choice of experimental conditions, it is often possible to selectively reduce a carbon-carbon double in the presence of an aldehyde or ketone 11-49 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Metal Hydride Reduction • The most common laboratory reagents for the reduction of aldehydes and ketones are NaBH4 and LiAlH4 • both reagents are sources of hydride ion, H:-, a very powerful nucleophile H H H Sodium borohydride Li + H- A l- H H Lithium aluminum hydride (LAH) •• + N a H- B- H H Hydride ion 11-50 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 NaBH Reduction 4 • Reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol • one mol of NaBH4 reduces four mol of aldehyde or ketone O 4 RCH + NaBH4 methanol + H2 O 4 RCH2 OH + borate ( RCH 2 O) 4 B Na salts A tetraalkyl borate 11-51 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 NaBH Reduction 4 • the key step in metal hydride reduction is transfer of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound H O + N a H- B- H + R- C-R' H O-BH3 N a+ R- C-R' H from the hydride reducing agent H2 O OH from water R- C-R' H 11-52 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 LiAlH Reduction 4 • Unlike NaBH4, LiAlH4 reacts violently with water, methanol, and other protic solvents • reductions using this reagent are carried out in diethyl ether or tetrahydrofuran (THF) O ether + LiA lH 4 RCR 4 - + ( R2 CH O) 4 A l Li A tetraalkyaluminate H2 O OH 4 RCHR + aluminum salts 11-53 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Metal Hydride Reduction • Metal hydride reducing agents do not normally reduce carbon-carbon double bonds, and selective reduction of C=O or C=C is often possible O 1 . Na BH 4 RCH= CHCR' 2 . H2 O O RCH= CHCR' + H2 Rh OH RCH= CHCH R' O RCH2 CH 2 CR' 11-54 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Reductive Amination • A value of imines is that the carbon-nitrogen double bond can be reduced to a carbon-nitrogen single bond O + Cyclohexanone H2 N H+ -H 2 O Cyclohexylamine H N (An imine) H2 /Ni N Dicyclohexylamine 11-55 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved. 11 Aldehydes & Ketones End Chapter 11 11-56 Copyright © 2000 by John Wiley & Sons, Inc. All rights reserved.