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Chapter 13: Aldehydes and Ketones Sections 13.1-13.8 Chemistry 2060, Spring 2060, LSU 13-1 Sections Chapter 13: Aldehydes and Ketones 1. 2. 3. 4. 5. 6. 7. 8. Introduction Structure and bonding Nomenclature Physical properties Reactions Addition of Grignard Reagents Addition of alcohols Addition of ammonia and amines Chemistry 2060, Spring 2060, LSU 13-2 The Carbonyl Group In this and several following chapters, we study the physical and chemical properties of classes of compounds containing the carbonyl group, C=O • aldehydes and ketones (Chapter 13) • carboxylic acids (Chapter 14) • acid halides, acid anhydrides, esters, amides (Chapter 15) • enolate anions (Chapter 16) Chemistry 2060, Spring 2060, LSU 13-3 Structure • the functional group of an aldehyde is a carbonyl group bonded to a H atom • the functional group of a ketone is a carbonyl group bonded to two carbon atoms O HCH Methanal (Formaldehyde) Chemistry 2060, Spring 2060, LSU O CH3 CH Ethanal (Acetaldehyde) O CH3 CCH3 Propanone (Acetone) 13-4 Nomenclature IUPAC names: • the parent chain is the longest chain that contains the carbonyl group • for an aldehyde, change the suffix from -e to -al • for an unsaturated aldehyde, show the carbon-carbon double bond by changing the infix from -an- to -en-; the location of the suffix determines the numbering pattern • for a cyclic molecule in which -CHO is bonded to the ring, add the suffix -carbaldehyde Chemistry 2060, Spring 2060, LSU 13-5 Nomenclature O O 3 4 O 1 1 3 H 2 2 3-Methylbutan al HO Cyclopen tanecarb aldehyde O 5-Methyl-3h exanone Chemistry 2060, Spring 2060, LSU H 8 4 6 3 4 1 H 2 (2E)-3,7-D imeth yl-2,6-octad ienal (Geran ial) 2-Propen al (A crolein ) CHO 5 7 1 CHO trans -4-Hyd roxycyclohexan ecarbald ehyde O 2-Methylcycloh exanone O Acetop hen on e O Benzoph enone 13-6 Nomenclature Functional Grou p Su ffix Carb oxyl -oic acid Ald ehyde -al Prefix Example of When the Fun ction al Grou p Has a Low er Priority O oxo- 3-Oxopropan oic acid COOH H O COOH Ketone -one oxo- 3-Oxobutanoic acid Alcoh ol -ol hydroxy- Amino -amine amino- COOH 4-Hydroxybutan oic acid HO NH2 COOH 3-Aminobutan oic acid Su lfh ydryl -thiol Chemistry 2060, Spring 2060, LSU mercapto- 2-Mercaptoethanol HS OH 13-7 Nomenclature Common names • for an aldehyde, the common name is derived from the common name of the corresponding carboxylic acid • for a ketone, name the two alkyl or aryl groups bonded to the carbonyl carbon and add the word ketone O H H Formaldehyde O O H OH Formic acid H Acetaldehyde O Ethyl is opropyl ketone Chemistry 2060, Spring 2060, LSU O OH Acetic acid O O Diethyl ketone Dicyclohexyl ketone 13-8 Physical Properties Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a C=O group is polar O Polarity of a carbonyl group : C C O: + C : : + - O: – More important contributing structure • aldehydes and ketones are polar compounds and interact in the pure state by dipole-dipole interactions • they have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight Chemistry 2060, Spring 2060, LSU 13-9 Reactions The most common reaction theme of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound : :O : R + C R O: : N u: - Nu - C R R Tetrahedral carbonyl addition compound Chemistry 2060, Spring 2060, LSU 13-10 Grignard Reagents 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 • Grignard reagents have the general formula RMgX, where R is an alkl or aryl group and X is a halogen Chemistry 2060, Spring 2060, LSU 13-11 Grignard Reagents Grignard reagents are prepared by adding an alkyl or aryl halide to a suspension of Mg metal in diethyl ether Br + Mg eth er 1-Bromobutane Br + Mg Bromoben zene Chemistry 2060, Spring 2060, LSU MgBr Butylmagn esium bromide eth er MgBr Phenylmagn esium bromide 13-12 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+ • in its reactions, a Grignard reagent behaves as a carbanion Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge • a carbanion is a good nucleophile and adds to the carbonyl group of aldehydes and ketones Chemistry 2060, Spring 2060, LSU 13-13 Grignard Reagents Reaction with protic acids • Grignard reagents are very strong bases and react with proton acids to form alkanes - + CH3 CH2 - MgBr + H-OH p Ka 15.7 Stronger Stron ger bas e acid CH3 CH2 -H + Mg 2+ + OH- + BrpK a 51 Weaker Weaker acid base • any compound containing an O-H, N-H, or S-H group reacts with a Grignard reagent by proton transfer HOH Water ROH Alcoh ols Chemistry 2060, Spring 2060, LSU ArOH Phenols RCOOH Carboxylic acids RNH2 Amines RSH Thiols 13-14 Grignard Reagents • reaction with formaldehyde gives a 1° alcohol O eth er CH3 CH2 -MgBr + H-C-H Formaldeh yd e O [MgBr]+ HCl CH3 CH2 -CH2 H2 O A magnes ium alkoxide OH CH3 CH2 -CH2 + Mg 2+ 1-Propanol (a 1° alcoh ol) • reaction with any aldehyde other than formaldehyde gives a 2° alcohol O Ph MgBr + CH3 -C-H eth er Acetaldeh yd e Chemistry 2060, Spring 2060, LSU O [MgBr] Ph CHCH3 A magnes ium alk oxid e + HCl H2 O OH Ph CHCH3 + Mg 2+ 1-Ph enyleth anol (a 2° alcohol) 13-15 Grignard Reagents • reaction with a ketone gives a 3° alcohol O [ MgBr] + O Ph MgBr + CH3 -C-CH3 Acetone eth er Ph CCH3 CH3 A magnes ium alkoxide HCl H2 O OH Ph CCH3 CH3 + Mg 2+ 2-Phen yl-2-propanol (a 3° alcoh ol) • problem: show how to synthesize this 3° alcohol by three different routes OH C-CH2 CH3 CH3 Chemistry 2060, Spring 2060, LSU 13-16 Addition of Alcohols Hemiacetal: a molecule containing an -OH group and an -OR group bonded to the same carbon H O CH3 CCH3 + OCH2 CH3 OH CH3 C-OCH2 CH3 CH3 A h emiacetal H+ • hemiacetals are minor components of an equilibrium mixture except where a 5- or 6-membered ring can form 5 3 4 O 2 1 H OH 4-Hydroxyp entanal Chemistry 2060, Spring 2060, LSU redraw to show th e OH close to th e CHO grou p 3 5 4 2 O H 1 3 H O 5 2 4 O 1 OH A cyclic h emiacetal (major form presen t at eq uilibrium) 13-17 Addition of Alcohols Acetal: a molecule containing two -OR groups bonded to the same carbon OH CH3 C-OCH2 CH3 + CH3 CH2 OH CH3 A hemiacetal H OCH2 CH3 + CH3 C-OCH2 CH3 + H2 O CH3 A diethyl acetal O H OH 4-Hydroxypentan al Chemistry 2060, Spring 2060, LSU O OH CH3 OH + H O OCH3 + H2 O A cy clic acetal 13-18 Acetal Formation 1. Proton transfer from HA to the hemiacetal oxygen + H O H R-C-OCH3 + A HO R-C-OCH3 + H A H An oxonium ion H 2. Loss of H2O gives a cation + H O H R-C-OCH3 H Chemistry 2060, Spring 2060, LSU + R-C OCH3 + R-C OCH3 + H2 O H H A resonan ce-stabilized cation 13-19 Acetal Formation 3. reaction of the cation (an electrophile) with an alcohol (a nucleophile) H + CH3 -O + R-C OCH3 H + H O CH3 R-C-OCH3 H A p rotonated acetal 4. proton transfer to A- gives the acetal and regenerates the acid catalyst + H O CH3 O CH3 HA + R-C-OCH3 + R-C-OCH3 A H H A p rotonated acetal An acetal Chemistry 2060, Spring 2060, LSU 13-20 Acetals Draw a structural formula for the acetal formed in each reaction (a) OH O + HO Eth ylen e glycol OH (b) O + H2 SO4 H2 SO4 OH Chemistry 2060, Spring 2060, LSU 13-21 Acetals as Protecting Groups • one way to synthesize the ketoalcohol on the right is by a Grignard reaction O Ph O H + Benzaldehyde Br H 4-Bromobutanal OH ?? O Ph H 5-Hydroxy-5-phenylpentanal • but first the aldehyde of the bromoaldehyde must be protected; one possibility is as a cyclic acetal O Br Chemistry 2060, Spring 2060, LSU H + OH HO Eth ylene glycol H O + Br + H2 O O A cyclic acetal 13-22 An Acetal as a Protecting Group • now the Grignard reagent can be prepared and the new carbon-carbon bond formed O O Br O A cyclic acetal O Ph BrMg + Mg ether O A Grignard reagent - H + BrMg O MgBr O + O O Ph A magnesiu m alk oxid e O • hydrolysis gives the hydroxyaldehyde - + O MgBr Ph Chemistry 2060, Spring 2060, LSU OH O O HCl, H2 O Ph O H + HO OH 13-23 Imines Imine: a compound containing a C=N bond; also called a Schiff base • formed by the reaction of an aldehyde or ketone with ammonia or a 1° amine O + H+ NH3 Cycloh exanone A mmonia O Chemistry 2060, Spring 2060, LSU An imine + CH3 CH + H2 N Ethanal NH + H2 O Aniline H CH3 CH=N + H2 O An imine 13-24 Imines 1. addition of the amine to the carbonyl carbon followed by proton transfer O C + H2 N-R O- H + C N-R H O H N-R H A tetrah edral carb on yl ad dition intermediate C 2. two proton-transfer reactions and loss of H2O H + O H + O H C H N-R H H + H O C H C N-R + H2 O + H O H N-R H O H An imine H Chemistry 2060, Spring 2060, LSU 13-25 Rhodopsin • reaction of vitamin A aldehyde (retinal) with an amino group on the protein opsin gives rhodopsin 11 12 + H2 N-Opsin 11-cis -Retinal H C=O Rhodopsin (Vis ual purple) Chemistry 2060, Spring 2060, LSU H C= N-Opsin 13-26 Reductive Amination Reductive amination: the formation of an imine followed by its reduction to an amine + O + H2 N Cyclohexanone Cyclohexylamine (a 1° amine) H -H2 O N H2 / Ni An imine (n ot isolated) H N D icyclohexylamin e (a 2° amine) • reductive amination is a valuable method for the conversion of ammonia to a 1° amine, and a 1° amine to a 2° amine Chemistry 2060, Spring 2060, LSU 13-27 Keto-Enol Tautomerism Enol: a molecule containing an -OH group on a carbon-carbon double bond of an alkene O CH3 -C-CH3 Acetone (keto form) the keto form predominates for most simple aldehydes and ketones Chemistry 2060, Spring 2060, LSU Keto form O CH3 CH O CH3 CCH3 O OH CH3 -C=CH2 Aceton e (enol form) % En ol at Enol form Equilib rium OH CH2 =CH 6 x 10 OH CH3 C=CH2 6 x 10 -5 -7 OH 4 x 10-5 13-28 Keto-Enol Tautomerism • Problem: draw two enol forms for each ketone O O (b) (a) • Problem: draw the keto form of each enol O OH CHOH (a) (b) OH (c) OH Chemistry 2060, Spring 2060, LSU 13-29 Keto-Enol Tautomerism Interconversion of keto and enol forms is catalyzed by both acid and base • following is a mechanism for acid catalysis 1. proton transfer to the carbonyl oxygen + •• H O • • •• O + H-A CH3 -C-CH3 + Th e conjugate acid of th e keton e A- • • CH3 -C-CH3 Keto form fast 2. proton transfer from the a-carbon to A:+•• H O • • Chemistry 2060, Spring 2060, LSU + • • CH3 -C-CH2 -H •• - A slow OH CH3 -C=CH2 + H-A En ol form 13-30 Racemization an at a-Carbon when an enantiomerically pure aldehyde or ketone with at least one a-hydrogen is treated with a trace of acid or base, it gradually becomes a racemic mixture; it loses all optical activity Ph O C C H C - or OH H3 C CH3 H (R)-3-Phenyl-2butanone Chemistry 2060, Spring 2060, LSU OH Ph + H3 C C CH3 An ach iral en ol H + or OH- Ph O C C H CH3 H3 C (S)-3-Ph enyl-2b utanone 13-31 a-Halogenation Aldehydes and ketones with an a-hydrogen react with Br2 and Cl2 to give an a-haloaldehyde or an a-haloketone O O + Br2 A cetophenone Chemistry 2060, Spring 2060, LSU CH3 COOH Br + HBr a-Bromoacetophen on e 13-32 a-Halogenation the key intermediate in a-halogenation is an enol 1. formation of the enol OH O H+ Keto form En ol form 2. nucleophilic attack of the enol on the halogen H O O + Br Br Chemistry 2060, Spring 2060, LSU Br + H-Br 13-33 a-Halogenation A value of a-halogenation is that the carbon adjacent to the aldehyde or ketone now bears a good leaving group and is susceptible to nucleophilic attack O O Br N + H N A n a-bromok eton e Chemistry 2060, Spring 2060, LSU Diethylamine + HBr An a-dieth ylaminoketone 13-34 Oxidation Aldehydes are one of the most easily oxidized of all functional groups CHO H2 CrO4 Hexan al MeO HO Van illin Hexanoic acid CHO + Ag2 O THF, H2 O NaOH 2 CHO + O2 Benzald ehyde Chemistry 2060, Spring 2060, LSU COOH HCl H2 O 2 COOH + Ag MeO HO V anillic acid COOH Benzoic acid 13-35 Oxidation Ketones are not normally oxidized by H2CrO4; in fact this reagent is used to oxidize 2° alcohols to ketones • they are oxidized by HNO3 at higher temperatures • oxidation is via the enol O OH O HNO3 HO OH O Cycloh exanone (k eto form) Cyclohexan one (enol form) Hexan edioic acid (Ad ipic acid ) • adipic acid is one of the starting materials for the synthesis of nylon 66 Chemistry 2060, Spring 2060, LSU 13-36 Reduction • aldehydes can be reduced to 1° alcohols • ketones can be reduced to 2° alcohols O R-CH A n aldehyde reduction R-CH2 OH A p rimary alcohol O OH reduction R-C-R' R-CH-R' A second ary A k eton e alcohol Chemistry 2060, Spring 2060, LSU 13-37 Catalytic Reduction Catalytic reductions are generally carried out from 25° to 100°C and 1 to 5 atm H2 OH O + H2 Pt 25 o C, 2 atm Cyclohexanone Cyclohexanol • a carbon-carbon double bond may also be reduced under these conditions O H trans- 2-Butenal (Crotonaldehyde) Chemistry 2060, Spring 2060, LSU 2 H2 Ni OH 1-Butanol 13-38 Metal Hydride Reductions 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 strong nucleophile H Na + H- B- H H Sodium borohydride Chemistry 2060, Spring 2060, LSU H Li + H- A l- H H Lithium aluminum hydride (LAH) H: Hydride ion 13-39 NaBH4 Reductions • reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol • one mole of NaBH4 reduces four moles of aldehyde or ketone O 4 RCH + NaBH4 methanol - + ( RCH2 O) 4 B Na A tetraalkyl borate Chemistry 2060, Spring 2060, LSU H2 O 4 RCH2 OH + borate salts 13-40 NaBH4 Reductions • the key step in metal hydride reductions is transfer of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound H O + Na H-B-H + R-C-R' H O BH3 Na + R-C-R' H from the hydride reducing agent H2 O from w ater O-H R-C-R' H Chemistry 2060, Spring 2060, LSU 13-41 Metal Hydride Reductions • 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 RCH= CHCR' 1 . Na BH 4 2 . H2 O O RCH= CHCR' Chemistry 2060, Spring 2060, LSU + H2 Rh OH RCH= CHCH R' O RCH2 CH 2 CR' 13-42 Aldehydes and Ketones End Chapter 13 Chemistry 2060, Spring 2060, LSU 13-43