L TPIC 3. ALDEYDES AND KETNES (Chapters 12 and 16) BJECTIVES 1. Describe the synthesis aldehydes and ketones. 2. Describe the carbonyl group and oxidation-reductions reactions associated with alcohols and carbonyl groups. 3. Describe some the addition reactions of aldehydes and ketones in which nucleophiles add to the electrophilic carbonyl. 4. Describe the mechanisms by which carbonyl groups are transformed to alcohols in C-C bond forming reactions. 5. Describe how C-C bonds can be formed by other reactions of organometallic compounds (not involving the formation of alcohols). 6. Use this knowledge to predict the products of reactions and synthesize complex compounds using these procedures. CEM2312: Spring 2009
ALDEYDES AND KETNES S:12.1; 16.1-3 Prob:16.23 R 1 C R2 R C ketone, R 1 or R 2 = alkyl, aryl or alkenyl aldehyde, R =, alkyl, aryl or alkenyl Carbonyls are electrophilic C Carbonyls are weakly basic; protonation makes the carbonyl more electrophilic C A C Nomenclature R 1 C R2 R C alkane #-alkanone or alkyl alkylketone alkane C 3 alkanal CEM2312: Spring 2009
Physical Properties The carbonyl group has a permanent dipole moment and is therefore much more polar than a hydrocarbon, but less polar than an alcohol Boiling point 0 49 56 97 MW 58 58 58 60 Sol. in water nil 20 miscible miscible g/100 ml XIDATINS AND REDUCTINS IN RGANIC CEMISTRY xidation-reduction Reactions in rganic Chemistry Reduction - adding electrons, more hydrogens, less oxygen xidation - removing electrons, less hydrogens, more oxygen S:12.2,4 Prob:12.14;16.27,29a,30a,b Calculating xidation State of Carbon Atoms in rganic Molecules The oxidation state of a carbon balances the contributions from each of the bonds to its substituents: = +1 and other electronegative atoms = -1 C = 0 R C [] [] R C [] [] R C [] [] R C CEM2312: Spring 2009
xidation of Alcohols (-1 +1 +3) R C [] R C R [] R R C R [] Strong xidants R C 2 1. KMn 4,K, 2 2. 3 + or Na 2 Cr 2 7, 2 S 4, 2 R C R C 2 CEM2312: Spring 2009
Chemical Tests for Functional Groups The molecular formula indicates one site of unsaturation. Is it a ring, or an alkene? Alkenes decolorize bromine Br 2 in CCl 3 Infrared spectroscopy indicates the presence of an alcohol (strong, broad absorption at 3500 cm -1 ). But what type of alcohol is it? 1 and 2 alcohols give a positive test with Jones reagent Na 2 Cr 2 7, 2 S 4 in 2 (orange = Cr (VII) ) alkane alkene alkane Decolorization alkene 1 or 2 alcohol Green solution (Cr (III) ) 1 or 2 alcohol xidation of 1 Alcohols with Mild xidants PCC R C 2 C 2 Cl 2 PCC=pyridinium chlorochromate + N Cr 3 Cl - PCC C 2 Cl 2 PCC C 2 Cl 2 CEM2312: Spring 2009
Reduction (+3 +1-1) Reduction with LiAl 4 or NaB 4 1. LiAl 4 R C 2. 2 R () or aldehyde or ketone 1. NaB 4 2. 2 R C R Al R C 1. LiAl 4 R' 2. () 2 acid or ester via R C R' () 1. NaB 4 2. 2 Reduction of Carboxylic Acid Derivatives with Mild Reducing Agents R C Cl R C Me 1. LiAl(t-Bu) 3-78 o C 2. 2 1. DIBAL- -78 o C 2. 2 LiAl(t-Bu) 3 : Li -t-bu Al -t-bu -t-bu DIBAL-: Al CEM2312: Spring 2009
L SYNTESIS F ALDEYDES S:16.4 xidation of 1 Alcohols PCC C 2 Reduction of Acid Derivatives Cl 1. LiAl(t-Bu) 3-78 o C 2. 2 Me 1. DIBAL- -78 o C 2. 2 SYNTESIS F KETNES S:16.5 xidation of 2 Alcohols Review: zonolysis of Alkenes 1. KMn 4, K, 2 2. 3 + 1. 3 2. Zn, Ac ydration of Alkynes gs 4 2 S 4 Friedel-Crafts acylation C 3 CCl 3 C AlCl 3 CEM2312: Spring 2009
Problem - Provide a synthesis of 3-hexanone from starting materials with three of fewer carbon atoms.? Problem - Provide a synthesis of cyclohexanone from cyclohexane? CEM2312: Spring 2009
XIDATIN F ALDEYDES AND KETNES xidation of Aldehydes 1. KMn 4,K, 2 2. 3 + or Na 2 Cr 2 7, 2 S 4, 2 Ag 2 is a selective oxidant for aldehydes, avoids use of strong acid or base Ag 2 Na 2 S:16.11,12 Prob:16.24,28,31 + AgN 3 Na N 3, 2 + Ag CEM2312: Spring 2009
Chemical Tests for Functional Groups Infrared spectroscopy indicates the presence of an aldehyde or ketone (strong, sharp absorption at ca. 1720 cm -1 ). Is the compound an aldehyde, or a ketone? aldehydes give positive Tollen s test (silver mirror) AgN 3, N 3, Na in 2 ketone aldehyde ketone silver mirror aldehyde xidation of Ketones xidation with peracids: The Baeyer-Villiger reaction RC 3 R 1 R 2 R 1 R 2 R 1 R 2 RC 3 R R RC 3 C 3 C Ph Migratory aptitude: Ph > 3 > 2 > 1 > Me CEM2312: Spring 2009
REDUCTIN F ALDEYDES AND KETNES S:12.3 Aldehydes R C Ketones R C R' 1. LiAl 4 or NaB 4 2. 2 1. LiAl 4 or NaB 4 2. 2 R C R C R' NUCLEPILIC ADDITIN REACTINS F ALDEYDES AND KETNES S:16.6 S:12.1B General reaction δ δ+ : Nu Examples 3 C C 3 3 C 3 C CEM2312: Spring 2009
? Prob:16.27,29a,30a,b?? Prob: 12.4,14; 16.23?? CEM2312: Spring 2009
L XYGEN NUCLEPILES: ADDITIN F WATER AND ALCLS Structure R 1 C R 2 R 1 C R 2 R R 1 R C R 2 R hydrate hemiacetal acetal R 1 or R 2 = or alkyl S:16.7 Prob: 16.48 ydrates Example 2 Cl 3 C Mechanism of base catalyzed reaction Base catalysis increases the nucleophilicity of the nucleophile 2 B B CEM2312: Spring 2009
Mechanism of acid catalyzed reaction Base catalysis increases the nucleophilicity of the nucleophile 2 A 3 A 3 2 2 Relative Reactivity (Electrophilicity) of Aldehydes and Ketones Equilibrium constants for ydrate Formation X Y X 2 K eq Y X K eq Y % hydrate at equilibrium 41 99.96 C 3 1.8 x 10-2 50 C(C 3 ) 3 4.1 x 10-3 19 C 3 C 3 2.5 x 10-5 0.14 CF 3 CF 3 22,000 99.9996 Data: 1 M carbonyl compound dissolved in 2 CEM2312: Spring 2009
Electronic factors Inductive electron donating groups decrease electrophilicity of carbonyl (and visa versa) R 1 δ C R2 δ+ R C R R C R C CF 3 Steric factors Bulky groups hinder attack of nucleophile and cause steric crowding in product R 1 C R2 + Nu R 1 R 2 C Nu sp 2, 120 sp 3, 109.5 emiacetals Example: Glucose C 2 C aldehyde form acid or C 2 base catalyzed hemiacetal form Formation: Base-catalyzed reaction R B R B R CEM2312: Spring 2009
Formation: Acid-catalyzed reaction R 2 S 4 R Problem: Draw the mechanism for the acid-catalyzed formation of an hemiacetal (this is analogous to the acid-catalyzed hydration) Acetals Examples + 2 + + + nly formed under acidic conditions CEM2312: Spring 2009
Mechanism for formation of acetals C C R C R hemiacetal R R C R R 1 C R 2 R All steps are reversible must remove 2 to drive reaction to completion. Sucrose (Sugar) A disaccharide C 2 C 2 C2 glucose fructose C 2 C 2 C2 CEM2312: Spring 2009
ydrolysis of Acetals: Mechanism for the REVERSE reaction C 3 C 3 2 C 3 + 2 proton n deproton n C 3 C 3 Nu attack 3 C C 3 C 3 Nu attack C 3 deproton n proton n dissoc n Principle of microscopic reversibility: Forward and back reactions take place via the same intermediates and transition states. Problem [Solomons 16.46] - Multistriatin is an aggregating pheromone of the European elm bark beetle, the vector of Dutch elm? disease. Multistriatin is an acetal. What is the product of hydrolysis of multistriatin formed upon treatment with aqueous acid? 3 + CEM2312: Spring 2009
NITRGEN NUCLEPILES: ADDITIN-ELIMINATIN S:16.8 Prob:16.24 Addition-elimination of 1º Amines R 1 R 2 ketone or aldehyde + R N 2-2 N R R 1 R 2 imine - E and Z isomers possible Mechanism Acid or base catalyzed, but requires careful control of p R N 2 + 3 R N 3 + 2 nucleophilic not nucleophilic + 3 + 2 less electrophilic more electrophilic 2 N R CEM2312: Spring 2009
Examples R R C R'() C R'() + C 3 N 2 1 o amine + N 2 hydroxylamine R C R'() + 2 N N 2 hydrazine R N 2 C + R'() N 2 N N 2 2,4-dinitrophenyl hydrazine Chemical Tests for Functional Groups Aldehydes and ketones give positive 2,4-DNP test 2,4-DNP in Et aldehyde or ketone organge ppt (hydrazone) aldehyde or ketone CEM2312: Spring 2009
L CARBN NUCLEPILES: ADDITIN F YDRGEN CYANIDE General Reaction R C R' + CN S:16.9 Example + CN RGANMETALLIC CMPUNDS AS NUCLEPILES S:12.5 rganometallic Compounds Examples: RMgal RLi RC CNa RZnal R 2 CuLi 2.5 1.2 2.5 1.0 2.5 1.0 2.5 1.7 2.5 1.8 C-Mg C-Li C-Na C-Zn C-Cu Contrast reactivity: C- C-Br C-M CEM2312: Spring 2009
RGANLITIUM AND RGANMAGNESIUM CMPUNDS S:12.6 Preparation: alogen-metal Exchange R-X + R-X + R-X + 2 Li Mg Zn I > Br > Cl >> F solvent is usually Et 2 or (TF) δ+ Ph-Mg-X δ Grignard and Lithium Reagents as Bases S:12.7 Prob:12.12 C 3 MgBr + C 3 C 2 Li + C 3 C 2 Li + C C C 3 CEM2312: Spring 2009
Grignard And Lithium Reagents React with Epoxides Nucleophilic Ring opening of Epoxides (example from rganic-i).. :.. C 3 rganometallics as Nucleophiles Ph MgBr C 3 C 3 Li C 3 RMgX and RLi do not undergo S N reactions with alkyl halides Br + 3 C Li C 3 LiBr CEM2312: Spring 2009
Lithium, Magnesium and Sodium Reagents Add to Carbonyl Groups S:12.8C-D Prob:12.12,19,20,21,24 3 C MgBr 2 Ph MgCl 2 3 C Li Ph 2 Ph Na C 3 2 Problem - Identify the structures of compounds A-E in the following scheme. 2 Cr 4 acetone 1. C 3 MgBr A, C 6 10 B, C 7 14 C, C 7 12 2. 2 2 S 4? 1. Ag 2, - E, C 7 12 3 D, C 7 12 2 2. 3 + 1. 3 2. Zn, Ac CEM2312: Spring 2009
Designing rganic Synthesis: Retroanalysis ow would you make 3 C Ph 1. Locate the hydroxyl-bearing carbon. This carbon must have been part of the C= group in the starting material? Ph 3 C C S:12.8A 2. "Disconnect" one of the substituents attached to the carbon bearing the hydroxyl group Ph 3 C C 3. These steps reveal the carbonyl-containing substrate and the Grignard (nucleophilic) component 3 C C Ph MgX 4. Check that you can indeed perform the forward reaction! ther ways to disconnect bonds in a Grignard alcohol synthesis 3 C C Ph Ph 3 C C CEM2312: Spring 2009
Preparation of 1 Alcohols formaldehyde 1. R-MgBr 2. 2 1. R-MgBr ethylene oxide 2. 2 Preparation of 2 Alcohols 1. R-MgBr R aldehyde 2. 2 Preparation of 3 Alcohols R' R'' ketone 1. R-MgBr 2. 2 CEM2312: Spring 2009
Problem - Propose a synthesis of 2-methyl-2-hexanol from starting materials with four or fewer carbon atoms?? Prob:12.12,19,20,21,24? CEM2312: Spring 2009
Restrictions on the use of Grignard, Lithium and Sodium Reagents S:12.8B Lithium, magnesium and sodium reagents are very reactive as nucleophiles and bases, limiting other functional groups in these reagents 3 C MgBr Ph MgCl 3 C Li Ph Na Magnesium Lithium Sodium Will react with the following functional groups. This means that we can not prepare them from any starting material containing these funtional groups. N 2 NR C 2 S 3 S C C N 2 C N C CR CR CNR 2 Protecting Groups in Synthesis S:12.10 ow would you achieve the following transformation? Br CEM2312: Spring 2009
L Problem: ow would you make the following 2 alcohol? Ph RGANZINC CMPUNDS: TE REFRMATSKY REACTIN C 2 Et Ph S:16.11 Prob:16.32 Grignard and lithium reagents react with esters! Solution: rganozinc reagents do not react with esters Br 1. Zn, benzene + Ph C 2 Et 2. water via: Why are esters less electrophilic than ketones? LITIUM DIAKLYCUPRATES IN CUPLING REACTINS Problem: Grignard and lithium reagents are strongly basic and promote elimination reactions with alkyl halides, e.g. RLi Br S:12.9 Prob:12.17 Solution: Use dialkylcuprates they are much less basic, but still nucleophilic 3 C Cu Li C 3 CEM2312: Spring 2009
Preparation of cuprates R-X + 2Li RLi + LiX 2RLi + CuI LiI + R 2 CuLi - "Lithium dialkyl cuprate" 3 C Li Cu I R'-X + R 2 CuLi R -X: R =Me, 1, 2, vinylic, phenyl R 2 CuCl: R=Me, 1, 2, 3, Comparison of reactions of alkyl halides with dialkylcuprates and alkyllithium reagents Br + C 3 Li Br + (C 3 ) 2 CuLi CEM2312: Spring 2009
Reactions of cuprates with sp 2 C-halides Vinyl halides Br + Et 2 CuLi Aryl halides I + Bu 2 CuLi? Prob: 16.32,12.17?? CEM2312: Spring 2009
ADDITIN F YLIDES T ALDEYDES AND KETNES: TE WITTIG REACTIN What is an ylide? S:16.10 Prob:16. 26, 39,50 C Y carbanion next to a positively charged heteroatom, most often phosphorous Preparation of phosphonium ylides ()R C Br R() PPh 3 Wittig Reaction: General Reaction R 1 R 2 + Example (Ph) 3 P R 3 R 4 + (Ph) 3 P C 3 CEM2312: Spring 2009
Mechanism of Wittig Reaction C C PPh 3 Alternate method - use of a phosphonate ester C 2 P Et Na C P Et Et Na Et + C P Et Na Et CEM2312: Spring 2009
Planning a Wittig Synthesis of an Alkene There are always two possible routes to make an alkene by Wittig chemistry. ow could you make 2-methyl-2-heptene? C 8 disconnect C 5 C 3 here Either C 5 or C 3 can be the carbonyl or ylide 3 C C 3 + P(Ph) 3 + 3 C C 3 P(Ph) 3 Problem [Solomons 16.39] - The sex attractant of the female tsetse fly can be prepared by the following route. Identify compounds A-C. 1. 2 eq. Ph 3 P BrC 2 (C 2 ) 7 C 2 Br 2. 2 eq. BuLi? A, C 45 46 P 2 C, C 37 76 C 3 (C 2 ) 11 C 3 2 /Pt B, C 37 72 http://entomology.unl.edu/history_bug/gallery/tsetse_drawing.htm CEM2312: Spring 2009
ther Reactions of rganometallic Reagents (covered later): RMgX + C 2 RMgX + ester RMgX + RCN RCu, R 2 CuLi + RCCl SPECTRSCPIC PRPERTIES F ALDEYDES AND KETNES Compound A: contains C,, Br and M + =184 and 186 S:16.13 Prob:16.41-44? positive Tollen s test IR 1690cm -1 1 NMR singlet at δ 10.1, doublets at 8.1 and 7.5 ppm. CEM2312: Spring 2009
Empirical Formula: C 5 10 2 Mass Spec: M + m/e= 102 IR 100 2 transmittance 50 0 4000 3000 2000 1500 1000 500 Wavenumber / cm -1 13 C NMR 1 NMR? Prob: 16.24,26,28,31,39,41-44,50?? CEM2312: Spring 2009
REVIEW F CARBNYL CEMISTRY: REACTINS AND MULTISTEP SYNTESIS S:16.14 Prob:16.50 Reactions xidation and Reduction R C [] [] R C [] [] R C [] [] R C Nucleophilic addition R 1 R 2 + Nu R 1 R 2 Nu Nucleophilic addition - Elimination R 1 R 2 + Nu Nu R 1 R 2 R-N 2 R 3 P-CR CEM2312: Spring 2009
Synthesis Problem - ow would you prepare mestanaol, a components of modern birth control pills, using organometllic addition to carbonyl groups? C 3 C C? C 3 Mestanaol an estrogen analog used in oral contraceptives Problem: ow could you make 2-phenyl-2-butanol from benzene and any other starting materials with two or fewer carbon atoms.? CEM2312: Spring 2009
Problem: ow could you make 1,4-diphenylbutane from PhC 2 C 2 C? 3 Ph Ph C 3 Ph Problem: ow could you make 1,3-diphenylpropanone from benzene? Ph Ph CEM2312: Spring 2009
Problem: ow could you make 1-phenyl1-butene from benzene?? Problem: ow could you prepare the following two alcohols from 2- propanol?? CEM2312: Spring 2009
TPIC 3 N EXAM 3 Types of Questions - Predict the products obtained from given starting materials, - Rationalize the outcome of a reaction (i.e., propose a mechanism, draw key intermediates) - Develop multistep synthetic strategies. Do the problems in the book; they are great examples of the types of problems on the exam! Preparing for Exam 3 - Get up-to-date NW! - Work as many problems as possible. Do the problems first, then consult the solutions manual. - Work in groups, discuss chemistry, teach and test each other. - Do the Learning Group Problem at the end of the chapter. CEM2312: Spring 2009