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Preview of Carbonyl Chemistry Kinds of carbonyls 1. Aldehydes and ketones O R C O H R aldehyde -al 2. Carboxylic acid derivatives O C carboxylic acids R OH esters carboxylic acid -oic acid acid chlorides acid anhydrides O C amides R Cl acid chloride nitriles -oyl chloride R R' ketone -one O O R C OR' C O R' lactone cyclic ester O R C R ester -oate O O C R acid anhydride -oic anhydride O O C C N R' R C R'' R C N R' R'' amide -amide N lactam cyclic amide nitrile -nitrile 132 Carbonyl groups have a significant dipole moment O C !- O !+ C O C Aldehyde Ketone Carboxylic acid Acid chloride Ester Amide Nitrile 2.72 D 2.88 1.74 2.72 1.72 3.76 3.90 Water 1.85 Carbonyl carbons are electrophilic sites and can be attacked by nucleophiles 133 67 Chapter 19: Aldehydes and Ketones: Nucleophilic Addition Reactions Recall: Grignard reaction and hydride reduction Chapter 20: Carboxylic Acids and Nitriles Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions O O R C R Y O R Nu + Y: Nu Y :Nu tetrahedral intermediate Y is a leaving group: -Cl (acid chloride), -OR (ester), -NR2 (amide) , -O2CR (anhydride) 134 Chapter 22. Carbonyl Alpha-Substitution Reactions Chapter 23. Carbonyl Condensation Reactions O ! C C O O R' C C C R' C O R' C H C R' E B: E Enolate anion E= alkyl halide or carbonyl compound Chapter 24. Amines Chapter 25. Biomolecules: Carbohydrates H O H C OH HO HO HO HO C H H C OH O HO H C OH OH CH2OH Chapter 26: Biomolecules: Amino Acids, Peptides, and Proteins H2N CO2H Ala H N - H2O + H2N CO2H Val Carboxylic acids + amino group H2N CO2H O Ala - Val amides (peptides & proteins) 135 68 Chapter 27. Biomolecules: Lipids fatty acids, steroids, terpenoids CO2H O HO Aracidonic Acid Cholesterol Camphour Chapter 28: Biomolecules: Heterocycles and Nucleic Acids DNA structure and function, RNA The central dogma: DNA → mRNA → proteins 136 Chapter 19: Aldehydes and Ketones: Nucleophilic Addition Reactions Aldehydes and ketones are characterized by the the carbonyl functional group (C=O) 19.1 Naming Aldehydes and Ketones Aldehydes are named by replacing the terminal -e of the corresponding alkane name with -al The parent chain must contain the -CHO group The -CHO carbon is numbered as C1 If the -CHO group is attached to a ring, name the ring andd add the suffix carboxaldehyde O O H butanal O H 2-ethyl-4-methylpentanal H cyclohexane carboxaldehyde 137 69 Ketones are named by replacing the terminal -e of the alkane name with –one Parent chain is the longest one that contains the ketone group Numbering begins at the end nearer the carbonyl carbon Non systematic names: 138 Ketones and Aldehydes as Substituents The R–C=O as a substituent is an acyl group is used with the suffix -yl from the root of the carboxylic acid The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain 139 70 19.2 Preparation of Aldehydes Oxidation of primary alcohols with pyridinium chlorochromate (PCC) Chapter 17.8 Ozonolysis of an alkene (with at least one =C-H) Chapter 7.8 R1 R2 O3, CH2Cl2 -78 °C R3 O O O R1 R3 R1 R4 electrical discharge 3 O2 Ozone (O3): R2 2 O3 O O R2 R4 O _ R3 O R4 O O R1 Zn R3 + O O R2 R4 + ZnO ozonide molozonide + 1) O3 2) Zn H + O=CH2 O 1) O3 2) Zn O H 140 O Hydroboration of a terminal alkyne (Chapter 8.5) 1) BH3, THF 2) H2O2, NaOH R C C H O R H Reduction of an ester with diisobutylaluminum hydride (DIBAH) - not really a reliable reaction. Reduction of a lactone or nitrile to an aldehyde is much better Al H O R C O [H] O R C OCH3 OCH3 R H C [H] H fast R CH2OH H iBu DIBAL O R C O Al iBu H3O+ R C OCH3 OCH3 O R H C H iBu R C N H DIBAL N R C Al iBu H H3O+ O R C H 141 71 19.2 Preparation of Ketones Oxidation of secondary alcohols with pyridinium chlorochromate (PCC) or chromic acid (Ch. 17.8) Ozonolysis of an alkene (Chapter 7.8) 1) O3 2) Zn + O O Oxymercuration of a terminal alkyne (methyl ketone) (Chapter 8.5) O HgSO , H O 4 R C C H 3 + R CH3 methyl ketone R1 C C R2 -orhydroboration O O HgSO4, H3O+ + R2 R1 R1 R2 142 Friedel-Crafts acylation (aryl ketone) O R C Chapter 16.4 O Cl R AlCl3 Reaction of an acid chloride with a Gilman reagent (diorganocopper lithium, cuprates) Chapter 10.9 ether 2 CH3Li + H3C CuI _ Cu Li+ + LiI H3C Gilman's reagent (dimethylcuprate, dimethylcopper lithium) O R C Cl + (H3C)2CuLi O R C CH3 143 72 19.3 Oxidation of Aldehydes and Ketones Chromic acid (CrO3/H3O+) oxidizes aldehydes to carboxylic acids Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes to carboxylic acids AgO2 NH4OH, H2O O R C H O R C + Ag OH Precipitated Ag(0) forms a silver mirror: chemical test for aldehydes 144 19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones Nucleophiles: Neutral: must have a lone pair of electrons w/ a formal negative charge OH C Nu H-A O O O C C C Nu Nu: H-A Nu-H OH C Nu-H -HOH Nu C :Nu-H 145 73 19.5 Relative Reactivity of Aldehydes and Ketones aldehydes are more reactive toward nucleophilic addition than ketones. In general aromatic aldehydes (benzaldehydes) are less reactive because of resonance with the aromatic ring 19.6 Nucleophilic Addition of H2 O: Hydration Water can reversibly add to the carbonyl carbon of aldehydes and ketones to give 1,1-diols (geminal or gem-diols) R R= H, H R= CH3, H R= (H3C)3C, H R= CH3, CH3 O C + H2O R - H2O OH R C OH R 99.9 % hydrate 50 % 20 % R 0.1 % O C 146 + H2O R - H2O OH R C OH R The rate of hydration is slow, unless catalyzed by acid or base Base-catalyzed mechanism (Fig. 19.4): hydroxide is a better nucleophile than water Acid-catalyzed mechanism (Fig. 19.5): protonated carbonyl is a better electrophile Does adding acid or base change the amount of hydrate? 147 74 The hydration is reversible Hydration is a typical addition reaction of aldehydes and ketones 148 19.7 Nucleophilic Addition of HCN: Cyanohydrin Formation Aldehydes and unhindered ketones react with HCN to give cyanohydrins (mechanism: p. 694) Equilibrium favors cyanohydrin formation O R H C N R' OH pKa ~ 9.2 R C C N R' The nitrile of a cyanohydrin can be reduced to an amine or hydrolyzed (with H3O+) to a carboxylic acid (Ch. 20.9) OH R R' C CH2NH2 LiAlH4 or B2H6 OH R R' C C N OH H3O+ R R' C C OH O 149 75 19.8 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation (also see Chapters 17.6 & 17.5) Preparation of alcohols from ketones and aldehydes MgX O C R-MgX O ether C O C MgX H3O+ OH C R R R: M O M-H O O C C C M H3O+ OH C H H H: Note: the mechanism (arrow pushing) is not much different than for the hydration of carbonyls O O C C H OH OH C OH + :OH OH :OH O C H OH2 OH OH OH C C C :OH2 OH H OH + H3O+ 150 :OH2 19.9 Nucleophilic Addition of Amines: Imine and Enamine Formation Primary amines, RNH2, will add to aldehydes and ketones followed by lose of water to give imines (Schiff bases) Secondary amines, R2NH, react similarly to give enamines, after lose of water and tauromerization (ene + amine = unsaturated amine) 151 76 Mechanism of Formation of Imines Fig. 19.8 Imines are isoelectronic with a carbonyl O H2N O NH-opsin HN H + Lys-opsin N H G-protein coupled receptor retinal + opsin N H h! G-protein Cascade 152 Chapter 19.15: Please read Pyridoxal Phosphate (Vitamin B6) Involved in amino acid biosynthesis, metabolism and catabolism R CO2- H 2 CO2- R NH2 N O OH O3PO - H2O + H2O 2 OH O3PO Imine (Schiff base) N H N H Pyridoxal phosphate dependent enzymes HO CO2 L-DOPA decarboxylase HO NH3 HO NH3 HO Dopamine CO2 NH3 HO N H aromatic amino acid decarboxylase NH3 HO N H Serotonin 153 77 Related C=N derivatives NO2 N OH H N O H2NOH N H N O2N hydroxylamine -H2O NO2 NO2 2,4-dinitrohydrazine -H2O oxime NH2 2,4-dinitrophenylhydrazone Enamine Formation: Mechanism (Fig. 19.10) 154 19.10 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction Reduction of aldehydes and ketones to a methylene group (CH2) with hydrazine (H2NNH2) and base (NaOH) H H N NH2 O H2N-NH2, NaOH H2O -N2 General reduction of ketones and aldehydes to -CH2 O H H H2, Pd/C Chapter 16.11 Limited to aryl ketones H2N-NH2, NaOH, H2O H3CO H3CO H2N-NH2, NaOH, H2O O H H2N-NH2, NaOH, H2O O HO2C CO2H HO2C Mechanism: Fig 19.11 (p. 702), please read CO2H 155 78 19.11 Nucleophilic Addition of Alcohols: Acetal Formation O R C H3CO OCH3 C R R' CH3OH, H+ R' ketone aldehyde + H2O ketal acetal Mechanism of acetal/ketal formation (Fig. 19.12) The mechanism for acetal/ketal formation is reversible How is the direction of the reaction controlled? OH OCH3 NaBH4 O OCH3 O cannot be done directly 156 O OH O keto-ester Chapter 17.5 HOCH2CH2OH, HCl, C6H6 O H3O+ - HOCH2CH2OH - H2O LiAlH4, ether O O O OCH3 OH O 1,3-dioxolane ketal or an ethylene ketal Dean-Stark trap O 1 2 3 6 4 5 O H+ O O O 7 8 9 1 2 1 OH 3 6 4 5 OH 7 H+ 4 8 9 O 2 3 5 6 O 8 7 9 Brevicomin 157 79 19.12 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction 1979 Nobel Prize: Georg Wittig- Wittig Reaction H.C. Brown- Hydroboration The synthesis of an alkene from the reaction of an aldehyde or ketone and a phosphorus ylide (Wittig reagent) A Wittig reagent is prepared from the reaction of an alkyl halide with triphenylphosphine (Ph3P:) to give a phosphonium salt. The protons on the carbon adjacent to phosphorous are acidic. Ph3P H3C Br H3CLi Ph3P CH3 Ph3P CH2 THF Br Ph3P ylide CH2 phosphorane Phosphonium salt Deprotonation of the phosphonium salt with a strong base gives an ylide, a dipolar intermediate with formal opposite charges on adjacent atoms (overall charge neutral). A phosphorane 158 is a neutral resonance structure of the ylide. Wittig reaction O CH2 Ph3P CH3 Br + H3CLi, THF Ph3P=O Accepted Mechanism: (Fig. 19.13) Please read O R1 C R2 + Ph3P O + PPh3 + R3 C R4 R4 R3 R2 R1 betaine ketone or aldehyde R4 R2 C C R3 Ph3P O C C C C + R4 R3 R2 R1 oxaphosphetane (never onserved) Ph3P=O R1 Predicting the geometry (E/Z) of the alkene product is complex and is dependent upon the nature of the ylide. 159 80 The Wittig reaction gives C=C in a defined location, based on the location of the carbonyl group (C=O) The Wittig reaction is highly selective for ketones and aldehydes; esters, lactones, nitriles and amides will not react but are tolerated in the substrate. Acidic groups (alcohols, amine and carboxylic acids) are not tolerated. CH3 CH2 1) CH3MgBr, THF 2) POCl3 + O CH2 + Ph3P CH2 THF 1 : 9 O + O H O PPh3 + O O CHO O O + + Ph3P O O O OCH3 OCH3 O 160 19.13 The Cannizzaro Reaction: Biological Reductions (please read)- not a particularly useful reaction, but mechanistically important O 2 C Ph A redox reaction between two aldehydes catayzed by a strong base O NaOH + H OH C Ph OH + PhCH2OH H OH The aldehyde -H is a source of hydride (carbon hydride); most hydride sources are metal hydrides O O OH C H + Ph Ph C H Nicotinamide coenzyme: Natures (carbon) hydride source H H2N N O N N O O N P OH O R OH O O P O O N OH HO reduced form OH H O NH2 H2N N O N N O O N P OH O R R= H NADH, NAD+ R+ PO32- NADPH, NADP+ OH O O O P O O N NH2 OH HO OH oxidized form 161 81 Alcohols dehydrogenase Enzyme Enzyme H B :B H3C H H H3C C O C O H H H H CONH2 N CONH2 CH3CH2OH N CH3CHO R R NAD NADH Glyceraldehyde-3-phosphate Dehydrogenase (G3PDH) H Csy S O H H H CONH2 H OH CH2PO32- + PO43- N R NAD+ glyceraldehyde-3-phosphate O OPO32- H OH CH2PO32- CONH2 + NADH O O P O O H H CONH2 H O Csy S H N R CONH2 H OH CH2PO32- N R O S Csy H OH CH2PO32- + N R NADH 162 19.14: Conjugate Nucleophilic Addition to α,β -Unsaturated Aldehydes and Ketones α,β -Unsaturated carbonyl have a conjugated C=C R= H, α,β-unsaturated aldehyde= enal 1O "' 3 R≠ H, α,β-unsaturated ketone= enone R 2 4 ! # α,β -unsaturated carbonyls react with nucleophiles at two possible sites: the carbonyl carbon: direct addition or 1,2-addition the β-carbon: conjugate addition, or 1,4-addition 163 82 NOTE: conjugation to the carbonyl activates the β-carbon toward nucleophilic addition. An isolated C=C does not normally react with nucleophiles O R C :Nu C C 1) Nu: 2) H3O+ O R Nu C C H C Nu: C No Reaction Conjugate addition of amines: α,β -unsaturated carbonyls react with primary (RNH2) or secondary (R2NH) amines to give the conjugate addition product R R N C O O C C R C C C + RNH2 R NHR C C H thermodynamically favored 164 Conjugate addition of organocopper (Gilman) reagents α,β -unsaturated ketones react with Gilman reagents to give conjugate addition products (C-C bond forming reaction) Formation of Gilman reagents, R can be alkyl, vinyl or aryl but not alkynyl. R-X 2 Li(0) pentane 2 R2Li + CuI R-Li ether + LiX Dialkylcopper lithium: (H3C)2CuLi Divinylcopper lithium: (H2C=CH)2CuLi R2CuLi + LiI Gilman's reagent (cuprate, organocopper lithium) Diarylcopper lithium: Ar2CuLi Organocopper reagents are primarily used for conjugates addition reactions with α,β-unsaturated ketones; however, they also undergo direct addition to non-conjugated ketones (1,2-additions), aldehydes and will react with alkyl halides and tosylates, and epoxides Mechanism of conjugate addition by organocopper reagents is complex (p. 714, please look over) 165 83 O O H3C (H3C)2CuLi C6H13 C6H13 C6H13 O O O !,"-unsaturated ketone Ph2CuLi H3C H3C H3C CH3 Ph H3C CH3 OH H3C-MgBr C6H13 O O H CH3 α,β-unsaturated aldehydes undergo direct (1,2-) addition with Grignard, organolithium, and organocopper reagents O (H2C=CH)2CuLi O C6H13 H !,"-unsaturated aldehyde O O OH (H3C)2CuLi O -orH3C-Li C6H13 CH3 α,β-unsaturated ketones undergo direct (1,2-) addition with Grignard, and organolithium reagents I O Li+ O CO2Me Li+ RCu Si O O O RO Si CO2Me O Si O CO2H Si O O Si HO 166 OH PGE2 19.16 Spectroscopy of Aldehydes and Ketones Mass spectrometry (p. 718-9, please read) Infrared Spectroscopy: highly diagnostic for carbonyl groups Carbonyls have a strong C=O absorption peak between 1660 - 1770 cm−1 Aldehydes also have two characteristic C–H absorptions around 2720 - 2820 cm−1 167 84 C=O stretches of aliphatic, conjugated, aryl and cyclic carbonyls: O O O aliphatic aldehyde 1730 cm-1 conjugated aldehyde 1705 cm-1 aromatic aldehyde 1705 cm-1 O O H3C H H H O CH3 aliphatic ketone 1715 cm-1 O CH3 CH3 conjugated ketone 1690 cm-1 aromatic ketone 1690 cm-1 O O 1715 cm-1 1750 cm-1 1780 cm-1 O 1815 cm-1 Conjugation moves the C=O absorption to lower energy (right) Ring (angle) strain moves the C=O absorption to higher energy (left) 168 1H NMR Spectra of Aldehydes and Ketones A typical 1H chemical shift for the aldehyde proton is ~ δ 9.8 ppm The aldehyde proton will couple to the protons on the α-carbon with a typical coupling constant of J ≈ 3 Hz A carbonyl will slightly deshield the protons on the α-carbon; typical chemical shift range is δ 2.0 - 2.5 ppm 9.8 (q, J =2.9 Hz) 2.2 (d, J =2.9 Hz) 169 85 O H3C H2C C CH3 δ= 2.5 (2H, q, J = 7.3) 2.1 (3H, s) 1.1 (3H, t, J = 7.3) O H H3C C C C CH2CH3 H δ 7.0 -6.0 δ 2.7 - 1.0 δ= 6.8 (1H, dq, J =15, 7.0) 6.1 (1H, d, J = 15) 2.6 (2H, q, J = 7.4) 1.9 (3H, d, J = 7.0 ) 1.1 (3H, t, J = 7.4) 170 13C NMR: The intensity of the carbonyl resonance in the 13C spectrum usually weak and sometimes not observed. The chemical shift range is diagnostic for the type of carbonyl ketones & aldehydes: carboxylic acids, esters, and amides O δ = ~ 190 - 220 ppm δ = ~ 165 - 185 ppm δ= 220, 38, 23 carbonyl CDCl3 171 86 C9H10O2 IR: 1695 cm-1 NMR: 191 163 130 128 115 65 15 13C 1H 2H d, J= 8.5 2H d, J= 8.5 3H (t, J= 7.5) 2H q, J= 7.5 C10H12O IR: 1710 cm-1 NMR: 207 134 130 128 126 52 37 10 2H (q, J= 7.3) 13C C9H10O 3H (t, J= 7.3) 2H 5H 172 9.8 (1H, t, J =1.5) 7.3 (2H, m) δ 9.7 - 9.9 7.2 (3H, m) 2.9 (2H, t, J = 7.7) δ 7.0 - 7.8 2.7 (2H, dt, J = 7.7, 1.5) δ 3.1 - 2.5 129,128, 125 28 45 201 140 CDCl3 173 87