DAT/OAT Organic Chemistry Outlines PDF

DAT / OAT ORGANIC CHEMISTRY OUTLINES Table of Contents 1 – Bonding & Molecular Geometry Page 1 2 – Acid & Bases & Introduction to Organic Reactions Page 3 3 - Nomenclature Page 6 4 - Stereochemistr...

DAT / OAT ORGANIC CHEMISTRY OUTLINES Table of Contents 1 – Bonding & Molecular Geometry Page 1 2 – Acid & Bases & Introduction to Organic Reactions Page 3 3 - Nomenclature Page 6 4 - Stereochemistry Page 10 5 – Intermolecular Forces and Laboratory Techniques Page 12 6 – Spectroscopy Page 15 7 – Alkenes & Alkynes Page 19 8 - Substitution and Elimination Reactions Page 22 9 - Free Radical Halogenation & Diels-Alder Reactions Page 25 10 - Aromatic Compounds Page 28 11 - Alcohols, Ethers, and Epoxides Page 31 12 - Aldehydes and Ketones Page 34 13 - Carboxylic Acids and Acid Derivatives Page 37 14 - Alpha Substitution Reactions of Carbonyl Compounds Page 40 15 - Amines Page 44 COMPLETE SUMMARY OF ORGANIC REACTIONS Page 46 ChadsPrep.com 0  1 - Bonding & Molecular Geometry Bonding and Molecular Geometry VSEPR Theory Electron Hybridization Bond Angle Geometry Domains 2 sp 180 Linear 3 sp2 120 Trigonal planar 4 sp3 109.5 Tetrahedral Sigma and Pi Bonds Structural Formulas and Line/Angle Formulas Resonance/Delocalization Non-bonding electrons can move to an adjacent bond only  electrons can move to an adjacent atom or adjacent bond Electrons tend to move toward a ‘+’ formal charge and/or away from a ‘-‘ formal charge ChadsPrep.com 1 Conformations of Alkanes Newman Projections Staggered, eclipsed, anti, gauche Cycloalkanes Ring strain Chair Conformations of Cyclohexane Substituents in axial positions are higher energy (less stable) due to 1,3-diaxial interactions ChadsPrep.com 2  2 - Acid & Bases & Introduction to Organic Reactions Acid-Base Chemistry ↓pKa = stronger acid, ↓pKb = stronger base The stronger the acid, the weaker its conjugate base and vice-versa. The more stable the base, the weaker the base. Ranking Acids and Bases 1) Charge - More negatively charged species are typically more basic, and more positively charged species are typically more acidic. 2) Atom - The larger and/or more electronegative the atom with a negative charge, the more stable it is. 3) Resonance-stabilization. 4) Dipole Induction - Electron withdrawing groups (i.e., electronegative atoms) near the atom that has the negative charge stabilize the ion/molecule. 5) Orbitals – a pair of electrons is more stable as follows: sp > sp2 > sp3 ChadsPrep.com 3 Introduction to Organic Reactions Types of Reactions 1) Substitution 2) Elimination 3) Addition 4) Pericyclic Nucleophile Strength -Nucleophiles are electron pair donors Most strong nucleophiles have a negative charge (most have a lone pair of electrons at the very least) Polar Aprotic Solvents DMSO acetone DMF acetonitrile ethers (diethyl ether, THF) Common Electrophiles -Electrophiles are electron pair acceptors ChadsPrep.com 4 Reaction Intermediates Carbocation Stability 3 > 2 > 1 > Me Radical Stability 3 > 2 > 1 > Me Carbanion Stability Me > 1 > 2 > 3 Electron-donating and Electron-withdrawing Groups Electron-donating groups increase basicity/nucleophilicity Electron-withdrawing groups increase acidity/electrophilicity ChadsPrep.com 5  3 - Nomenclature Nomenclature of Alkanes RULES FOR NAMING ALKANES Prefixes 1 Identify the longest continuous carbon chain (a.k.a the parent chain). 1 meth -If there are multiple ways to come up with the longest chain, then choose the one with 2 eth the most substituents as the parent chain. 3 prop 2 Number the carbons in the parent chain starting on the end closest to the first substituent. 4 but If there is a tie, then move on to the second substituent and so on until there is not a tie. 5 pent -If the substituents are ALL located at the same chain locations in the parent chain when 6 hex numbered in both directions, then compare the 1st substituent encountered in both 7 hept 8 oct directions and rank by alphabetical order. If there is a tie, then move on to the second 9 non substituent and so on until there is not a tie. 10 dec 3 Identify the substituents attached to the parent chain. Carbon substituents end with the 11 undec suffix -yl (methyl, ethyl, propyl, etc.). 12 dodec -For multiple identical substituents use the prefix di-, tri-, tetra- etc. Use the chain number (and a hyphen) as the locator before each substituent. For multiple identical substituents list all chain locators separated by commas. 4 List substituents in alphabetical order. In determining alphabetical order ignore numerical prefixes and hyphenated prefixes (tert- and sec-), but not iso and cyclo. -Use the chain number (and a hyphen) as the locator before each substituent. -For multiple identical substituents use the prefixes di-, tri-, tetra- etc. - For multiple identical substituents list all chain locators separated by commas. 5 The name ends with the name of the parent chain. There should NOT be a space between the substituents and the name of the parent chain. ChadsPrep.com 6 Naming Complex Substituents NAMING COMPLEX SUBSTITUENTS 1 Identify the longest continuous carbon chain of the complex substituent starting with the carbon attached to the parent chain being designated #1. -If there are multiple ways to come up with the longest chain, then choose the one with the most substituents. 2 Number the carbons in the longest chain starting with the carbon attached to the parent chain being designated #1. 3 Identify the substituents attached to the longest chain. -For multiple identical substituents use the prefix di-, tri-, tetra- etc. Use the chain number (and a hyphen) as the locator before each substituent. For multiple identical substituents list all chain locators separated by commas. 4 List substituents in alphabetical order. In determining alphabetical order use the first letter of the complex substituent’s name (even if it is part of a numerical prefix). -Use the chain number (and a hyphen) as the locator before each substituent. -For multiple identical substituents use the prefixes di-, tri-, tetra- etc. - For multiple identical substituents list all chain locators separated by commas. 5 The name ends with the name of the longest chain with a -yl suffix. There should NOT be a space between the substituents and the name of the longest chain. The name of the complex substituent should be in parenthesis preceded by the appropriate chain locator on the parent chain. COMMON COMPLEX SUBSTITUENTS Structure Common Systematic Name Name isopropyl (1-methylethyl) isobutyl (2-methylpropyl) sec-butyl (1-methylpropyl) tert-butyl (1,1-dimethylethyl) (t-butyl) ChadsPrep.com 7 Naming Bicyclic Compounds NAMING BRIDGED AND FUSED BICYCLIC COMPOUNDS 1 Name the substituents before the parent chain just as with other alkanes. 2 Start the name of the parent chain with the bicyclo- prefix. 3 List the number of carbon atoms between bridgeheads in each path. List these three numbers in brackets from highest to lowest separated by periods. To do this: Identify the ‘bridgehead carbons.’ Identify the 3 pathways from one bridgehead carbon to the other and note how many carbon atoms are in between the bridgehead carbon atoms on each path (not including the bridgehead carbons). 4 End the name of the parent chain with the alkane name that corresponds to all carbon atoms in the ring system including the bridgehead carbon atoms. 5 Number the parent chain beginning with one of the bridgehead carbons as #1. Number through the path between bridgehead carbons with the most carbons 1 st. Continue through the 2nd bridgehead carbon and number the path with the 2nd most carbons. Continue numbering the last remaining path with the fewest carbons. Choose the bridgehead carbon to be #1 which results in the first substituent encountered having a lower chain locator. If there is a tie repeat with the next substituent just as with other alkanes. NAMING SPIRO BICYCLIC COMPOUNDS 1 Name the substituents before the parent chain just as with other alkanes. 2 Start the name of the parent chain with the spiro- prefix. 3 List the number of carbon atoms in each ring excepting the spiro carbon. List these two numbers in brackets from lower to higher separated by a period. 4 End the name of the parent chain with the alkane name that corresponds to all carbon atoms in the ring system including the spiro carbon atom. 5 Number the parent chain beginning with one of the carbons in the smaller ring adjacent to the spiro- carbon as #1. Number through the smaller ring ending with the spiro-carbon. Continue numbering through the second ring. Choose the carbon of the smaller ring adjacent to the spiro-carbon to be #1 which results in the first substituent encountered having a lower chain locator. If there is a tie repeat with the next substituent just as with other alkanes. ChadsPrep.com 8  NOMENCLATURE OF COMMON FUNCTIONAL GROUPS Functional Suffix Prefix Example Name Group (Parent Chain) (Substituent) Carboxylic -oic acid carboxy- ethanoic acid Acid Acid -oic anhydride alkanoyloxy- propanoic anhydride Anhydride Ester -oate alkoxycarbonyl- ethyl propanoate Acyl -oyl halide halocarbonyl- propanoyl chloride Halide Amide -amide carbamoyl- ethanamide Nitrile -nitrile cyano- propanenitrile Aldehyde -al formyl- propanal Ketone -one oxo- propan-2-one Alcohol -ol hydroxy- propan-2-ol Thiol -thiol -mercapto propane-2-thiol Amine -amine amino- propan-2-amine Alkene -ene but-1-ene Alkyne -yne but-1-yne Ether N/A alkoxy- 1-methoxypropane Sulfide N/A alkylthio- 1-methylthiopropane Alkyl N/A halo- 1-chloropropane Halide ChadsPrep.com 9  4 - Stereochemistry Isomers Vocabulary Chiral compounds have non-superimposable (non-identical) mirror images called enantiomers. Enantiomers have many of the same physical properties: b.p., m.p., polarity, etc. Chiral compounds are said to be optically active as they rotate plane-polarized light. Achiral compounds are superimposable (identical) with their mirror images. Achiral compounds are optically inactive as they do not rotate plane-polarized light. A racemic mixture is a 50/50 mixture of enantiomers and is optically inactive. Meso compounds are achiral but have chiral centers. Diastereomers are non-superimposable (non-identical) non-mirror images. Diastereomers typically have different physical properties: b.p., m.p., polarity, etc. ChadsPrep.com 10 Chiral Centers Chiral centers are tetrahedral centers with four different substituents (i.e. asymmetric centers). -R vs. S -Nomenclature with R/S Compounds with Multiple Chiral Centers 2n = max possible stereoisomers n = # stereocenters Diastereomers Meso Compounds (achiral but having chiral centers) Fischer projections ChadsPrep.com 11  5 – Intermolecular Forces and Laboratory Techniques Intermolecular Forces 1) Hydrogen Bonding – a super strong dipole-dipole force -must have hydrogen bonded to F, O, or N to H-bond as a pure substance - only need F, O, N to hydrogen bond with protic compounds 2) Dipole-Dipole Forces – interaction between molecules having permanent dipole moments -the larger the dipole moment, the larger the force 3) London Dispersion Forces – weak interactions due to a transient (temporary) dipole -all molecules have these; the larger the molecule, the larger the force Effects of Branching on Melting Points and Boiling Points Branching (usually) decreases the boiling pt, but increases the melting pt Ranking Boiling Points 1) Network Covalent (Cdiamond , SiO2) 2) Ionic 3) Hydrogen Bonding 4) Dipole-Dipole 5) London Forces Solubility – Like dissolves like. ChadsPrep.com 12 Laboratory Techniques and Separations Melting Pt Determination -Impurities lower the melting point and broaden the range Extractions 1. Simple Aqueous Extractions –solutes separated between aqueous and organic phases 2. Acid/Base Extractions a) Amines removed by HCl b) Carboxylic acids removed by NaHCO3 or NaOH c) Phenols removed by NaOH Distillation 1. Simple distillation -Liquids with lower boiling pts are distilled before liquids with higher boiling pts -Works well if liquids have a very large difference in boiling point (>100ºC) -Works well if there is one major component 2. Fractional distillation -Equivalent to multiple simple distillations ChadsPrep.com 13 Chromatography 1) GC (gas chromatography) -Separation is due to a difference in boiling points (mostly). -The compound with a lower boiling pt is eluted first. -The areas under peaks give relative abundances. 2) TLC (thin layer chromatography) -Separation is due to a difference in polarity. -More polar solutes have a lower Rf value. -Less polar solutes have a higher Rf value. -Polar solvents increase Rf values. Relative Polarity of Organic Functional Groups 3) Column Chromatography -Separation is due to a difference in polarity. -A mixture of liquids is filtered through a column of polar beads. -More polar compounds have longer retention times. Recrystallization -Purification (separation) due to a difference in solubility -Solute has a higher solubility at high temps but lower solubility at low temps ChadsPrep.com 14  6 - Spectroscopy IR (infra-red) Spectroscopy -IR light causes vibrational transitions of bonds called “stretches” and “bends” -Allows for the identification of functional groups COMMON ABSORPTIONS Aromatic C-C two peaks usually in the range of 1500-1600 cm-1 C=C ~1650 cm-1 C=O ~1710 cm-1 (shifts to ~1735 cm-1 for esters) CC ~2100-2300 cm-1 CN ~2100-2300 cm-1 C-H (aldehyde) Two peaks at 2710 and 2810 cm-1 sp3 C-H just to the right of 3000 cm-1 sp2 C-H just to the left of 3000 cm-1 sp C-H ~3300 cm-1 N-H ~3300 cm-1 (one peak for -NH-, two peaks for -NH2) O-H (alcohol) ~3400 cm-1 (a broad, smooth peak) O-H (acid) ~2500-3500 cm-1 (a very broad, ugly peak--not smooth) Mass Spectrometry -An electron is knocked out of a molecule by a beam of electrons. -This often results in fragmentation of a molecule. -Parent Peak (Molecular Ion Peak) -Base Peak (tallest peak) UV/Vis Spectroscopy -Absorption in the visible region leads to the complimentary color. -The more conjugated the system, the longer the max -Typically results from the excitation of pi electrons (especially in the visible spectrum) ChadsPrep.com 15 ChadsPrep.com 16 ChadsPrep.com 17 13 C NMR Gives the number of carbon environments in a molecule The chemical shift also tells whether the carbon is an alkane, alkene, aromatic, or carbonyl (C=O) 1 H NMR -Gives the number of hydrogen environments in a molecule 1) Chemical shift tells whether the hydrogen is an alkane, alkene, aromatic, aldehyde, or carboxylic acid 2) Integration or area under the signal tells how many hydrogens a signal represents (or at least the ratio) 3) Splitting number of peaks = n + 1 where n = number of neighbors -Fast Proton Transfer (Proton Exchange) – H bonded to O or N can be exchanged with protic solvents (like D2O) - Degrees of Unsaturation from molecular formula or structure (CNH2N+2) ChadsPrep.com 18  7 – Alkenes & Alkynes Alkenes Nomenclature -ene suffix -E/Z Electrophilic Addition Reactions to Alkenes Reagents What’s Regioselectivity Stereo Intermediate Rearrange Added selectivity ments HBr (or HCl, HI) H+ and Br- Markovnikov - carbocation Possible H3O+ H+ and OH- Markovnikov - carbocation Possible + H , ROH H+ and OR- Markovnikov - carbocation Possible Br2/CCl4 Br+ and Br- - Anti bromonium No (or Cl2) ion Br2/H2O Br+ and OH- Markovnikov Anti bromonium No Cl2/H2O Cl+ and OH- ion Br2/ROH Br+ and OR- Markovnikov Anti bromonium No Cl2/ROH Cl+ and OR- ion (1) Hg(OAc)2, H2O H+ and OH- Markovnikov Anti mercurinium No (2) NaBH4 ion (1) Hg(OAc)2, ROH H+ and OR- Markovnikov Anti mercurinium No (2) NaBH4 ion (1) BH3.THF H+ and OH- Anti-Markovnikov Syn - No - (2) H2O2, OH , H2O H2/catalyst H and H - Syn - No (Catalyst = Pd/C, Pt/C, or Ni) HBr/ROOR (peroxide) H. and Br. Anti-Markovnikov - radical No RCO3H (MCPBA) O - Syn - No (1) RCO3H (MCPBA) OH and OH - Anti - No (2) H3O+ (1) OsO4 OH and OH - Syn - No (2) H2O2 KMnO4 (cold, dilute)/ OH- OH and OH - Syn - No Chiral Usual # Centers of products Formed 0 1 1 2 2 Syn = 2 Oxidative Cleavage of Alkenes Anti = 2 Reducing Conditions None = 4 (1) O3, -78C (2) (CH3)2S or Zn/H2O Oxidizing Conditions (1) O3 (2) H2O2 KMnO4 (hot, concentrated)/OH- (or with H3O+) ChadsPrep.com 19 Alkynes Nomenlature -yne suffix Reduction (Addition of Hydrogen) Addition of HX or X2 ChadsPrep.com 20 Addition of H2O Terminal alkynes require HgSO4 as a catalyst (Markovnikov) Hydroboration-oxidation with a terminal alkyne produces an aldehyde (anti-Markovnikov) Nucleophilic Addition of Acetylide Ions ChadsPrep.com 21  8 - Substitution and Elimination Reactions Substitution Reactions SN2 reactions – Substitution Nucleophilic Bimolecular Rate = k[electrophile][nucleophile] Transition state is trigonal planar SN1 reactions – Substitution Nucleophilic Unimolecular Rate = k[electrophile] -solvolysis SN2 vs. SN1 SN2 SN1 Aprotic Solvents Nucleophile strong required weak is ok DMSO Electrophile CH3 > 1 > 2 3 > 2 acetone polar aprotic polar protic DMF Solvent acetonitrile Leaving Group Good (I- > Br- > Cl- > F-) Good (I- > Br- > Cl- > F-) ethers Rearrangements Not Possible Possible Inversion Yes No (Racemization) aryl and vinyl halides are unreactive (leaving group can’t be on an sp2 carbon) ChadsPrep.com 22 Elimination Reactions E2 reactions – Elimination Bimolecular rate = k[substrate][base] H and X (leaving group) should be anti-periplanar (anti-coplanar) Forms most substituted double bond (Zaitsev’s Rule) Forms least substituted if a bulky base is used like t-butoxide (CH3)3CO- E1 reactions – Elimination Unimolecular Rate = k[substrate] Forms most substituted double bond (Zaitsev’s Rule) E2 vs. E1 E2 E1 Electrophile 3 > 2>1 3 > 2 Base strong required weak is ok Solvent polar aprotic (preferred*) polar protic Leaving Group Good (I- > Br- > Cl- > F-) Good (I- > Br- > Cl- > F-) Rearrangements Not possible Possible Stereochemistry Anti-periplanar None ChadsPrep.com 23 Substitution/Elimination Map Weak Strong nuc/base nuc/base Strong nuc/weak base Strong base/poor (CN-, N3-, Cl-, Br-, I-, nuc RS-, HS-, R3N, R3P) (bulky base, t-buO-) SN1/E 1 SN2 if methyl, 1, or 2 E2 if 3, 2, or 1 Strong nuc/strong base Strong nuc/strong base - - - - (RO , OH , etc.) (RO , OH , etc.) protic solvent aprotic solvent E2 SN2 is major for Both E2 and E2 is major methyl and 1 SN2 for 2 for 3 SN2 E2 SN1 E1 Electrophile CH3 > 1 > 2 3 > 2>1 3 > 2 3 > 2 Nucleophile/Base strong nuc strong base weak nuc weak base Solvent polar aprotic polar aprotic* polar protic polar protic Leaving Group good good good good ChadsPrep.com 24  9 - Free Radical Halogenation & Diels-Alder Reactions Free Radical Halogenation 1) Cl2 / h (not very selective) 2) Br2 / h (highly selective) 3) NBS / h (typically used for allylic bromination) Selectivity and stability of radicals (chlorination vs. bromination) Mechanism 1) Initiation 2) Propagation (where products are formed) 3) Termination ChadsPrep.com 25 Diels-Alder Reactions -A 4 + 2 cycloaddition -concerted mechanism -syn addition between a dienophile and a conjugated diene Stereoselectivity in Diels-Alder Reactions Predict the products for the following reactions. Diels-Alder Reactions with Cyclic Dienes Endo Rule ChadsPrep.com 26 Pi Molecular Orbitals Ethylene 1,3-Butadiene 1,3,5-hexatriene Allyl Cation, Radical, and Anion ChadsPrep.com 27  10 - Aromatic Compounds Criteria for Aromatic Compounds 1) Cyclic and conjugated 2) No sp3-hybridized atoms in the ring 3) Planar 4) 4N+2 π electrons (odd # of pairs) Antiaromatic compounds satisfy the first 3 rules above but have 4N π electrons. Nonaromatic compounds don't satisfy one or more of the first 3 rules above. Side-Chain Reactions of Benzenes Side-Chain Oxidation Side-Chain Reduction Clemmenson Reduction / Wolff Kishner Reduction – reduce ketones/aldehydes to alkanes ChadsPrep.com 28 Electrophilic Aromatic Substitution (EAS) EAS Reaction Example Reaction Electrophile Nitration Sulfonation Chlorination Bromination Friedel-Crafts Alkylation Friedel-Crafts Acylation Formylation (Gatterman-Koch Synthesis) ChadsPrep.com 29 EAS Reactions for Substituted Benzenes ChadsPrep.com 30  11 - Alcohols, Ethers, and Epoxides Alcohols Nomenclature As the main functional group: -ol ending As a substituent: hydroxy Acidity of Alcohols General trend: Methyl > 1 > 2 > 3 Acidity of Phenols Rank the following phenols in terms of increasing acidity: Substitution and Elimination Reactions of Alcohols Lucas Test for Alcohols Reaction with H-X (HBr or HCl/ZnCl2) HCl/ZnCl2 is the Lucas reagent -SN1 for 3 and 2 alcohols; SN2 for 1 alcohols and methanol Turbidity is the positive test 3º alcohols react immediately 2º alcohols react within a few minutes 1º alcohols do not react Reaction with PBr3 (for 1 and 2 alcohols) Reaction with SOCl2 (for 1 and 2 alcohols) ChadsPrep.com 31 Conversion to Sulfonate Esters (tosylates and mesylates) Dehydration with H2SO4 (or H3PO4) -E1 for 3 and 2 alcohols; E2 for 1 alcohols Oxidation of Alcohols Chromic Acid oxidizes 1 alcohols and aldehydes to carboxylic acids, and 2 alcohols to ketones Chromic Acid H2CrO4 Chromic Acid Test Na2Cr2O7 / H2SO4 Orange → Green as positive test for 1º and 2º alcohols CrO3 / H2SO4 PCC oxidizes 1 alcohols to aldehydes and 2 alcohols to ketones ChadsPrep.com 32 Ethers and Epoxides Nomenclature Ethers named as an 1) alkoxy substituent (IUPAC) or 2) as an alkyl alkyl ether (common name) Epoxides named as 1) alkene oxides, 2) epoxy substituents, or as 3) oxiranes Reactions Williamson Ether Synthesis (SN2) Reaction with H-X Ring Opening of Epoxides (In Acid or Base) Base-Catalyzed (Nucleophile attacks the less substituted side) Acid-Catalyzed (Nucleophile attacks the more substituted side) ChadsPrep.com 33  12 - Aldehydes and Ketones Nomenclature aldehydes as the main functional group: -al ending aldehydes as a substituent: formyl ketones as the main functional group: -one ending ketones as a substituent: oxo Nucleophilic Addition Reactions -Carbonyl acts as an electrophile -aldehydes are more reactive than ketones (sterics and induction) Addition of alcohols (formation of hemiacetals, acetals, hemiketals, and ketals) Base-catalyzed (Forms hemiacetal/hemiketal) Acid –catalyzed (Forms acetal/ketal) -Protecting groups with ethylene glycol ChadsPrep.com 34 Addition of 1 Amines (Formation of Imines (Schiff bases) and Imine Derivatives) Addition of 2 Amines (Formation of Enamines) Hydride Reduction Addition of Organometallics (including Grignard Reagents) Formation of Organometallics ChadsPrep.com 35 Wittig Reaction Formation of a Phosphoylide Michael Reaction (Addition to an α, β-Unsaturated Carbonyl Compounds) ChadsPrep.com 36  13 - Carboxylic Acids and Acid Derivatives Nomenclature Physical Properties -Higher boiling pts of carboxylic acids (due to H-bonding and dimerization) Nucleophilic Acyl Substitution ChadsPrep.com 37 Reactivity (acid chlorides > anhydrides > esters/carboxylic acids > amides > carboxylates) Fischer Esterification Saponification ChadsPrep.com 38 Hydride Reduction NaBH4 reduces ketones, aldehydes, and acid halides LiAlH4 reduces ketones, aldehydes, acid chlorides, esters, carboxylic acids, and amides (and others) DIBALH reduces esters to aldehydes Lithium tri-t-butoxy aluminum hydride reduces acid chlorides to aldehydes Addition of Grignard Reagents to Acid Chlorides, Esters, and CO2 ChadsPrep.com 39  14 - Alpha Substitution Reactions of Carbonyl Compounds Alpha Substitution Reactions Carbonyls as nucleophiles – enolates and enols -Keto/enol tautomerism -Acidity of -hydrogens (use of LDA) ChadsPrep.com 40 Alpha Halogenation Acid-catalyzed Base-promoted Haloform Reaction HVZ Rxn ChadsPrep.com 41 Aldol Condensation Acid catalyzed - enol adds to a ketone or aldehyde Base-catalyzed - enolate adds to a ketone or aldehyde Claisen Condensation -Enolate adds to an ester ChadsPrep.com 42 -decarboxylation Acetoacetic Ester Synthesis -forms a substituted acetone (methyl ketone) Malonic Ester Synthesis -forms a substituted acetic acid ChadsPrep.com 43  15 - Amines Nomenclature amines as the main functional group: -amine ending amines as a substituent: amino Basicity and Nucleophilicity Reactions of Amines Alkylation (SN2) Gabriel Synthesis ChadsPrep.com 44 Hofmann Elimination Reductive Amination Reaction with Nitrous Acid (Sandmeyer Reactions) ChadsPrep.com 45 Summary of Substitution and Elimination Reactions (SN1, SN2, E1, E2) Weak Strong nuc/base nuc/base Strong nuc/weak base Strong base/poor (CN-, N3-, Cl-, Br-, I-, nuc RS-, HS-, R3N, R3P) (bulky base, t-buO-) SN1/E 1 SN2 if methyl, 1, or 2 E2 if 3, 2, or 1 Strong nuc/strong base Strong nuc/strong base - - - - (RO , OH , etc.) (RO , OH , etc.) protic solvent aprotic solvent E2 SN2 is major for Both E2 and E2 is major methyl and 1 SN2 for 2 for 3 SN2 E2 SN1 E1 Electrophile CH3 > 1 > 2 3 > 2>1 3 > 2 3 > 2 Nucleophile/Base strong nuc strong base weak nuc weak base Solvent polar aprotic polar aprotic* polar protic polar protic Leaving Group good good good good *Polar protic solvents are preferred for E2 reactions but not required. ChadsPrep.com 46  SUMMARY OF ALKENE REACTIONS Reagents What’s Regioselectivity Stereo- Intermediate Rearrangements Added selectivity HBr (or HCl, HI) H and Br- + Markovnikov - carbocation Possible H3O+ H+ and OH- Markovnikov - carbocation Possible H+, ROH H+ and OR- Markovnikov - carbocation Possible Br2/CCl4 Br+ and Br- - Anti bromonium ion No Cl2/CCl4 Cl+ and Cl- chloronium ion Br2/H2O Br+ and OH- Markovnikov Anti bromonium ion No Cl2/H2O Cl+ and OH- chloronium ion Br2/ROH Br+ and OR- Markovnikov Anti bromonium ion No Cl2/ROH Cl+ and OR- chloronium ion 1. Hg(OAc)2, H2O H+ and OH- Markovnikov Anti mercurinium No 2. NaBH4 ion 1. Hg(OAc)2, ROH H+ and OR- Markovnikov Anti mercurinium No 2. NaBH4 ion 1. BH3.THF H+ and OH- Anti-Markovnikov Syn - No - 2. H2O2, OH , H2O H2/catalyst H and H - Syn - No (Catalyst = Pd/C, Pt/C, or Ni) HBr/ROOR (peroxide) H. and Br. Anti-Markovnikov - radical No RCO3H (MCPBA) O - Syn - No 1. RCO3H (MCPBA) OH and OH - Anti - No 2. H3O + 1. OsO4 OH and OH - Syn - No 2. H2O2 KMnO4 (cold, dilute)/ OH- OH and OH - Syn - No ChadsPrep.com 47  SUMMARY OF ALKENE REACTIONS Hydrohalogenation Acid-Catalyzed Hydration Acid-Catalyzed Hydration (with rearrangement) Acid-Catalyzed Addition of an Alcohol Halogenation Halogenation in H2O Halogenation in Alcohol Oxymercuration-Demurcuration Alkoxymercuration- Demurcuration Hydroboration-Oxidation Catalytic Hydrogenation (Catalytic Reduction) Hydrobromination with Peroxide Epoxidation Anti-Hydroxylation Syn-Hydroxylation Syn-Hydroxylation Ozonolysis under Reducing Conditions Ozonolysis under Oxidizing Conditions ChadsPrep.com 48  SUMMARY OF ALKYNE REACTIONS Reduction (Addition of Hydrogen) Hydrohalogenation (HCl, HBr, HI) Hydrobromination with Peroxide Halogenation (Br2 or Cl2) Acid-Catalyzed Hydration of a Terminal Alkyne Hydroboration-Oxidation of a Terminal Alkyne Hydration of an Internal Alkyne Alkylation of Acetylide Ions Addition of an Acetylide Ion to a Ketone Addition of an Acetylide Ion to an Epoxide ChadsPrep.com 49  SUMMARY OF FREE RADICAL HALOGENATIONS Free Radical Bromination (high selectivity) Free Radical Chlorination (low selectivity) Allylic / Benzylic Bromination ChadsPrep.com 50  SUMMARY OF ALCOHOL REACTIONS Substitution with Iodide Substitution with Bromide Substitution with Chloride Substitution with Bromide (only for 1 and 2) Substitution with Chloride (only for 1 and 2) Conversion to a tosylate ester (a good leaving group) Acid-catalyzed Dehydration (Zaitsev product is major) Chromic Acid Oxidation of a 1 Alcohol PCC Oxidation of a 1 Alcohol Chromic Acid Oxidation of an Aldehyde Chromic Acid Oxidation of a 2 Alcohol PCC Oxidation of a 2 Alcohol SUMMARY OF ETHER REACTIONS Williamson Ether Synthesis (2nd step is SN2) Acid-Catalyzed cleavage of Ethers (also works with HI and HCl) Acid-Catalyzed cleavage of Phenyl Ethers SUMMARY OF EPOXIDE REACTIONS Base-Catalyzed Ring Opening of an Epoxide (Attacks less substituted side) Acid-Catalyzed Ring Opening of an Epoxide (Attacks more substituted side usually) SUMMARY OF ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS (EAS) ChadsPrep.com 51  Name Electrophile EAS Reaction / Reagents Nitration Sulfonation Desulfonation n/a Chlorination Bromination Friedel-Craft Alkylation Friedel-Craft Alkylation (less common variation) Friedel-Craft Alkylation (less common variation) Friedel-Craft Acylation Friedel-Craft Acylation (less common variation) Friedel-Craft Acylation (less common variation) Formylation (Gattermann-Koch Synthesis) ChadsPrep.com 52  SUMMARY OF BENZENE SIDE CHAIN REACTIONS Side-chain Oxidation (Benzylic Oxidation) Side-chain Oxidation (Benzylic Oxidation) -All but the benzylic carbon are cleaved. Clemmensen Reduction Wolff-Kishner Reduction ChadsPrep.com 53  SUMMARY OF HYDRIDE REDUCTION REACTIONS Reduction of a ketone to a 2 alcohol Reduction of a aldehyde to a 1 alcohol Reduction of an acid chloride to a 1 alcohol Reduction of an ester to two alcohols Reduction of a carboxylic acid to a 1 alcohol Reduction of an amide to an amine Reduction of an ester to an aldehyde using DIBALH (also called DIBAH) DIBALH = diisobutylaluminum hydride (shown below) Reduction of an acid chloride to an aldehyde using tri-t-butoxyaluminum hydride ChadsPrep.com 54  SUMMARY OF KETONE / ALDEHYDE REACTIONS Addition of a Grignard Addition of an Acetylide Ion Addition of a 1 amine to form an imine (can be reversed with H3O+) Addition of a 2 amine to form an enamine Forms on less substituted side if there’s a difference (can be reversed with H3O+) Addition of water to form a hydrate Addition of an alcohol under basic conditions to form a hemi-ketal Addition of 1eq of an alcohol in acid to form a hemi-ketal and then a 2nd eq to form a ketal Addition of ethylene glycol to from a cyclic acetal which functions as a protecting group H3O+ is used to de-protect Michael Addition (also called -addition or conjugate addition) Michael Addition with a lithium dialkylcuprate (Gilman reagent) Wittig Rxn Addition of a phosphylide to form an alkene ChadsPrep.com 55 Formation of a phosphoylide from an alkyl halide Summary of Reactions of Carboxylic Acids and Carboxylic Acid Derivatives ChadsPrep.com 56  SUMMARY OF ALPHA SUBSTITUTION REACTIONS Alpha Halogenation HVZ Reaction Alpha Alkylation Stork Reaction (Alternative for alpha alkylation) Self Aldol Condensation Mixed Aldol Condensation Self Claisen Condensation Mixed Claisen Condensation Malonic Ester Synthesis Acetoacetic Ester Synthesis ChadsPrep.com 57  SUMMARY OF AMINE REACTIONS Gabriel Synthesis Hofmann Rearrangement Hofmann Elimination Reductive Amination Sandmeyer Reactions (of Arenediazonium Salts) ChadsPrep.com 58