Organic Reaction Guide Beauchamp 1 Chem 316 / Beauchamp Reactions Review Sheet Name SN2 Reactions - special features: biomolecular kinetics Rate = kSN2[RX][Nu ], single step concerted reaction, E2 is a competing reaction o o o o relative order of reactivity: CH3X > 1 RX > 2 RX >> 3 RX (based on steric hinderance, no SN2 at 3 RX) allylic & benzylic RX are very reactive, adjacent pi bonds help stabilize transition state and lower TS energy (Ea) o complete substitution at Cα (3 RX) or Cβ (neopentyl pattern) almost completely inhibits SN2 reactions vinyl & phenyl are very unreactive, bonds are stronger and poor backside approach leaving group ability: OTs = I > Br > Cl in neutral or basic conditions (just like E2, SN1 adn E1), and neutral molecule leaving groups are good from protonated, cationic intermediates in acid conditions, + + + + -OH2 , -ORH , -OR2 , -NR3 , etc. we will consider all anions, ammonia, amines, thiols and sulfides to be strong nucleophiles (favors SN2 and E2 reactions) in our course some electron pair donors are mainly nucleophiles (sulfur, azide, cyanide, carboxylates) and - + + - + - some are mainly bases (t-BuO K , Na H2N , Na H ) polar, aprotic solvents work best for SN2 reactions because nucleophiles are relatively unencombered for electron doantion (dimethyl sulofoxide = DMSO, dimethylformamide = DMF, acetonitrile = AN, acetone, etc.) in our course some electron pair donors are mainly nucleophiles (sulfur, azide, cyanide, carboxylates) and we will consider neutral solvent molecules such as water, alcohols and acids to be weak nucleophiles (favors SN1 and E1) stereoselectivity: 100% inversion of configuration from backside atack regioselectivity: reacts at carbon with leaving group, completely unambiguous chemoselectivity: N/A The following list is designed to emphasize SN2 reactions. Other possibilities (E2) are not listed. a. primary RX (X = Cl, Br, I, OTs) Possible additional steps 1. make amide (HCl/H2O) 2. make acid (H2SO4/∆) N C 3. make aldehyde (DIBALH) X N C 4. make ketone (RMgBr) 5. make 1o amine (LiAlH4) Limitations nitrile S 2 at Me, 1o and 2o RX N Possible additional steps 1. make cis alkene (Pd/H2/quinoline) 2. make trans alkene (Na/NH3) 3. make alkane (Pd/H ) R 2 4. make ketone (H SO /Η Ο) X R C C 2 4 2 5. make aldehyde (a.R2BH, b.H2O2) (from alkyne + NaNH ) 2 6. zipper reaction (NaNR2) Limitations alkyne (terminal or internal) S 2 at Me and 1o RX N Possible additional steps 1. make RX (SOCl2,PBr3,HI) 2. make tosylate (TsCl/py) H O 3. make aldehyde (PCC/no H2O) X OH 4. make acid (Jones/Η2Ο) 5. make alkoxide (NaH) alcohol Limitations S 2 at Me and 1o RX N Possible additional steps 1. protonate in acid 2. stable in base X R O OR (from alcohol + NaH) Limitations S 2 at Me and 1o RX ether N C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 2 Possible additional steps O 1. hydrolyze in acid or base R 2. reduce with LiAlH4 X O O R 3. react twice with organometallics (from acid + NaOH) ester O Limitations o o SN2 at Me, 1 and 2 RX Possible additional steps 1. make thiolate with NaOH (good nucleophile) H S X SH (from NaSH) thiol Limitations o o SN2 at Me, 1 and 2 RX Possible additional steps 1. can oxidize ro sulfoxide or sulfone R S X SR (from thiol + NaOH) sulfide Limitations o o SN2 at Me, 1 and 2 RX O O Possible additional steps imide 1. hydrolyze to 1o amine with N NaOH/H2O X N (or hydrazine, H2NNH2) NaOH/H2O O O Limitations NH2 o o (from phthalimide + NaOH) 1o amine SN2 at Me, 1 and 2 RX N3 Possible additional steps NNN 1. azides can by hydrogenated azide (reduced) to a 1o amines with X 2 Pd/H2 NNN Pd/H2 (from NaN3) NH2 Limitations o o o sodium azide 1 amine SN2 at Me, 1 and 2 RX Possible additional steps P Ph Ph 1. make carbanion nucleophile with n-BuLi and react with P Ph X X = Ph P aldehydes and ketones to make 3 very specific alkenes alkyltriphenylphosphonium Limitations halide, this salt is used in triphenylphosphine o o Wittig reactions SN2 at Me, 1 and 2 RX C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 3 H Possible additional steps 1. makes RX center into H Al H Li alkane functionality X H lithium aluminium hydride Limitations (LAH) o o SN2 at Me, 1 and 2 RX H Possible additional steps 1. makes RX center into X H B H Na alkane functionality H Limitations o o SN2 at Me, 1 and 2 RX Possible additional steps 1. Couples two "R" parts from two different RX starting structures, one is made into an alkyl lithium, then a cuprate and coupled to Cu another RX compound, cuprates X Li are needed because this reaction organocuprate (from We will view cuprate + RX does not work with Mg or Li organolithium from as an SN2 reaction, eventhough reagents. free radicals may be involved Limitations RX compound) o o SN2 at Me, 1 and 2 RX O Possible additional steps 1. LDA is made from diisopropyl amine and n-BuLi, usually in R CH2 Li R THF at room temperature and X enolates from carbonyl the alkylation reaction run at compounds + lithium O -78oC diisopropyl amide (LDA), Limitations at very low temperatures, o o SN2 at Me, 1 and 2 RX many variations possible special RX (allyl, benzyl, vinyl, phenyl, neopentyl) X X X X X allyl RX benzyl RX vinyl RX phenyl RX neopentyl RX exceptionally good electrophiles in SN2 reactions very poor electrophiles in SN2 reactions A good exercise would be to write out each reaction above with allyl and benzyl RX compounds. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 4 b. secondary RX (X = Cl, Br, I, OTs) Possible additional steps 1. see 1o RX, cyanide is not X N C N too basic for mainly SN2 at C o 2 RX, acid's pKa = 9 Limitations nitrile o o SN2 at Me, 1 and 2 RX Possible additional steps mainly E2 reaction 1. not useful at 2o RX, see 1o RX reactions, acdtylides X R C C are too basic for mainly SN2 at o 2 RX, acid's pKa = 25 2-E and 2-Z and 1- alkenes Limitations o SN2 at Me and 1 RX OH Possible additional steps 1. not useful at 2o RX, see alcohol o X H O 1 RX reactions, messy product mixture (SN2 and E2), acid's pKa = 16 Limitations 2-E and 2-Z and 1- alkenes o SN2 at Me and 1 RX OR Possible additional steps 1. not useful at 2o RX, see alcohol 1o RX reactions, messy X R O product mixture (SN2 and E2), acid's pKa = 16-18 Limitations 2-E and 2-Z and 1- alkenes o SN2 at Me and 1 RX Possible additional steps O 1. see 1o RX, less basic carboxylates R are better behaved nucleophiles X O R O and give good yields for SN2 at 2o RX centers, conjugate acid's O pKa = 9 ester Limitations o o SN2 at Me, 1 and 2 RX Possible additional steps 1. see 1o RX reactions H S X SH thiol Limitations o o SN2 at Me, 1 and 2 RX C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 5 Possible additional steps 1. see 1o RX reactions X R S SR Limitations sulfide o o SN2 at Me, 1 and 2 RX O O Possible additional steps o N 1. see 1 RX reactions X N O O NaOH/H2O NH2 Limitations o o 1o amine SN2 at Me, 1 and 2 RX N3 Possible additional steps NNN o azide 1. see 1 RX reactions X 2 NNN Pd/H2 (from NaN3) NH2 Limitations o o sodium azide 1o amine SN2 at Me, 1 and 2 RX Ph Possible additional steps Ph 1. see 1o RX reactions Ph P Ph P X Ph X Ph alkyltriphenylphosphonium triphenylphosphine halide, used in the Wittig Limitations o o reaction, SN2 at Me, 1 and 2 RX Possible additional steps o H 1. see 1 RX reactions, We use LAH as nucleophilic H Al H Li hydride in this book. If X H we need basic hydride, we'll use sodium hydride, NaH. lithium aluminium hydride Limitations o o (LAH) SN2 at Me, 1 and 2 RX Possible additional steps o H 1. see 1 RX reactions, We use NaBH4 as nucleophilic H B H Na hydride in this book. If X H we need basic hydride, we'll use sodium hydride, NaH. Limitations sodium borohydride o o SN2 at Me, 1 and 2 RX C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 6 Possible additional steps 1. see 1o RX reactions Cu X Li Limitations organocuprate o o SN2 at Me, 1 and 2 RX O Possible additional steps 1. see 1o RX reactions R CH2 Li X R enolate chemistry O Limitations o o SN2 at Me, 1 and 2 RX Br O Intramolecular SN2 reaction. O O O special RX (allyl, benzyl, vinyl, phenyl, neopentyl) X X X X X allyl RX benzyl RX vinyl RX phenyl RX neopentyl RX very poor electrophiles in S 2 reactions exceptionally good electrophiles in SN2 reactions N SN reactions of epoxide electrophiles are shown in a later table.