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Organic Reaction Guide Chem 316 / Beauchamp Reactions Review Sheet Beauchamp 1 Name SN2 Reactions special features: biomolecular kinetics Rate = kSN2[RX][Nu-], single step concerted reaction, E2 is a competing reaction relative order of reactivity: CH 3X > 1oRX > 2o RX >> 3oRX (based on steric hinderance, no SN2 at 3o RX) allylic & benzylic RX are very reactive, adjacent pi bonds help stabilize transition state and lower TS energy (Ea) complete substitution at Cα (3o 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) X N C C N nitrile X R C R C (from alkyne + NaNH2) alkyne (terminal or internal) X H O OH alcohol X R O OR (from alcohol + NaH) ether Possible additional steps 1. make amide (HCl/H2O) 2. make acid (H2SO 4/∆) 3. make aldehyde (DIBALH) 4. make ketone (RMgBr) 5. make 1o amine (LiAlH4) Limitations SN2 at Me, 1o and 2o RX Possible additional steps 1. make cis alkene (Pd/H2/quinoline) 2. make trans alkene (Na/NH3) 3. make alkane (Pd/H2) 4. make ketone (H2SO4/Η2Ο) 5. make aldehyde (a.R2BH, b.H2O2) 6. zipper reaction (NaNR2) Limitations SN2 at Me and 1o RX Possible additional steps 1. make RX (SOCl 2,PBr 3,HI) 2. make tosylate (TsCl/py) 3. make aldehyde (PCC/no H2O) 4. make acid (Jones/Η2Ο) 5. make alkoxide (NaH) Limitations SN2 at Me and 1o RX Possible additional steps 1. protonate in acid 2. stable in base Limitations SN2 at Me and 1o RX C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 2 O R O X O (from acid + NaOH) R ester O Possible additional steps 1. hydrolyze in acid or base 2. reduce with LiAlH4 3. react twice with organometallics Limitations SN2 at Me, 1o and 2o RX Possible additional steps 1. make thiolate with NaOH (good nucleophile) X H S SH (from NaSH) Limitations SN2 at Me, 1o and 2o RX thiol X R Possible additional steps 1. can oxidize ro sulfoxide or sulfone S SR (from thiol + NaOH) Limitations SN2 at Me, 1o and 2o RX sulfide O O Possible additional steps 1. hydrolyze to 1o amine with NaOH/H 2O (or hydrazine, H2NNH2) imide N N X NaOH/H2O O O NH2 1o amine (from phthalimide + NaOH) N3 N N N X azide 2 N N N Pd/H2 (from NaN 3) sodium azide P Ph Ph Ph X = Ph3P triphenylphosphine Possible additional steps 1. azides can by hydrogenated (reduced) to a 1o amines with Pd/H 2 Limitations NH2 o o o 1 amine SN2 at Me, 1 and 2 RX P X Limitations SN2 at Me, 1o and 2o RX alkyltriphenylphosphonium halide, this salt is used in Wittig reactions Possible additional steps 1. make carbanion nucleophile with n-BuLi and react with aldehydes and ketones to make very specific alkenes Limitations SN2 at Me, 1o and 2o RX C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 3 Possible additional steps 1. makes RX center into alkane functionality H H Al H Li H X lithium aluminium hydride (LAH) Limitations SN2 at Me, 1o and 2o RX Possible additional steps 1. makes RX center into alkane functionality H X H B H H Na Limitations SN2 at Me, 1o and 2o RX Cu X Li organocuprate (from organolithium from RX compound) 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 another RX compound, cuprates are needed because this reaction We will view cuprate + RX does not work with Mg or Li as an SN2 reaction, eventhough reagents. Limitations free radicals may be involved SN2 at Me, 1o and 2o RX O R X CH2 Li R enolates from carbonyl compounds + lithium diisopropyl amide (LDA), at very low temperatures, many variations possible O Possible additional steps 1. LDA is made from diisopropyl amine and n-BuLi, usually in THF at room temperature and the alkylation reaction run at -78oC Limitations SN2 at Me, 1o and 2o RX special RX (allyl, benzyl, vinyl, phenyl, neopentyl) X X X allyl RX X X benzyl RX exceptionally good electrophiles in SN2 reactions vinyl RX phenyl RX neopentyl RX 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 b. secondary RX (X = Cl, Br, I, OTs) Beauchamp X 4 N C C N Limitations SN2 at Me, 1o and 2o RX nitrile mainly E2 reaction X R C C 2-E and 2-Z and 1- alkenes OH H O X alcohol 2-E and 2-Z and 1- alkenes OR R O X alcohol 2-E and 2-Z and 1- alkenes O R X O Possible additional steps 1. see 1o RX, cyanide is not too basic for mainly SN2 at 2o RX, acid's pKa = 9 O R O ester Possible additional steps 1. not useful at 2o RX, see 1o RX reactions, acdtylides are too basic for mainly SN2 at 2o RX, acid's pKa = 25 Limitations SN2 at Me and 1o RX Possible additional steps 1. not useful at 2o RX, see 1o RX reactions, messy product mixture (SN2 and E2), acid's pKa = 16 Limitations SN2 at Me and 1o RX Possible additional steps 1. not useful at 2o RX, see 1o RX reactions, messy product mixture (SN2 and E2), acid's pK a = 16-18 Limitations SN2 at Me and 1o RX Possible additional steps 1. see 1o RX, less basic carboxylates are better behaved nucleophiles and give good yields for SN2 at 2o RX centers, conjugate acid's pKa = 9 Limitations SN2 at Me, 1o and 2o RX Possible additional steps 1. see 1o RX reactions X H S SH thiol Limitations SN2 at Me, 1o and 2o 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 R X S SR Limitations SN2 at Me, 1o and 2o RX sulfide O O N N X O Possible additional steps 1. see 1o RX reactions O NaOH/H 2O NH2 o 1 amine N3 N N N Possible additional steps 1. see 1o RX reactions azide X 2 N N N (from NaN 3) sodium azide Pd/H2 NH2 o 1 amine Ph P Ph P Ph Limitations SN2 at Me, 1o and 2o RX Possible additional steps 1. see 1o RX reactions Ph Ph X Limitations SN2 at Me, 1o and 2o RX X Ph triphenylphosphine H H Al H X Li H lithium aluminium hydride (LAH) H H B H X H Na sodium borohydride alkyltriphenylphosphonium halide, used in the Wittig reaction, Limitations SN2 at Me, 1o and 2o RX Possible additional steps 1. see 1o RX reactions, We use LAH as nucleophilic hydride in this book. If we need basic hydride, we'll use sodium hydride, NaH. Limitations SN2 at Me, 1o and 2o RX Possible additional steps 1. see 1o RX reactions, We use NaBH4 as nucleophilic hydride in this book. If we need basic hydride, we'll use sodium hydride, NaH. Limitations SN2 at Me, 1o and 2o 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 SN2 at Me, 1o and 2o RX organocuprate O R Possible additional steps 1. see 1o RX reactions CH2 Li X R O enolate chemistry Limitations SN2 at Me, 1o and 2o 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 exceptionally good electrophiles in SN2 reactions vinyl RX phenyl RX neopentyl RX very poor electrophiles in SN2 reactions SN reactions of epoxide electrophiles are shown in a later table. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 7 E2 Reactions are emphasized in this section special features: biomolecular kinetics (Rate = kE2[RX][B-], single step concerted reaction, competing reaction is SN2 favored reactivity: 3oRX > 2o RX > 1oRX (none at CH3X, need Cβ-H), 1oRX will produce mainly SN2 product excet for mostly E2 with the sterically hindered and highly basic potassium t-butoxide and generally more E2 occurs from the less hindered side of the RX allylic & benzylic RX are very reactive if a conjugated pi bond can form complete substitution at Cα (3o RX) shuts down SN2 and makes E2 the only choice, but there maay be many possible E2 products a completely substituted Cβ makes E2 impossible from that position, but if other Cβ's are present with a hydrogen present, then E2 can occur from those atoms vinyl & phenyl are fairly unreactive, but with really stong bases (R2N ) E2 can form an alkyne, or if the alkyne pi bond becomes conjugated, the reaction can occur more easily with less basic ROleaving group ability: OTs = I > Br > Cl in neutral or basic conditions (just like SN2/E2 reactions) anions whose conjugate acids have high pK a's (weaker acids have stronger bases) generally produce more E2 relative to SN2, the two examples we will emphasize at 2o RX centers are carboxylates (SN2 > E2) vs hydroxide and alkoxides (E2 > SN2) and cyanide (SN2 > E2) vs terminal acetylides (E2 > SN2) we will consider neutral solvent molecules such as water, alcohols and acids to be weak nucleophiles (favors SN1 and E1) stereoselectivity: mainly anti Cβ-H and Cα-X elimination since parallel orbital overlap of the favored staggered conformation allows formation of pi bonds with lower Ea , syn elimination can occur in rigid systems that lock in the required ecliplsed conformation, there can be a lot of possibilities to consider with up to three beta atoms with hydrogen atoms, also each hydrogen of a C-beta CH 2 will often be different, producing E or Z stereoisomer alkenes depending on the anti conformations present, also a chiral 3o RX Cβ-H may have R (E or Z) and S (Z or E). regioselectivity: anti C-beta atoms (or syn in rigid systems) having a hydrogen are required relative to the C-alpha with the leaving group chemoselectivity: N/A Two different perspectives to show either SN2 or E2 reactions. Additional features need to be drawn in. The three templates can work for 1o, 2o and 3o RX compounds. A cyclohexane template is also provided. The anti requirement for E2 reactions requires that X be in an axial position in cyclohexanes, which also works better for SN2 reactions. 1o RX template H E2 target B Nu H Cβ SN 2 target H Cα H Nu H B H H Cβ B Cα H X Cβ Nu = B 3o RX template X perspective 2 Nu H H H Cβ Cβ Cβ Cβ Cα perspective 1 Nu H H Cβ H B Cα At 1o RX SN2 is usually favored over E2, except if the sterically large and very basic potassium t-butoxide is used. perspective 2 Nu Nu perspective 1 X = B 2o RX template B Nu Cβ Cα X H perspective 1 B H X Cβ H H Cβ Cβ Cα Nu = B perspective 2 At 2o RX SN2 and E2, are in competition, less basic electron pair donors tend to favor SN2 and more basic electron pair donors tend to favor E2 reactions, any feature that adds sterically large groups pushes the reaction towards E2. Only E2 reactions are expected at 3o RX when reactied with strong electron pair donors. X C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 8 Templates for both cyclohexane chair possibilities with a carbon substituent present. The leaving group, X, can be added at any blank bond position and needs to be in an axial position to be anti in the ring (not true for carbon branch). 4 6 5 2 1 C interconvert in fast equilibrium 3 C possible reactions an axial "X" is necessary for a succesful E2 reaction and also works better for SN2 possible reactions ? ? An example of some possible choices for SN2 versus E2 in reactions at a secondary RX center having a chiral Cα, chiral Cβ and a beta CH2. SN 2 CH2CH3 OCH 3 Cβ H Nu Ha Nu Hb Cβ C Cβ Ha CH3 CH2CH 3 OCH 3 Cβ H B Cα H Ha Cβ CH2CH3 OCH 3 Cβ H B H Hb Hb CH3 Cα H Ha H H C C I CH2CH3 OCH3 C Hb Cβ CH3 (3R,4S) (3S,4S) E2 CH2CH3 Cβ OCH 3 I Cα H E2 H CH3 CH3 H (2E,4S)-3-methoxy-2-hexene E2 CH3CH2 C I H B C H CH2CH 3 OCH 3 Cβ OCH 3 CH2CH3 Cα H Hb Cβ H C I C CH2CH3 OCH 3 C CH3 H Ha (3Z)-3-methoxy-3-hexene H CH3 (2Z,4S)-3-methoxy-2-hexene a. primary RX (X = Cl, Br, I, OTs), typically see mostly SN2 and do not consider the E2 product, unless the base is potassium t-butoxide, then E2 is the major product OH X H O or or OR R O Contrast with the reaction below. mainly SN2 BUT O K X mainly E2 Contrast with the reaction above. a big, bulky, very strong base C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 9 o b. secondary RX (X = Cl, Br, I, OTs), SN2 and E2 products are both competitive at 2 RX, less basic anions are often good nucleophiles and produce more SN2 product, while more basic anions are better at plucking off a Cβ−Η producing more E2 product, any feature that introduces steric hindrance will favor E2 product (hindrance at Cα, Cβ or in the electron pair donor = base/nucleophile) similar looking base/nucleophiles (used in this book) that react differently with 2oRX structures less basic, mainly SN2 reaction more basic, mainly E2 reaction R C N C pKa of conjugate acid = 9 C pKa of conjugate acid = 25 less basic, mainly SN2 reaction O R O pKa of conjugate acid = 5 more basic, mainly E2 reaction H O R O pKa of conjugate acid = 16-18 E2 reactions of 2o RX (and a few 3o RX) compounds X H O or R O E2 products E2 requires Cβ-H and Cα-X bonds to be in anti conformation OH (or OR) SN2 product Possible additional steps 1. many additional alkene reactions, are possible although in this reaction these would not be productive because too many different products are obtained Limitations SN2 and E2 products obtained Possible additional steps 1. alkene reactions H O X or R O only one hydrogen can be anti or three Cβ-H's Limitations mainly E2 product CH3 H 3C C O only E2 reaction, t-butoxide is too big and bulky for SN2 reactions, an anti Cβ -H is possible on either side when the Br is axial K CH3 Br enantiomers CH3 H 3C Br C O K CH3 6 1 2 Br R 3N (DBU or DBN) No reaction High pKa , sterically bulky base, should be only E2, but Br cannot significantly rotate to an axial position since the very large t-butyl group locks the ring into confromation having t-but yl equatorial. Only E2 at a 3o RX with a strong base/nucleophile. There are three Cβ's but only C6 and the methyl carbons allow the necessary anti conformation for E2 reactions. C2 cannot rotate its hydrogen anti. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 10 Only E2 at a 3o RX with a strong base/nucleophile. All three Cβ's can rotate a hydrogen anti and form E2 product. 6 1 F Br 3 6 A Cβ carbon is fully substituted so SN2 reaction is greatly inhibited. There is an anti Cβ-H possibility on the other side so E2 can occur there. C N Br H Br 5 4 3 2 1 H CH3 H H SN2 and E2 reactions possible, this is a good example for showing why you need o be able to draw and understand 3D drawings, this example is comprehensively viewed below. CH3O See choices below. Br CH3 (3S,4S) H SN2 reaction H CH3O OCH3 H H SN 2 S Br H R H Br S H S H E2 reactions H H S Br H S H C-C rotation CH3O H CH3 H H H H CH3 CH3O C-C rotation H H H Br E2a H CH3O H C-C rotation H H CH3 Br Br E2c E2b H CH3 CH3 CH3 H H H H H "Z" configuration H H "E" configuration CH3 H "E" configuration C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 11 SN1 and E1 Reactions (they share a common carbocation intermediate) special features: unimolecular kinetics ( Rate = kSN1[RX] or Rate = kE1[RX], the relative rates depend on the k's ), multi step reaction, SN1 and E1 are c ompeting reactions (usually SN1 dominates) favored reactivity: 3oRX > 2o RX and we say none at a 1o RX or CH3X because those carbocations are too unstable to form allylic & benzylic RX are reactive because of resonance stabilization of carbocation (even if 1o RX) the number of R gourps at Cβ is not especially important in our course, because the key step in either SN1 or E1 is the first step involving ionization of the Cα-X bond, but highly substituted Cβ positions mean there will probably be rearrangements there is no anti Cβ-H requirement for E1 because the carobcation is so reactive and any Cβ-H can be rotated parallel to the empty p orb ital, generally the more substituted, more stable alkene forms to the greatest extent vinyl & phenyl are completely unreactive because the sp2 bonds are generally too strong to break and the sp carbocation is too unstable in the case of vinyl and the empty sp2 orbital is too unstable in the case of phenyl leaving group ability: OTs = I > Br > Cl in neutral or basic conditions (same for all of the reactions), and neutral molecule leaving groups are good from protonated, cationic intermediates in acid conditions, -OH2+, -ORH+, -OR2+, -NR3+, etc. only weak base/nucleophiles (usually the same molecule: H-B: = H-Nu:) will be used in these reactions, usually it is the solvent molecule (H2O, ROH or RCO2H in this book) the solvent is usually a polar, protic solvent that is capable of stabilizing charged intermediates the only synthetically useful E1 reaction in this book will be dehydration of alcohols, ROH, in concentrated H2SO4 with heating (∆) which distills out the alkene and shifts the equilibrium towards E1 whenever carbocations are formed, rearrangements must be considered and are likely if similar or more stable carboncations can form (we will usually only emphasize rearrangements to more stable carbocations), but the ultimate two leading to stable products reactions are add a nucleophile or lose a beta hydrogen stereoselectivity: any Cβ-H can be lost in an E1 reaction because any Cβ-H can be rotated parallel to the empty p orbital allowing formation of pi bonds, generally the most stable, more substituted (or E over Z) alkene forms to the greatest extent, SN1 reactions lead to racemization of chiral RX centers regioselectivity: any Cβ hydrogen atom can be lost in E1 reactions, in SN1 reactions the nucleophile will add to either face of the Cα carbon unless there rearrangement occurs chemoselectivity: N/A In this book SN1 reactions attack will occur from either side of the flat Cα carbon. This will result in racimization of configuration at chiral centers or cis/trans products in rings. i. (R racemization) or (S racemization) 2 X 2 C H Nu X C H Nu 4 3 ii. (cis ring Nu H R H H Nu 3 3 "R" configuration leads to racemization (50/50 mixture for our course) R R Nu H R X Br proton transfer Nu trans ring H H CH3 only one anti Cβ-H "IF" E2 reaction. "IF" RO SN2/E2 H H H first step for SN1/E1 reactions ROH Nu cis ring attack can occur from top or bottom of carbocation Nu H Br = 4 "S" configuration H H C cis/trans ring) X trans ring Nu 4 3 attack can occur from either face of the flat carbocation cis/trans ring) or (trans ring 2 C Nu 4 "S" configuration X 2 proton transfer H H H H H CH3 H conformation changes of two chairs allows any beta hydrogen to be lost from the carbocation CH3 1. rearrange 2. add Nu (likely in this reaction because a 3o R+ can form) 3. lose beta-H C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 12 via Br Our general rules are SN1 > E1, except for high temperature, acid dehydration of alcohols. Rearrnagement here is not a E1 (minor) problem because nothing changes. No stereochemistry or regiochemistry to consider. H2O OH SN1 (major) via Br ROH E1 (minor) OR SN1 (major) via O OH Br E1 (minor) O O SN1 (major) Our general rules are SN1 > E1, except for high temperature, acid dehydration of alcohols. Rearrnagement here is not a problem because nothing changes. No stereochemistry or regiochemistry to consider. Our general rules are SN1 > E1, except for high temperature, acid dehydration of alcohols. Rearrnagement here is not a problem because nothing changes. No stereochemistry or regiochemistry to consider. via E1 (minor) Br H 2O enantiomers OH SN1 (major) diastereomers Rearrangement of 2o OH carbocation is possible, but not shown in this problem. via E1 (minor) enantiomers ROH Br OR SN1 (major) diastereomers Rearrangement of 2o OR carbocation is possible, but not shown in this problem. via E1 (minor) O Br enantiomers OH O O ester on top and bottom SN1 (major) diastereomers Rearrangement of 2o carbocation is possible, but not shown in this problem. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 13 via Br H2O E1 (minor) Rearrangement is likely because a 3o OH carbocation can form from the originally formed 2o carbocation. SN1 (major) via ROH Br E1 (minor) SN1 (major) OR Rearrangement is likely because a 3o carbocation can form from the originally formed 2o carbocation. via O OH Br E1 (minor) O SN1 (major) via Br H 2O OH SN 1 Rearrangement is likely because a 3o carbocation can form from the originally formed 2o carbocation. O Rearangement is likely since a 3o carbocation can form, normally SN1 dominates over E1, with racimization of a chiral center (stereogenic centers are drawn with a wiggly lines), however significant E1 is expected because the alkene is E1 tetrasubstituted. via Br ROH OR SN 1 E1 via O Br OH O O SN 1 E1 Rearangement is likely since a 3o carbocation can form, SN1 will dominate over E1, racimization of chiral center is expected (stereogenic centers are drawn with a wiggly line, only the most stable E1 alkene is shown. Rearangement is likely since a 3o carbocation can form, normally SN1 dominates over E1, with racimization of a chiral center (stereogenic centers are drawn with a wiggly lines), however significant E1 is expected because the alkene is tetrasubstituted. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Br Beauchamp 14 OH H 2O SN1, very good at benzylic even though primary can still occur because of resonance stabilization of carbocation, E1 is not possible here because there is no Cβ-H to lose a hydrogen. O Br Br OR or ROH Br kinetic product H2O Phenyl carbocation is VERY difficult to form in sp2 orbital. No reaction OH SN1, very good at allylic R+ common intermediate via resonance, two different products formed from a commonintermediate having OR partial positive charge at two thermocynamic sites as shown by the product resonance structures Vinyl carbocation is VERY difficult to form in p orbital of sp hybridized carbon. Carbocations that we typically see are empty p orbitals of a sp2 hybridized carbon. No reaction Br SN1, acid protonates OH and makes OH -OH2+. Water is a good leaving group HI cis or trans and when at 2o or 3o forms a carbocation. Mainly SN1 with HX acids. Nucleophile adds from top and bottom. I cis and trans OH SOCl 2 cis or trans Cl SO2 leaving group, HCl also formed. View reaction as SN1 at 2o and 3o ROH. cis and trans OH PBr3 cis or trans Br cis and trans O S Cl = TsCl OH OTs O N = pyridine cis goes to cis and trans goes to trans Oxygen first does SN2 at phosphorous and then HOPBr 2 is the leaving group in second step (repeated two more times). View reaction as SN1 at 2o and 3o ROH and SN2 at methyl or 1o ROH. Substitution reacton is at the sulfur and represents another way to make the OH into a good leaving group, as a tosylate (inorganic sulfur ester). Pyridine added to sponge up (neutralize) the HCl generated in the reaction. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide OH Beauchamp 15 Dehydration of alcohols in strong acid, with heat, represents our main E1 conditions. Rearrangement is possible, but not shown. H2SO4 / ∆ enantiomers cis or trans OH OH OH OH would protonate, but -OH2+ cannot leave from a phenyl carbon. the empty sp2 orbital (NOT a p orbital!) is too unstable. HBr No Reaction Just a reminder at 1o ROH, OH would protonate, but -OH2+ HBr Br H2SO4 / ∆ cannot leave from a 1o carbon. It needs to be pushed off via SN2 by the bromide. E1, initial carbocation rearranges and then eliminates at high temperature. The alkene(s) distill out. Tetrasubstitution is the most stable alkene shown. major E1 E1 product. The most stable alkene is shown due to more substituted, trans and conjugated. H2SO4 / ∆ HO OH Br PBr3 1. TsCl, pyridine 2. NaBr OH Br SOCl 2 OH Cl Oxygen first does SN2 at phosphorous and then HOPBr2 is the leaving group in second step (repeated two more times). View reaction as SN1 at 2o and 3o ROH and SN2 at methyl or 1o ROH. 1. makes tosylate (good leaving group) reaction occurs at sulfur, not carbon so no change in chiral center 2. SN2 by bromide at carbon, chiral center inverts SO2 leaving group, HCl also formed. View reaction as SN1 at 2o and 3o ROH and SN2 at methyl and 1o ROH. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Reactions of Alkenes (and Alkynes) - Beauchamp 16 Stereoselectivity (cis vs trans, E vs Z, R vs S) and Regioselectivity (reacts at C1 vs C2), it is sometimes possible to see these features in the product structures which can be achiral, enantiomers, diasteromers and/or meso. Reagents generally can attack from either face. Sometimes the approaches are equivalent and sometimes one face is preferred over the other. In the reactions below, if "Stereo = Y" is written, then the reaction can be stereoselective even if not all products will show it. If "Regio = Y" is written, the reaction can be regioselective even if not all products will show it. Br 1 Stereo = N Regio = Y HBr racemic 2 a. Hg(OAc) 2 H2O (or ROH) b. NaBH4 3 OH Stereo = N Regio = Y Markovnikov addition, intermediate carbocation does not rearrange because of mercury bridge, NaBH4 reduces off mercury to hydrogen Stereo = N Regio = Y Markovnikov addition, intermediate carbocation can rearrange if more stable carbocation can form, if heated the E1 alkene is the product racemic OH H 2SO4 / H 2O racemic 4 OH a. BH3 b. H2O2 / HO 5 Br a. BH3 b. Br2 / CH3O 6 Br Br Br2 Stereo = Y (syn) Regio = Y Stereo = Y (syn) Regio = Y Stereo = Y (anti) Regio = N racemic 7 OH Br Br2 / H2O Stereo = Y (anti) Regio = Y racemic 8 a. Br2 / H 2O b. NaOH O racemic Markovnikov addition, intermediate carbocation (can rearrange, add a nucleophile or lose a beta hydrogen. Stereo = Y (anti, SN2) Regio = N (overall) anit-Markovnikov addition, borane forms trialkylborane, second step oxidizes boron position to an OH Same as above, but instead of boron becoming an OH, it becomes a Br Bromonium bridge prevents rearrangement, bromide adds anti to first bromine at more partial postive carbon. Bromonium bridge prevents rearrangement, hydroxide adds anti to first bromine at more partial positive carbon. Similar to above reaction. Product from #7 forms an epoxide. Oxgen attacks from backside in anti conformation. Can also be made directly from alkene with mCPBA. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 17 9 Stereo = Y (syn) Regio = N O mCPBA 10 11 a. mCPBA b. H3O / H2O or b. HO / H2O OsO4 or KMnO4 racemic Stereo = Y (anti) OH Regio = N OH racemic Stereo = Y (syn) OH Regio = N OH racemic Stereo = Y (syn) Regio = N 12 H2 / Pd 13 o 1. O 3, -78 C 2. CH3SCH3 or Zn achiral H O O H 14 o 1. O3, -78 C 2. NaBH 4 OH 15 1. O 3, -78oC 2. H 2O2 16 1. Br2 2. NaNH 2 3. WK OH O Reaction occurs in a single step via concerted mechanism. Net result of epoxidation followed by opening the epoxide in acid or base is anti addition of two vicinal alcohol groups. This is opposite to the next reaction (syn addition). Dioxygenation occurs in a single concerted step via syn addition, followed by aqueous hydrolysis to form a vicinal diol. This is opposite to the above reaction (anti addition). The metal activates the hydrogen and two hydrogen atoms add to the pi bond in a cis or syn manner. Stereo = N Regio = N Ozone cuts pi bond in two and workup leaves a carbonyl bond H at each carbon (aldehydes and/or ketones are the products). Stereo = N Regio = N Ozone cuts pi bond in two and workup reduces carbonyl bonds HO CH3 at each carbon to alcohol groups. Stereo = N Ozone cuts pi bond in two and Regio = N workup oxidizes carbonyl bonds O OH at each carbon to carboxylic = CO2 acids or ketones if the alkene carbon is geminally substituted. OH Stereo = N Bromine adds as in reaction 6 above. Regio = N Sodium amide performs two E2 reactions and then deprotonates the alkyne. Workup with acid protonates the sp carbanion to form an alkyne. H2 / Pd Stereo = Y The metal activates the hydrogen Regio = N and two hydrogen atoms add to the first pi bond in a cis or syn manner to form an alkene, which then reduces to the alkane. H2 / Pd / quinoline Stereo = Y The metal activates the hydrogen Regio = N and two hydrogen atoms add to the first orbital in a cis or syn manner. The quinoline poisons the catalyst so that alkenes do not react further. 17 18 C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 18 Stereo = Y An electron from sodium adds to Regio = N the LUMO orbital. the resulting anion protonates. Another electron adds and the resulting anion protonates to form the more stable E alkene. 19 Na / NH3 Stereo = N Markovnikov addition, intermediate Regio = Y carbocation (can rearrange, add a Br nucleophile or lose a beta hydrogen. achiral, but cis/trans diastereomers 20 HBr 21 a. Hg(OAc) 2 H2O (or ROH) b. NaBH4 24 a. BH3 b. Br2 / CH3O Stereo = N Regio = Y Markovnikov addition, intermediate carbocation can rearrange if more stable carbocation can form, if heated the E1 alkene is the product OH H 2SO4 / H 2O a. BH3 b. H2O2 / HO Markovnikov addition, intermediate carbocation does not rearrange because of mercury bridge, NaBH4 reduces off mercury to hydrogen OH 22 23 Stereo = N Regio = Y OH Stereo = Y anit-Markovnikov addition, Regio = Y boron and hydrogen add syn, OH borane forms trialkylborane, second step oxidizes boron position to an OH Br Stereo = Y Regio = Y Same as above, but instead of Br boron becoming an OH, it becomes a Br Br 25 Br Br2 Br Br 26 Br Br2 / H 2O OH Stereo = Y, Regio = Y 27 a. Br2 / H 2O b. NaOH Stereo = Y Regio = N Bromonium bridge prevents rearrangement, bromide adds anti to first bromine. Bromonium bridge prevents rearrangement, hydroxide adds anti to first bromine at more partial positive carbon. Similar OH to above reaction. Br Product from #7 forms an epoxide. Oxgen attacks from O O backside in anti conformation. Can also be made directly from alkene with mCPBA. Stereo = Y, Regio = N 28 O mCPBA Reaction occurs in a single O step via concerted mechanism. Epoxide oxygen adds syn. Stereo = Y, Regio = N C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 29 30 Beauchamp a. mCPBA b. H3O / H2O or b. HO / H2O OsO4 or KMnO4 19 OH Net result of epoxidation followed by opening the epoxide in acid or base is anti addition of two vicinal alcohol groups. This is opposite to OH the next reaction (syn addition). OH OH Stereo = Y, Regio = N OH OH Stereo = Y, Regio = N 31 Dioxygenation occurs in a single OH concerted step via syn addition, followed by aqueous hydrolysis to OH form a vicinal diol. This is opposite to the above reaction (anti addition). The metal activates the hydrogen and two hydrogen atoms add to the pi bond in a cis or syn manner. H2 / Pd Stereo = Y, Regio = N O 32 o 1. O 3, -78 C 2. CH3SCH3 or Zn O OH 33 o 1. O3, -78 C 2. NaBH 4 OH O 34 1. O 3, -78oC 2. H 2O2 35 H Ozone cuts pi bond in two and workup leaves a carbonyl bond at each carbon (aldehydes and/or ketones are the products). 1. Br2 2. NaNH2 3. WK 36 H2 / Pd 37 H2 / Pd / quinoline O OH Ozone cuts pi bond in two and workup reduces carbonyl bonds at each carbon to alcohol groups. Ozone cuts pi bond in two and workup oxidizes carbonyl bonds at each carbon to carboxylic acids or ketone if the alkene carbon is geminally substituted. Bromine adds as in reaction 6 above. Sodium amide performs two E2 reactions and then deprotonates the alkyne. Workup with acid protonates the sp carbanion to form an alkyne. The metal activates the hydrogen and two hydrogen atoms add to the first pi bond in a cis or syn manner to form an alkene, which then reduces to the alkane. The metal activates the hydrogen and two hydrogen atoms add to the first pi bond in a cis or syn manner. The quinoline poisons the catalyst so that alkenes do not react further. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 20 An electron from sodium adds to the LUMO pi bond. the resulting anionprotonates. Another electron adds and the resulting anion protonates to form the more stable E alkene. 38 Na / NH3 39 Zipper reaction, tautomer-like proton exchanges that move pi bonds to the terminal position where anion is most stable (in sp orbital) as: R 1. Na NR2 2. workup 40 1. Na NR2 2. O Zipper reaction, R opens epoxide, workup protonates the alkoxide. 3. workup OH 41 1. Na NR2 2. Br 3. workup 1. Na NR2 2. H 2C=O 3. workup 42 H 1. 43 H Zipper reaction, R does SN2 on R-Br. OH Na NR2 O OH 2. H 3. workup 44 H O H2SO4 / H2O HgSO4 O 45 2-hexanone H 2SO4 / H 2O HgSO4 O 3-hexanone 46 O H2SO4 / H 2O HgSO4 47 H a. R2BH b. H2O2 / HO O H Step one forms terminal sp carbanion nucleophile. Step 2 adds methanal (formaldehyde) as a one carbon electrophile. Workup protonates the alkoxide anion. Similar to above except a generic aldehyde is used as the carbon electrophile. Workup protonates the alkoxide anion. Markovnicov addition of water (H and OH) via most stable carbocation. Forms enol which tautomerizes to methyl ketone when a terminal alkyne reacts. If a nonterminal alkyne is used, reaction could occur from either side, possibly producing different ketones probably in similar amounts. If some special feature makes one side preferred (e.g. resonance) then a single ketone might be preferred. Anti-Markovnikov addition of dialkylborane to a terminal alkyne. Two large R groups are used (9-BBN is common) so the addition only occurs once to the skinny alkyne. Workup with H2O2 oxidizes carbon with boron to an enol-like structure which when released protonates to form an aldehyde C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 21 O 48 2-hexanone a. R2BH b. H2O2 / HO O 3-hexanone If a nonterminal alkyne is used, reaction could occur from either side, possibly producing different ketones probably in similar amounts. Miscellaneous alkenes and alkynes to consider. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp Reactions of Alcohols (SN, E, oxidation, esterification, acetal/ketal formation, acid/base...) 22 There is methanol and there are primary, secondary, tertiary, allylic, benzylic alcohols. Phenols (aromatic alcohols) are considered separately. R R H OH R C R C OH OH OH OH R C OH H3C OH H R H o o o methanol phenols allylic alcohols benzylic alcohols 1 ROH 2 ROH 3 ROH 1 HI No carbocations at primary carbon. Mechanism is SN2. I OH 2 OH SOCl 2 Carbocations form at secondary carbon. Mechanism is SN1. Cl 3 OH Br PBr3 Carbocations form at secondary carbon. Mechanism is SN1. 4 OH H 2SO4 / ∆ E1 conditions, alkene would distill out and shift equilibrium towards products. Rearrangements are expected. major 5 OH H 2SO4 / ∆ E1 conditions, alkene would distill out and shift equilibrium towards products. Rearrangements are expected. H2SO4 / ∆ E1 conditions, alkene would distill out and shift equilibrium towards products. Rearrangements are expected. 6 OH major minor 7 OH Na H Na(s) metal can also be used O Na a strong base/nucleophile 8 OH Na H Na(s) metal can also be used O Na a strong base/nucleophile Sodium hydride is only basic in our course. It is very useful for pulling off very weakly acidic protons. LAH and NaBH4 can be nucleophilic in our course. Sodium hydride is only basic in our course. It is very useful for pulling off very weakly acidic protons. LAH and NaBH4 can be nucleophilic in our course. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 23 9 OH Na(s) metal can also be used 10 11 The first reaction is acid/base and the second reaction is SN2. This reaction would work in either direction of alcohol and RX compound. 2. O Br The first reaction is acid/base and the second reaction is SN2. If the reaction were tried the other way around there would be consideralbe E2 product 1. NaH OH OH O 2. Br 1. NaH 2. OH The first reaction is acid/base and the second reaction is SN2. If the reaction were tried the other way around there would only be E2 product O Br O 13 tosyl S Cl chloride O pyridine = proton sponge The OH of an alcohol can be made into a toslyate (an inorganic ester). OTs Tosyl group is a very good leaving group in SN and E chemistry (similar 1o tosylate, good leaving group to iodides). O 14 OH 15 a strong base/nucleophile 1. NaH OH 12 Na O Na H tosyl S Cl chloride OTs O 2o tosylate, good leaving group pyridine = proton sponge Ts-Cl = tosyl chloride N pyridine = proton sponge The OH of an alcohol can be made into a toslyate (an inorganic ester). Tosyl group is a very good leaving group in SN and E chemistry (similar 3o tosylate, good leaving group to iodides). Susceptible to E1. O TsOH (cat.) OH (remove H2O) OH O O Fischer esterification O 17 OH The OH of an alcohol can be made into a toslyate (an inorganic ester). Tosyl group is a very good leaving group in SN and E chemistry (similar to iodides). OTs OH 16 Sodium hydride is only basic in our course. It is very useful for pulling off very weakly acidic protons. LAH and NaBH4 can be nucleophilic in our course. TsOH (cat.) OH (remove H2O) O O Removing water shifts equilibrium to the right and adding water shifts equilibrium to the left. Toluene sulfonic acid is a common catalyst. Removing water shifts equilibrium to the right and adding water shifts equilibrium to the left. Toluene sulfonic acid is a common catalyst. Fischer esterification C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 24 O 18 TsOH (cat.) OH (remove H2O) OH 19 OH Removing water shifts equilibrium to the right and adding water shifts equilibrium to the left. Toluene sulfonic acid is a common catalyst. E1 possible at 3oRX, reducing yields. O Fischer esterification O CrO3 / pyridine / no H2O PCC O H aldehyde at 1o ROH 20 OH CrO3 / pyridine / no H2O PCC O ketone at 2o ROH 21 OH CrO 3 / pyridine / no H2O PCC No reaction at 3o ROH OH CrO3 / H2O / acid Jones reagent OH acid at 1o ROH 23 OH CrO3 / H2O / acid Jones reagent Need OH and H on the same carbon atom. Highly oxidized chromium strips electrons from oxygen and base removes proton in E2 reaction to form pi bond between the carbon and the oxygen. In acid the aldehyde hydrates and OH and H are on the same carbon atom again. The second oxidation forms a carboxylic acid. O 22 Need OH and H on the same carbon atom. Highly oxidized chromium strips electrons from oxygen and base removes proton in E2 reaction to form pi bond between the carbon and the oxygen. Need OH and H on the same carbon atom. Highly oxidized chromium strips electrons from oxygen and base removes proton in E2 reaction to form pi bond between the carbon and the oxygen. No further reaction is possible on a ketone because there is no hydrogen atom to allow the E2 reaction to occur. O ketone at 2o ROH 24 OH 25 diol = ethylene glycol OH O H aldehyde 26 CrO3 / H2O / acid Jones reagent ketone 27 O O O (remove H2O) DHP = dihydropyran O ketal (remove H2O) TsOH O H acetal HO toluene sulfonic acid = TsOH enol ether OH O HO toluene sulfonic acid = TsOH (remove H2O) diol = ethylene glycol OH O No reaction at 3o ROH O acetal OTHP THP = tetrahydropyran Tertiary alchols do not react because there is not hydrogen atom to allow the E2 reaction to occur. Acetals are used to protect aldehydes. They are stable in neutral and basic solution, but reactive in acid solution. Removing water shifts equilibrium to the right, adding it shifts to the left. Ketals are used to protect ketones. They are stable in neutral and basic solution, but reactive in acid solution. Removing water shifts equilibrium to the right, adding it shifts to the left. Alcohols can be protected with DHP forming a THP acetal. There is a disquised carbonyl and second OH hidden in the DHP and THP groups. THP acetals are stable in neutral and basic solution, but reactive in acid solution. Removing water shifts equilibrium to the right, adding it shifts to the left. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 25 Reactions of Epoxides (mainly SN2-like reactions, E2-like reactions are possible but not emphasized in our course) Epoxides are unusual ethers. Because of their large ring strain (26 kcal/mole) they can open in acid or base conditions. In base the attack of the strong nucleophile is at the less hindered position as one would expect in an SN2-like reaction. But in acid the attack of the weak nucleophile is at the more hindered position because it carries more of the partial positive charge which more strongly attracks the weak nucleophile. In both reaction attack is forced to occur from the opposite side of the epoxide bridge. In the second compound below, no inversion is observed at the more hindered position in base and inversion is observed there in acid. 1R 1R H O O O O O 4S 4S 2S 2R 2S ethylene oxide (2R)-propylene oxide cyclohexene oxide (1R,2S,4S)-methylcyclohexene oxide (1R,2S,4S)-2,4-dimethylethenoxirane (2R)-propenoxirane cyclohexenoxirane (1R,2S,4S)-methylcyclohexenoxirane cyclohexenoxirane Opens trans or anti from backside attack. Cannot tell in this simple epoxide. 1 H2O / H3O+ O OH HO 2 H O H 2O / H3O + OH HO 2R 2S OH 3 Opens trans or anti from backside attack at the more substituted, more partial positive carbon. Chiral center does invert, becomes S. H OH H 2O / H3O+ O OH OH 50/50 mixture of enantiomers OH 4 5 O HO / H2O a strong base/nucleophile 6 H OH H 2O / H3O+ O HO In strong base/nucleophile conditions attack is at the less hindered positon as expected in SN2-type reactions. A chiral center at the more substituted position is not inverted. / H2O 2R HO 2R 7 OH O HO Similar to #1. Opens trans or anti from backside attack. Diasteromers are formed in unequal amounts. OH OH unequal mixture of diasteromers In strong base/nucleophile conditions attack is at the less hindered positon HO as expected in SN2-type reactions. OH A chiral center at the more substituted position is not inverted. H OH O Similar to #1. Opens trans or anti from backside attack. Enantiomers are formed in equal amounts (a racemic mixture). / H 2O OH racemic mixture of enantiomers Similar to #5. Opens trans or anti from backside attack. Enantiomers are formed in a 50/50 racemic mixture. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 8 O 9 HO / H 2O 2. workup Grignard, lithium or cuprate organometallic H HO H OH CH2 (MgBr) O 2. workup Grignard, lithium or cuprate organometallic 2R 11 2. workup Grignard, lithium or cuprate organometallic 12 OH 13 2. workup Grignard, lithium or cuprate organometallic H O OH H H O Na 2. workup terminal acetylides 2R Similar to #8. OH unequal mixture of diasteromers SN2 reaction at less hindered center. The acetylide is made from a terminal alkyne + NaNH2. Na 2. workup terminal acetylides Similar to #7. racemic mixture of enantiomers CH2 (MgBr) O Similar to #6. 2R CH2 (MgBr) O 14 Similar to #5. Mg and Li reagents are formed from the metals and an RX compound. Cuprates are made from lithium reagents and cuprous bromide (CuBr). Workup is necessary CH2 (MgBr) O 10 26 OH OH Similar to #5. Opens trans or anti from backside attack. Diasteromers are formed in OH OH unequal amounts. unequal mixture of diasteromers HO HO H Similar to #6. 2R OH 15 O H Similar to #7. Na 2. workup terminal acetylides racemic mixture of enantiomers OH 16 O H Na 2. workup terminal acetylides Similar to #8. OH unequal mixture of diasteromers C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 27 Reactions of Aldehydes and Ketones (mainly carbonyl addition reactions in strongly acidic or strongly basic conditions) 1. Carbonyl groups in strong acid (weak base/nucleophile conditions) a. Always begin by protonating the carbonyl oxygen lone pair. b. Protonation on oxygen generates a resonance stabilized carbocation with reactions of carbocations 1. add nucleophile = first step of carbonyl addition and substitution reactions 2. lose beta hydrogen = tautomer reactions 3. no rearrangements because of resonance. C O H X C O H Cα C O addition could produce enantiomers, if the carbon with the OH group is the only chiral center...or could lead to diasteromers, if there is one or more other chiral centers H H C O C O H Cα X addition product H Cα top/bottom or syn/anti addition is not relevant in our course, but could lead to R/S stereochemistry (loss of "β H" is also possible) resonance shows that the positive charge is spread over the carbon and oxygen atoms, the first resonace structure is better with full octets and an extra bond, but the second resonance structure is very informative about the ultimate fate of the intermediate competing pathway, redrawn from above (keto/enol tautomerization) H C O X H Cα H Cα The addition is totally regioselective. Use a lone pair for electron donation. In our course, begin every carbonyl reaction in acid this way. X H H Cα enol structure 2. Carbonyl groups in strong nucleophile/base conditions (weak acid or nonacidic conditions). Two sites of attack are possible by strong electron pair donation (recall SN2 at carbon and E2 at hydrogen). a. Nucleophilic attack at carbon (C=O) or b. Basic attack at an adjacent hydrogen (Cα-H) Remember a similar competition about where to donate the electrons in SN (carbon) versus E (hydrogen) reactions. a. Nucleophilic attack is possible at electrophilic carbon using strong electron pair donation. Often all acidic protons are excluded to avoid quenching the strong electron pair donor. H X Nu C O H Cα often all acidic protons are excluded to avoid protonating the nucleophile Nu Nu C O C O H H Cα H Cα addition product neutralize, often as a second workup step C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 28 b. Basic attack is possible at the “relatively acidic” Cα-H. Often all acidic protons are avoided to avoid quenching the strong electron pair donor. reaction with an electrophile, usually at carbon C O Cα C O C E α Eδ B C O C H α carbon electrophiles often add at Cα carbonyl with electrophile "keto" tautomer reaction with a proton, can occur at carbon or oxygen (tautomers) C O Cα Cα-H's to carbonyl groups are more acidic than typical C-H bonds due to resonance stabilization by oxygen in the enolate conjugate base. hydrogen usually C O H equilibrates among Cα all basic positions, preferred location depends on thermo"enol" dynamics though tautomer less stable contributors may be more reactive H X enolate intermediate tautomerization further reactions at C or O are possible pKa (CH in alkane) = 50 pKa (CH α to C=O) = 20 Reactions of Aldehydes and Ketones (mainly carbonyl addition reactions) O O O H H propene O O 2S-methylbutanal 2-butanone 2R-methylpentan-2-one 4-methylcyclohexan-1-one 3R-methylcyclohexan-1-one Hydration of a carbonyl. Equilibrium favors the keto form. Very fast in acid or base and very slow in neutral water. Keto/enol tautomeriztion is also possible. 1 O H2O / H3O+ H 2 HO OH H Same as #1. O H2O / H3O + HO OH 3 Same as #1. O 4 OH H 2O / H3O + O HO / H 2O H 5 O OH HO OH H O HO / H 2O HO OH Hydration of a carbonyl. Equilibrium favors the keto form. Very fast in acid or base and very slow in neutral water. Keto/enol tautomeriztion is also possible. Same as #2. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 29 6 OH O 7 O Same as #2. OH OH Li 1. H 8 / H 2O HO Organometallic (from RX compound) adds to carbonyl electrophile. Racemic (R/S) 2o benzylic ROH forms in this reaction. 2. workup 1. CH3CH2 (MgBr) O Organometallic (from RX compound) adds to carbonyl electrophile. Achiral 3o ROH forms in this reaction. OH 2. workup 1. 9 Na Terminal acetylide adds to top and bottom of carbonyl face. Cis/trans diastereomers form. O OH 2. workup "OH" on top and bottom 10 O 1. Na OH CN 2. workup H C N 1o RNH2 + aldehyde or ketone forms imines. Removing water shifts equilibrium to right and adding water shifts it to left. Many 1o RNH2 derivatives react similarly. E/Z stereochemistry is possible but not shown. 11 O H 2N TsOH pH = 5 (-H2O) N 12 O H N N TsOH pH = 5 (-H2O) 13 O H 14 O CrO3, H2O, H3O+ (Jones) Pyrolidine (2o amine) forms enamines with carbonyl compounds. Removing water shifts equilibrium to right and adding water shifts it to left. Makes Cα into a neutral nucleophilic carbon. Oxidizes via carbonyl hydrate. O OH OH Zn, HCl Clemmenson Reduction Cyanide nucleophile forms cyanohydrin with carbonyls and slow addition of acid. Aldehydes and less substituted ketones work best. R/S is possible here. H OH Reduces C=O to CH2 in acid. Zn supplies the electrons and HCl supplies the protons C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 15 O 16 Beauchamp H2NNH2, KOH, ROH (Wolff -Kishner Reduction) O O TsOH (-H2O) O H O TsOH (-H2O) O O OH HO 18 O 1. NaBH4 2. workup H Acetals form (via hemiacetals). Removing water shifts equilibrium to right and adding water shifts it to left. Makes carbonyls unreactive under neutral and basic conditions (protects them), but are reactive in acid to break down back to the carbonyl. OH HO H 17 30 Reduces C=O to CH2 in base. A hydrazone forms, there are a number of proton transfers, some resonance structures and loss of nitrogen. OH 19 20 H 1. LiAlH4 2. workup O OH 1. H Ph 2. workup 21 O 1. Ph Ph P HO O (diol) HO TsOH, (-H2O) 23 O O O H N H Lithium aluminium hydride reduces all carbonyl compounds, nitriles and opens epoxides. Workup protonates intermediate anion. A ketone forms a 2o ROH. Cis/trans diastereomers form in this example. Wittig reaction. Wittig salt formed via RX + Ph3P. Carbanion generated with nBuLi. Ph 2. workup 22 Sodium borohydride only reduces aldehydes and ketones and opens epoxides. Workup protonates intermediate anion. An aldehyde forms a 1o ROH. Wittig reactions form really specific alkenes. The Wittig salt is formed via RX + Ph3P. Nucleophilic carban is generated with nBuLi. Ph Ph P O Similar reaction with ketones. Ketals form (via hemiketals) and are used to protect ketones. Removing water shifts equilibrium to right and adding water shifts it to left. TsOH pH = 5 (-H2O) N Ketal formation (remove water). Hydrolyze ketal to ketone under same conditions, but add water. Protecting group for carbonyls. Pyrolidine (2o amine) forms enamines with carbonyl compounds. Removing water shifts equilibrium to right and adding water shifts it to left. Makes Cα into a neutral nucleophilic carbon. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 1. H2N 24 31 pH = 5 (-H2O) H O N 2. Na H3BCN H 1. 25 1o amines form imines with carbonyl compounds, which can be reduced to 2o amines by NaBH3CN. 2o amines react in an analogous way to form 3o amines (see next example). pH = 5 (-H2O) H N O 2o amines form iminium ions with carbonyl compounds, which can be reduced to 3o amines by NaBH3CN. (See examples above.) N 2. Na H3BCN 26 β 1. O Li α H α,β-unsaturated carbonyl 27 β α Li and Mg organometallics prefer 1,2 attack of α,β-unsatruated c arbonyls. Cuprates prefer attack at Cβ, called conjugate addition or 1,4-addition. Allylic/benzylic OH probably unstable in this example. OH 2. workup O 1. O α,β-unsaturated carbonyl 28 O α β α,β-unsaturated carbonyl Li and Mg organometallics prefer 1,2 attack of α,β-unsatruated c arbonyls. Cuprates prefer attack at Cβ, called conjugate addition or 1,4-addition. Carbonyl group is retained in this example. Cu Li 2. workup Na O CN H2O/ROH C N More stable nucleophiles, like cyanide, prefer attack at Cβ, forming the more stable, thermodynamic product, also called conjugate addition or 1,4-addition. Stabilized enolates, discussed later, react in a similar manner in the Michael reaction. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp Reactions of Carboxylic Acids and their derivatives (typically acyl substitution reactions, because there is a leaving group at the acyl carbon, as opposed to typically addition reactions at aldehydes and ketones) O O O O O O Cl propanoyl chloride propanoic anhydride OH propanoic acid O O ethyl propanoate C NH2 propanamide 32 N propanenitrile Which C=O groups are most reactive? Why? (The answers are found in steric, inductive and resonance effects.) Thiol esters (structure C, below) are not usually emphasized in organic chemistry, but are very important for living organisms (biochemistry). Acetyl CoA is a well known example. One might say that thioesters are nature's acid chlorides. In carboxylic acids and their derivatives, the third resonance structure is a strong contributor when the contributing lone pair comes from a 2p orbital (oxygen and nitrogen) that overlaps well with the 2p orbitals of the C=O pi bond (the third resonance structure is more important than the second resonance structure). However, resonance donation from chlorine and sulfur is not as good becasue the 3p orbital is larger and electron delocalization is not as efficient. Because chlorine and sulfur are somewhat electronegative there is increased partial positive character on the carbonyl carbons from an inductive effect, with little return of electron density via resonance. Additionally, chloride and sulfides are stable anions and good leaving groups which leads to high reactivity in acyl substitution reactions. The middle oxygen of anhydrides has good overlap with the carbonyl carbons, but is split between two carbonyls, which reduces its resonance effect, while the electron withdrawing inductive effect is even larger than that found in an ester. The carboxylate group of an anhydride is also a good leaving group. Aldehydes and ketones do not have a stabilizing third resonace contributor which makes them more reactive than those functional groups that do, where resonance donation is important (esters and amides). Aldehydes are more reactive than ketones because they have a sterically small hydrogen substituent and aldehydes do not have the extra "R" group of a ketone which is inductively donating and reduces the parital positive of the carbonyl carbon and thereby reducing their reactivity with nucleophiles. Esters (we will consider carboxylic acids and esters equivalently) and amides are less reactive than any of the previously discussed groups, because the third resonance structure below significantly reduces the partial positive at the carbonyl carbon. Amides are less reactive than esters because nitrogen is many orders of magnitude better at donating electrons than oxygen on the basis of electronegativity. Normally, we would never even think of a negatively charged carboxylate as being an electrophile, however, even the carboxylate will react that way with an excess of organolithium compounds, the most pushy electron pair donors that we enounter. Thus, the typical order of reactivity is that shown below (A>B>C>D>E>E>F>G>H) A B O 1 C R O Cl R O 2 R C R C O O Cl R O 3 C O C -7 (-10) pKa (∆G) of HCl R C R R O O O Cl C C C D E F G H O O O O O O C SR R R R C SR R C H R R C C R R H R C SR C OR R O O R R no additional resonance O R C O O O O C C C NR2 R O OR R O R C C R C O O NR2 R O OR C C O O NR2 R C O +5 (+7) +25 (+35) +7 (+10) +40 (+56) +18 (+25) +37 (+52) +50 (+70) The first number represents the pK a of LG part of acyl group when protonated (the corresponding ∆G in parentheses in kcal/mole). This provides a measure of how stable the leaving group is on its own. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 33 O 1 O Cl Cl OH Cl thionyl chloride O O 2 OH There are a variety of ways to transform a carboxylic acid into an acid chloride. Two of these are shown and use thionyl chloride or oxalyl chloride. O S O Cl oxalyl chloride Cl Cl O O 3 O O Carboxylates are even better nucelophiles and are easily formed by neutralizing the acid. O HO O anhydride Cl O 4 O O Cl OH See #1. Acid chlorides are at the top of the reactivity hill and all of the other acid derivatives can be made from them by using the appropriate nucleophile. O O anhydride 5 O SH Cl O This would probably be a pretty stinky reaction. S ethanethiol O O 6 Cl Ester synthesis. Adding a 3o amine will neutrialize the HCl that also forms and protect an organic molecule that has other sensitive functionality. HO O pyridine (proton sponge) 7 O HO O Ester synthesis. O Cl pyridine (proton sponge) 8 O O Cl 9 H 2O O OH Generally, we are doing everything in our power to avoid this reaction. It undoes the first two reactions above that made the acid chlorides. NH2 Reaction with ammonia will form 1o amides. An extra equivalent is needed to neutralize the HCl formed. O Cl NH3 C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 34 10 o O O Reaction with 1 amines will form 2o amides. An extra equivalent is needed to neutralize the HCl formed. H 2N N Cl 11 H O O Reaction with 2o amines will form 3o amides. An extra equivalent is needed to neutralize the HCl formed. HN Cl 13 O N Reaction with diisobutyl aluminium hydride (DIBALH) at very low temperature will form aldehydes, after acidic workup. Nitriles and esters also form aldehydes with DIBALH. O 1. H Al -78oC Cl H DIBALH 2. workup O 14 O Cu Li Cl cuprates -78oC O 15 O Reaction with cuprates at very low temperature will form ketones. O O A more complex anhydride is prepared from a simpler anhydride. Ethanoic anhydride (acetic anhydride) is readily available and commonly used in this manner. O HO O O 16 O O O 17 O Ester synthesis. A carboxylic acid also forms. If the molecule has other sensitive functionality then an amine base may be needed to neutrialize the acid. O HO O O Ester synthesis. DMAP is a common catalyst in these reactions. O HO O O (CH 3)2N N N,N-dimethylaminopyridine (DMAP) 18 O O O H 2O O 19 OH 2 O O O H2N N O pyridine (proton sponge) H Generally, we are doing everything in our power to avoid this reaction. 1o, 2o or 3o amide synthesis is possible in a manner similar to the acid chlorides above from ammonia, 1o amines or 2o amines. Excess amine is needed to neutralize the carboxylic acid. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 20 O Beauchamp 1. LiAlH4 2. workup O 21 35 Lithium aluminium hyhdride, (LAH) OH reduces all carbonyl functional groups, as well as nitriles. LAH supplies discarded nucleophilic hydride and workup OH in workup supplies acidic (electrophilic) hydrogen. isolated O O O OH O TsOH (cat.), (-H2O) O 22 OH 23 1. LiAlH4 2. workup 1. NaOH 2. Br O OH 24 Fischer ester synthesis. Uses a catalytic amount of acid and water is removed, which shifts the equilibrium to the ester side. Adding water under the same conditions would hydrolyze the ester back to an alcohol and a carboxylic acid. HO OH Hydroxide neutralizes the carboxylic acid. The carboxylate acts as a well behaved nucleophile to do SN2 reactions at methyl, 1o and 2o RX compounds. O O Amides are pretty hardy and require pretty harsh acid or base conditions to hydrolyze them to carboxylic acids. In base the formation of a carboxylate drives the reaction and in acid complete protonation of the amine drives the reaction (no longer nucleophilic). The target molecule could be either part (the acid or the amine) or both of them. To extract the neutral acid into an ether layer a low pH extraction would be necessary, while to get the amine into an ether layer a high pH extraction would be needed. O O H2SO4 / H2O / ∆ N OH H H3N O 25 O 1. NaOH / H2O / ∆ 2. neutralize with acid N OH H H N after acidic workup 26 O 1. LiAlH4 2. workup N 26 A 3o amide generally forms a 3o amine when reduced with LAH. N O N H 1. LiAlH4 2. workup N H H 27 Lithium aluminium hyhdride reduces all carbonyl functional groups, as well as nitriles. H A 1o, 2o or 3o amide generally forms a 1o, 2o or 3o amine when reduced with LAH, followed by acidic workup. O N H 1. LiAlH 4 2. workup N H C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 28 Beauchamp 36 O 1. LiAlH4 2. workup N 29 N O O 3o amindes + Grignard reagents lead to ketones after hydrolytic workup. 1. (MgBr) N 2. workup 30 O O H N Cl H S Cl N NH2 C HCl / H2O / ∆ O 32 C N OH H2SO4 / H2O / ∆ C 1. NaOH / H2O 2. workup C N H Al 34 C N As with amides, nitriles require harsh acid or base conditions to hydrolyze them to first amides, then carboxylic acids. In base the formation of a carboxylate drives the reaction and in acid complete protonation of the ammonia drives the reaction (no longer nucleophilic). O 33 C 1o amindes can be dehydrated with thionyl chloride to form nitriles. thionyl chloride 31 C N C OH O H -78oC O DIBALH Reaction with diisobutyl aluminium hydride (DIBALH) at very low temperature will form aldehydes, after acidic workup. Acid chlorides and esters also form aldehydes with DIBALH. Esters should have been placed up above carboxylic acid reactions. 35 O O O H2SO4 / H2O / ∆ OH HO 36 O O O NaOH / H2O / ∆ OH HO Esters are hydrolyzed back to a carboxylic acid and an alcohol in aqueous acid. Either compound could be the desired target. Overall this is the reverse of Fischer ester synthesis. Esters can also be hydrolyzed back to a carboxylic acid and an alcohol in aqueous base. Either compound could be the desired target. This is sometimes called saponification (soap making). C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 37 from reduced carbonyl, desired target O 37 OH O 1. LiAlH4 2. workup discarded in workup HO from reduced carbonyl, discarded in workup 38 1. LiAlH4 2. workup O O 39 HO O 1. H Al O -78oC desired O target H DIBALH 2. workup 40 desired target OH O OH O 1. CH3CH2 Li 2. workup LAH reduces esters to 1o alcohols after acidic workup. Either product alcohol could be the desired target. While NaBH4 will reduce aldehydes and ketones, it will not reduce esters (no reaction). LAH reduces esters to 1o alcohols after acidic workup. Either product alcohol could be the desired target. Reaction with diisobutyl aluminium discarded hydride (DIBALH) at very low in workup temperature will form aldehydes, after acidic workup. Acid chlorides and nitriles also form aldehydes with HO DIBALH. Esters react twice with Mg and Li organometallics forming 3o ROH after acidic workup. Two of the R groups of the 3o ROH are the same, being added from the organometallic. Benzylic, 3o ROH would be sensitive to substitution (SN1) or elimination (E1) in the workup in this example. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Reactions of Aromatic Compounds Beauchamp 38 1. Electrophilic aromatic substitution reactions a. (activating substituents) Common ortho / para directing substituents: any alkyl substituent, any group with a lone pair next to the aromatic ring that can be used in resonance with the intermediate carbocation. This could include the following commonly encountered groups in our course. R R OH OR O N NR2 O R = alkyl phenols ethers esters R amides amines (except in strong acid where they are protonated) 1 HNO3 / H2SO4 faster than benzene NO2 2 SO3 / H2SO4 SO3H faster than benzene 3 FeCl3 / Cl 2 Cl faster than benzene 4 AlCl3 / Cl O AlCl3 / faster than benzene Cl Nitration conditions (HNO3/H2SO4) make nitroaromatic compounds. Here with an ortho/para activating substituent. Ortho product expected, but not shown. A small amount of meta product is also likely. Sulfonation conditions (H2SO4/SO3, oleum), makes aromatic sulfonic acids. Mainly ortho/para product with methyl substituent. Halogenation (FeX3/X2), (Cl 2 and Br2), halogenates (chlorine or bromine) aromatic compounds. Mainly ortho/para product with methyl substituent. Friedel Crafts alkylation (RX/AlX3), forms carbocations and rearrangements are likely, adds alkyl groups to aromatic ring, which makes the aromatic ring more activated and likely to react again. faster than benzene 5 R X O halogen comounds (X = F, Cl, Br, I), while ortho/para directing, these substituents are deactivating O Friedel Crafts acylation (RCOCl/AlCl 3), forms a resonance stabilize carbocation (an acylium ion) so no rearrangement is expected, makes aromatic ketones, which deactivate the ring and make it less likely that another reaction will occur C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 39 b. Electrophilic aromatic substitution reactions (deactivating substituents) Common meta directing substituents: any strongly electron withdrawing substituent by resonance or inductive effect. They often have an atom with a double bond to oxygen next to the aromatic ring (can be carbon, nitrogen, sulfur and others). The attached group is destabilizing to the positively charged aromatic substitution intermediate when they are directly facing one another which occurs with ortho/para attack, so electrophiles prefer the meta position for attack in substitution reactions and the reaction is always slower than benzene. Some commonly encountered groups in our course are shown below. O C O S X O X O sulfonic acids, amides, esters, X = OH, NR2, OR NR3 N nitro groups slower than benzene NO2 Nitration conditions (HNO3/H2SO4) make nitroaromatic compounds. Here with an meta deactivating substituent. Meta is the main product expected and a slow reaction is likely. SO3H Sulfonation conditions (H2SO4/SO3, oleum), makes aromatic sulfonic acids. Mainly meta product with a nitro substituent. O 2N 7 SO3 / H2SO4 slower than benzene O 2N 8 O 2N X sp3 carbon with strongly withdrawing groups attached positively charged groups, like ammonium ions HNO3 / H2SO4 O 2N C X O 6 O 2N Br FeCl3 / Cl 2 slower than benzene O 2N 9 O 2N AlCl3 / Cl No reaction does not typically work with deactivated aromatic rings O 10 O 2N AlCl3 / NR2 amides esters acids ketones aldehydes C OR OH R O C C C H O O O Cl does not typically work with deactivated aromatic rings No reaction Halogenation (FeX3/X2), (Cl2 and Br2), halogenates (chlorine or bromine) aromatic compounds. Mainly metal product with a nitro substituent. Friedel Crafts alkylation (RX/AlX3), forms carbocations and rearrangements are likely, but the reaction is rarely successful with only deactivating substituents present. Friedel Crafts acylation (RCOCl/AlCl 3), forms a resonance stabilize carbocation so no rearrangement is expected, but the reaction is rarely successful with only deactivating substituents present. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 2. Nucleophilic reactions (addition/elimination), diazonium chemistry (Ar-N2+) from following sequence: HNO3 H 2SO4 nitro Æ amino Æ diazonium salts NaNO2 / HCl (makes HONO) Fe / HCl O2N 40 H2N reduce nitro group N N diazonium salt, stable below 5oC, decomposes to carbocation (or free radical ) above 5oC, see reactions below O possible reactions at meta position(s) T > 5oC Cl O aromatic ring is the electrophile ! reactions are more controlable with less activating amide than amine, possible reactions at ortho/para position(s), can hydrolyze amide back to the amine to continue the reaction sequence towards the diazonium chemistry N H 1 HNO 3 / H2SO4 First step to diazonium salt is nitration of an aromatic ring. O 2N 2 Fe / HCl or SnCl2/HCl O 2N reduce nitro group 3 H 2N O O H 2N Meta groups might be added at this stage before the nitro group is reduced to an amine. A metal in a reduce state donates electrons and an acid donates the protons. Cl N H 4 O N H H3O+ / H 2O or NaOH / H 2O H 2N 5 H 2N NaNO2 / HCl (makes HO-N=O) N N 6 N N T > 5oC aromatic ring is the electrophile ! 7 T > 5oC N N CuCl Cl If additional substitution at this stage is desired, the amine group is usually protected as an amide to reduce its basicity and activating power. All available positions (o + p) might be substituted or the amine might be protonated and turned into a meta director. If the amine is protected as an amide it must be hydrolyzed in acid or base to get back the amine functionality Nitrous acid is the electrophile and the aromatic amine group is the nucleophile, which joins two nitrogen atoms together, followed by some proton transfers, loss of water and resonance. diazonium salt is stable below 5oC, it decomposes to an unusual carbocation in that the empty orbital is sp2, (some reactions may proceed by a free radical intermediate), a variety of nucleophiles can be added at this point, see reactions below Ipso substitution (same position), Copper reactions are called Sandmeyer reactions, the chlorine put on in this reaction is backwards to the way it was put on above, nucleophilic chloride adds here. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 41 8 Ipso substitution (same position), Copper reactions are called Sandmeyer reactions, the bromine put on in this reaction is backwards to the way it was put on above, nucleophilic bromide adds here. T > 5oC N N Br CuBr 9 T > 5oC N N Ipso substitution (same position), Copper reactions are called Sandmeyer reactions, cyanide is nucleophilic in this reaction, the aromatic ring is the electrophile. NC CuCN 10 T > 5oC N N Ipso substitution (same position), iodide is the nucleophile. I KI 11 T > 5oC N N Ipso substitution (same position), water is the nucleophile. HO H 2O 12 T > 5oC N N Ipso substitution (same position), a fluoride from tetrafluoroborate is the nucleophile. F BF4 13 Ipso substitution (same position), hypohphosphorous acid is a very unusual ACID hydride donor. A possible reaction sequence is shown below. T > 5oC N N H H 3PO2 H H O P OH H Electrophile H Electrophile O P OH OH2 lose proton H O P O H OH Hypohphosphorous acid is a very unusual ACID hydride donor. The hydride reduces something and the phosphorous gets oxidized. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 42 Nucleophilic reactions (addition / elimination), similar to conjugate substitution at an α,β-unsaturated carbonyl having a leaving group, except followed by elimination to reform the aromatic compound Electron poor aromatic rings with a good leaving group attached allow nucleophiles to add at the carbon with the leaving group, followed by rearomatization when the good leaving group leaves. The leaving group has to be ortho or para to the electron withdrawing group so that the substituent can stabilize the negative charge in the intermediate. It is similar to the diazonium intermediate in that the aromatic ring is the electrophile. 1 O2N Cl 2 OH H2O O2N Br OH CH3O OCH3 CH3OH O 2N O O 2N O N N O Br The nitro substituent is electron withdrawing and can stabilize negative charge by resonance and chloride is a good leaving group, attack by a nucleophile can displace the chloride, the reaction is somewhat like a substitution reaction on a vinylogous acid halide. O N O Br Nu O Nu Nu O O O analogous nucleophilic substitution reaction on a vinylogous acid chloride Cl Cl Nu Nu Nu 3. Benzyne (elimination / addition), uses a very strong base, sodium amide (NaNH2)to force a 1,2 elimination beta to good leaving group forming highly reactive benzyne. A nucleophile can add to the “pseudo” triple bond on either side, after which the aromatic ring protonates at the other position. Benzyne forms in an E2-like reaction requirering a very strong base (often some sort of sodium amide, NaNR2), except because of the rigid, flat nature of the aromatic ring, no real pi bond can form. The parallel sp2 orbitals are angled away from one another making for a very unstable and highly reactive arrangement of orbitals. An electron pair donor in the vacinity of either sp2 ortibal will add its electrons to form a sigma bond and isolate the pseudo pi electrons in a highly basic sp2 orbital which quickly protonates in an acid/base reaction to regenerate a neutral aromatic ring. If an unchanged substituent is present on the ring, it is easily seen that either carbon of the pseudo pi bond can be attacked by a nucleophile, because isomeric products are obtained. 1 Br N(CH3) 2 Nu: adds at either position HN(CH3)2 benzyne intermediate 2 N meta and para products obtained Nu: adds at either position Cl N(CH3) 2 N N ortho and meta products obtained HN(CH 3)2 C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc N Organic Reaction Guide Beauchamp 4. Miscellaneous side chain reactions 1 O R 2 CH2 HCl / Zn CH2 R CH2 R H2NNH2/RO /∆ O R Clemmenson reduction (HCl/Zn), reduces aromatic ketone to methylene carbon (CH2) under acid conditions. The Zn supplies the electrons and the HCl supplies the protons. R O R 3 43 Pd / H2 Wolff Kishner reduction (H2NNH2/RO /∆), reduces aromatic ketone to methylene carbon (CH2), under base conditions. Imine-like structure forms, acid/base proton transfers, tautomer-like changes and ultimately loss of nitrogen gas. Pd/H2 reduction, reduces aromatic ketone to methylene carbon (CH2) because it's benzylic, reduces, reaction occurs under neutral conditions unlike Clemmenson's (acidic) or Wolff-Kishner (basic). 4 CrO3/∆ HO2C CO2H 6 KMnO4/∆ HO2C CrO3/∆ or KMnO 4/∆ oxidations, very harsh conditions, no sensitive groups tolerated, oxidizes any carbon side chain with a benzylic hydrogen to a carboxylic acid, a quaternary benzylic carbon will either not react or if really pushed the aromatic ring is oxidized away, leaving a carboxylic acid in place of the ring. 7 KMnO4/∆ forcing conditions HO2C 8 Br Br2 / hν + Free radical substitution (Cl 2 or Br2 HBr and light, hν), chain reaction mechanism prefers benzylic position because of weaker C-H bond C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 44 Synthesis of Functional Groups – most of the reactions listed below have been listed above, but are listed here by the common theme of functional group preparation so you can consider a variety of possibilities when considering the synthesis of a particular functional group. 1. Synthesis of RX compounds RX compounds from free radicals substitution of sp3 C-H bonds - the weakest C-H bond is attacked fastest Typical range of sp3 C-H bonds CH4 H3C CH3 Typical free radical substitution mechanism 1. initiation Br hν and/or ∆ Br Br Br 2 propagation a. abstraction of H - bromine atom abstracts hydrogen atom from weakest C-H bond fastest (3o > 2o > 1o > methyl). H H Br H H 2o > 1o Br ∆Hrxn depends on difference in C-H and H-Br bond energies. b. abstraction of Br - carbon free radical abstracts Br from Br2 molecule (very weak bond). ∆Hrxn is always favorable because Br Br Br-Br bond is so Br Br weak. 3 termination - two free radicals diffuse near one another and quench each other in bond formation. H H H H C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 45 a. Synthesis of RX compounds from alcohols 1 OH 2 Br HBr Use of HX acids (HCl, HBr, HI). Cl OH SOCl 2 3 OH 4 OH Use of thionyl chloride. Br PBr3 a. Use of phosphorous trichloride (PCl3, PBr3 or P/I2). b. O S Cl O a. Na I OTs b. Make tosylate followed by an SN2 reaction (Me, 1o, 2o RX) with a sodium halide salt I N b. Synthesis of RX compounds from alkenes 5 HBr a. 6 b. 1. BH3 2. Br2 / CH3O HX acids (Markovnikov addition) Br a. CH3 b. H B CH3 H R Br R i. BH3 ii. H2O2/HO (anti-Markovnikov & "syn" addition) 2. Synthesis of alcohols a. Synthesis of alcohol compounds from RX compounds 1 Br 2 Br NaOH 1. CH3CO2Na 2. NaOH OH OH (via ester) 3 Br OH H 2O SN2 at Me, 1o with NaOH SN2 at Me, 1o , 2o with CH3CO2Na, followed by base hydrolysis to form the alcohol and acetate which is discarded. SN1 at 2o, 3o RX with H2O, possible rearrangements, reasonable if rearrangement is not a problem C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 46 b. Synthesis of alcohol compounds from alkenes OH 1 Mercury bridge of cation intermediate minimizes rearrangement. Borohydride reduces mercury off and substitutes hydrogen on. 1. HgX 2 / H2O 2. NaBH4 2 OH Aqueous acid forms carbocation intermediate which can rearrange H3O+ / H2O 1. O 3 / -78oC 2. NaBH 4 3 4 1. BH3 2. H2O2 / HO CH3OH OH lost in aqueous workup Ozonolysis cuts double bond in two forming carbonyls and sodium borohydride workup reduces carbonyls to alcohols. Anti-Markovnikov and "syn" addition of borane, BH3, followed by oxidation with perioxide to form an alcohol, OH c. Synthesis of alcohol compounds from RMgX & RLi organometallics reacted with aldehydes, ketones, esters (twice) and epoxides (all followed by acid workup) 1. Mg Organomethallics + aldehydes and 1 2. O ketones makes 1o (from CH2=O), Br 2o (from RCH=O) or 3o (from R2C=O) H OH 3. WK alcohols. 1. Mg (2 eqs.) 2. O 2 Organomethallics + esters (react twice) makes 3o alcohols. Br 3. WK OCH3 OH 1. Li 2. O 3 Br 3. WK OH Organomethallics + epoxides, SN2-like reaction at less hindered side of the epoxide, workup protonates the alkoxide. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 47 d. Synthesis of alcohol compounds from metal hyrides, LiAlH4 or NaBH4 reacted with aldehydes, ketones, esters and acids (twice & only with LAH) and epoxides (all followed by acid workup) 1 O H 2 O OCH 3 1. NaBH4 2. workup OH 1. LiAlH4 2. workup OH Sodium borohydride (or LAH) + aldehydes and ketones makes 1o or 2o alcohols after workup. Only lithium aluminium hydride works on esters, reacts twice to make 1o alcohols after workup. (+ CH 3OH, discarded) 3 O OH 4 O 1. LiAlH4 2. workup OH NaBH4 or LiAlH4 + epoxides, SN2-like reaction at less hindered side of the epoxide, workup protonates the alkoxide. OH 1. NaBH4 2. workup (R) Only lithium aluminium hydride works on esters, reacts twice to make 1o alcohols after workup. (R) e. Acid or base hydrolysis of esters forms a carboxylic acid and an alcohol (either or both could be the desired result). O 1 O OCH 3 2 1. H2O / HO 2. WK OH CH3OH (discard ?) O O + H3O / H2O O 3. OH (discard ?) HO Base hydrolysis of esters is often called saponification (soap making) Acid hydrolysis of esters is the reverse of Fischer ester synthesis. Water is added instead of removed. Synthesis of ethers from alcohols and alkenes 1 2 OH OH 3 1. NaH 2. Make an alcohol into a stronger nucleophile by removing proton with hydride (strong base). SN2 works OK at methyl and primary RX centers. O Br conc. H 2SO4 cold An SN1 reaction at 2o adn 3o ROH (could have E1 complications), and an SN2 reaction at 1o ROH. O 1. HgX2 OH 2. NaBH 4 O Markovnikov addition of an alcohol at an alkene. Rearrangement is minimized by bridging mercury atom, which gets reduce off with hydride (free radical intermediate). Note that the alcohol used in this reaction could have been made by a similar procedure between and alkene and water. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 4. Synthesis of epoxides from alkenes 48 Br 1 1. Br2 H2O H OH First, a halohydrin is made from an alkene. Products in this example are enantiomers. (d / l) 2 H Br NaOH H O OH (d / l) CH3 H 3 mCPBA O H 5. In a second reaction, the alkoxide is formed and does an SN2 on the vicinal bromide to form the epoxide. Products in this example are enantiomers. meta-chloroperoxybenzoic acid (mCPBA) accomplished the same transformation in a single step. The products in this example is meso (achiral with chiral centers). Synthesis of alkenes 1 OH These are E1 conditions. Rearrangements are possible. H 2SO4 / ∆ (dehydration) 2 O K Br 3 4 5 (major) This represents our only productive conditions for E2 at a primary center and is due to the sterically bulky and very basic potassium t-butoxide. Br NaOH Strong base/nucleophile and a 3o RX mean an E2 reaction. Only the more stable alkene is shown. O 1. Ph3P=CH2 (from CH3X) 2. WK Wittig reaction, generally the best bet to get the exact alkene you are looking for. Pd / H2 quinoline Poisoned Pd catalyst stops at the cis alkene. (Lindlar's cat.) 6 Na / NH3(l) Birch reduction of alkyne mostly forms E (trans) alkene. (Birch) C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 7 Beauchamp 49 (Birch) Birch reduction of aromatic ring puts two pi bonds opposite one another. If an electron donating substituent is present, it will be at one of the sp2 positions. Pd / H 2 Complete reduction of an alkyne to an alkane for comparison. Na / NH3(l) ROH 8 6. Synthesis of alkynes 1 1. NaNH 2 Terminal acetylide carbanion works well at methyl and primary RX. Br 2. SN 2 2 Br Double elimination product (plus loss of terminal sp C-H under the reaction conditions. Workup protonates or an electrophile could be added. The starting dibromide can be made from an alkene + Br2. 1. excess NaNH2 2. WK Br 3 7. The Zipper reaction moves a triple bond through any number of CH2's until the termial position is found, where the sp C-H is lost, forming the most stable anion in the pot. 1. excess NaNH2 2. WK Synthesis of amines O O 1. NaOH 1 N H O N Br 2. SN 2 O NaOH NH2 Gabriel amine synthesis, starts with phthalimide, removes proton on nitrogen, does an SN2 reaction on an RX and hydrolyzes off the two carbonyl portions to obtain a 1o RNH2. O 2 N 1o amines O 3 O 1. H 4 NH2 2. NaBH 3CN 3. WK 1. O H 1o amines H Reductive alkylation of imine with sodium cyanoborohydride to make o o 3o amines 2 or 3 amines. N H N H 2. NaBH 3CN 3. WK N 3o amines Reductive alkylation of imine with sodium cyanoborohydride to make 2o or 3o amines. H C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 5 O NH2 Beauchamp 50 1. LiAlH4 2. WK NH2 LAH reduction of 1o, 2o and 3o amides makes 1o, 2o and 3o amines. 1. LiAlH4 2. WK NH2 LAH reduction of nitriles makes 1o amines after workup. 6 C 8. N Synthesis of ketones 1 OH O CrO3 (no H2O or H2O) PCC or Jones at 2o ROH. 2 C N O Li Nitriles + RLi compounds, followed by hydrolysis form ketones. 2. WK 3 O H3O+ /Hg+2 H2O 4 5 1. O3, -78o 2. CH3SCH 3 O (CH 3)2Cu Cl 6 S S 1. nBuLi 2. CH3Br 3. WK 1. nBuLi 2. CH3CH2Br 3. WK S 8 O 2 O Li S 7 Hydration of an alkyne. Markovnikov additon, forms enol, which tautomerizes to ketone. S S S Ozonolysis of alkene, DMS workup. Many other workup conditions are possible. For best results here, it would be nice to have a symmentrical alkene. Cuprates + acid chlorides form ketones. Cuprates come from organolithium compounds which come from RX compounds. Dithiane alkylation (twice), then hydrolysis to the carbonyl compound. If hydrolyzed after one alkylation, then an aldehyde is obtained. S S O Hg+2 / H2O S C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 9 Beauchamp 51 2 eqs. O 2 eqs.RLi + carboxylic acid, forms a double alkoxide because of the power of the organolithium nucleophile, which hydrolyzes to a ketone in the workup. O CH3 Li OH 2. WK 10 O O Friedel Crafts Acylation, makes aromatic ketones, deactivating substituents inhibit the reaction. Only reacts one time because keto group is a deactivating, meta director. Cl AlCl3 9. Synthesis of aldehydes 1 OH 2 N C 3 O CrO3 (no H2O) PCC H Nitriles + DIBALH, followed by hydrolysis form aldehydes. O 1. DIBAH -78oC 2. WK H hydroboration of an alkyne, then H2O2/HO O 1. BH3 2. H 2O2./ HO H 4 5 1. O3, -78o 2. CH3SCH3 O Cl 6 S 7 2 H 1. DIBAH -78oC 2. WK 1. nBuLi 2. CH3CH2Br 3. WK S O S O H Cuprates + acid chlorides form ketones. Cuprates come from organolithium compounds which come from RX compounds. Dithiane alkylation (once) , then hydrolysis to the carbonyl compound. An aldehyde is obtained. S S O Hg +2 / H2O H S 8 Ozonolysis of alkene, DMS workup. Many other workup conditions are possible. For best results here, it would be nice to have a symmentrical alkene. O O 1. DIBAH -78oC 2. WK O H DIBAH + ester at low temperature makes aldehydes after hydrolysis. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 52 O 9 C O HCl AlCl3 H Vilsmeier reaction on activated aromatics (many variations) to make aromatic aldehydes. 10. Protection of aldehydes and ketones 1 O N HO OH TsOH (-H2O) C N 2 N 3 O O C O O O 1. CH3Li 2. mild WK O O O O O O C O Protection of aldehyde or ketone with ethylene glycol. Acid catalysis and removal or water forms acetal or ketal. Carbonyl becomes inert to many strong nucleophiles that would otherwise react with it. Run the desired reaction, an organometallic reaction here. It is possible to do a mild workup and not hydrolyze the ketal, or a more vigorous workup, as in the next frame could deptrotect the ketal at the same time as the other reaction is worked up. + H 3O / H 2O 11. Synthesis of acids 1 O OH 2 CrO3 (H2O) i. O 3 / -78oC ii. H2O2 /HO 3 C N 4 C 5 N O H2SO4 H2O / ∆ 1. H 2O/HO ∆ 2. WK aqueous acid or base OR OH 2 O OH O Jones conditions oxidize 1o ROH to carboxylic acids and 2o ROH to ketones. Ozonolsis with oxidative workup, using H2O2, forms acid if alkene carbon has a hydrogen and ketones if alkene carbon is geminally disubstituted. Full acid hydrolysis of a nitrile. OH O Full base hydrolysis of a nitrile. OH O Aqueous hydrolyisis of acid derivatives. OH C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 6 O O O 53 O aqueous acid or base Cl 7 Beauchamp Aqueous hydrolyisis of acid derivatives. OH O aqueous acid or base 8 O O H2SO4 H2O / ∆ NH2 9 Full acid hydrolysis of a amide. OH 1. Mg 2. CO2 3. WK Br Aqueous hydrolyisis of acid derivatives. OH O Grignard reagent reacted with carbon dioxide, then workup. O OH 12. Synthesis of acid chlorides 1 O OH A few ways to make an acid chloride from a carboxylic acid: thionl chloride, oxalyl chloride and phosphorous trichloride. O SOCl 2 Cl thionyl chloride O 2 O Cl OH O Cl O Cl oxalyl chloride 3 O O PCl3 OH Cl phosphorous trichloride 13. Synthesis of anhydrides O O 1 O OH O O O 2 O O OH Cl O O A couple ways to make an unsymmetrical anhydride from a carboxylic acid and either another anhydride or an acid chloride. O O C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 14. Synthesis of esters 1 Beauchamp 54 1. NaOH 2. Br O O OH 2 O O OH O TsOH (-H2O) OH 3 O OH O O O O 5 O O A tertiary amine is sometimes used to make the reaction work faster and better. O OH Fischer ester synthesis, acid catalysis and remove water to from ester. Use opposite conditions to hydrolyze ester (acid catalysis and lots of water). A tertiary amine is sometimes used to make the reaction work faster and better. O Cl 4 Make a good carboxylate nucleophile then ract with a methyl, 1o or 2o RX compound. O O Cl O O O O Another use of mCPBA is to oxidize ketones to esters. Called the Baeyer Villegar Rxn. NH2 Milder conditions hydrolyze nitriles to amides, harsher conditions hydrolyze nitriles to carboxylic acids. H mCPBA 15. Synthesis of amides 1 C 2 N O HCl H2O Acid chlorides + ammonia, 1o or 2o amines makes 1o, 2o or 3o amides. O O Cl NH3 NH2 O 3 N Anhydrides + ammonia, 1o or 2o amines makes 1o, 2o or 3o amides. N Anhydrides + ammonia, 1o or 2o amines makes 1o, 2o or 3o amides. O N Cl 4 H O O O O N H C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 16. Synthesis of nitriles 1 Beauchamp Br 55 Na N C SN2 reactions of cyanide with methyl, 1o or 2o RX compounds N C 2 O SOCl 2 NH2 C N Dehydration of primary amide with thionyl chloride. (-H2O) 17. Enamine Chemistry 1 Start with carbonyl, make enamine, alkylate enamine, hydrolyze back to carbonyl compound with extra R group added (methyl, allyl or benzyl in our course). N H O N pH = 5 (-H2O) Hydrolyze alkylation product via this intermediate 2 1. N Br O 2. WK = aq. hydrolysis H 2O N 18. Synthesis of β-hydroxycarbonyl and α,β-unsaturated carbonyl O 1 α O H O H Na RO β OH β-hydroxy carbonyl H O 2 O α α H H β OH acid. hydrolysis H3O+ / H2O / ∆ β α,β-unsatruated carbonyl Aldol reaction of two carbonyls, usually the same one. Base is used to make an enolate which then attacks another carbonyl to form a β-hydroxy carbonyl structure that can be isolated or dehydrated to an α,β-unsatruated carbonyl shown in the next frame. this often done with acid, but in this book we will indicate the next step with the symbol for heat, ∆. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 19. Malonic ester synthesis (produces mono and di- substituted acetic acids) 1 O 1. CH3CH2O 2. Br O O O O O O O O O H3O+ / H2O (-CO2) product from 1 O O 3. WK O 2 OH monoalkylated acetic acid O 3 O O product from 1 O 4 O 1. CH3CH2O 2. Br O O O O 56 Malonic ester synthesis. Remove acidic proton with alkoxide base then alkylate with electrophile (RX, epoxide or another carbonyl). Can hydrolyze ester at this point, decarboxylate (-CO2) to obtain a monoalkylated ethanoic acid (acetic acid), or repeat the reaction a second time and then decarboxylate to obtain a dialkylated ethanoic acid (acetic acid). It's also possible to do similar chemistry by using the dianion of ethanoic acid or using a simple ethanoate ester and LDA to generate the ester enolate and perform an alkylation at low temperature (-78oC) 3. WK O O O O H3O+ / H2O (-CO2) OH dialkylated acetic acid product from 3 20. Ethyl acetoacetate synthesis (produces mono and di- substituted acetones) 1 O O O O 1. CH3CH2O 2. Br O O 3. WK O O 2 O + H 3O / H 2O (-CO2) O product from 1 O monoalkylated acetone O 1. CH3CH2O 2. Br 3 O product from 1 O O O Acetoacetic ester synthesis. Remove acidic proton with alkoxide base then alkylate with electrophile (RX, epoxide or another carbonyl). Can hydrolyze ester at this point, decarboxylate (-CO2) to obtain a monoalkylated 2-propanone (acetone), or repeat the reaction a second time and then decarboxylate to obtain a dialkylated 2-propanone (acetone). It's also possible to do similar chemistry by using a simple ketone and LDA to generate the ketone enolate and perform an alkylation at low temperature (-78oC) O 3. WK O O 4 O product from 3 H3O+ / H2O (-CO2) dialkylated acetone C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 21. Cuprate chemistry Beauchamp 57 1 Br Organolithium reagents come from RX compounds + Li metal. Li Li RX compound organolithium reagent Cu Cuprates are prepared from organolithium reagents + CuBr (cuprous salt) in a 2 to 1 ratio. Li organocuprate There are three choices for a cuprate in our course. 2 Li 0.5 eq CuBr O 3 4 Cu α Li organocuprate β α,β-unsaturate carbonyl Cu 2. Cuprate coupling reaction with an RX compound. Remember the cuprate comes from an organolithium, which comes from another RX compound. It hard to tell which bond was formed and in what direction the atoms were used because there are a lot of possibilities Br Li organocuprate 5 1. conjugate addition to an α,β-unsaturate carbonyl O RX compound O Cu 3. Cuprate substitution of chlorine in an acid chloride to make a ketone. There are two possible ways you could consider joining the acid chloride and cuprate. O Cl Li organocuprate acid chloride 22. Conjugate addition – stable anions often add at the C-β carbon O O O O Na N C O O H3O+ / H2O (-CO2) O C O N 23. Dithiane Chemistry – see aldehydes and ketones above 1 S S 2 1. nBuLi 2. CH3CH2Br 3. WK S Dithiane alkylation (once) , then hydrolysis to the carbonyl compound. An aldehyde is obtained. S S O Hg +2 / H2O H S 3 S S 1. nBuLi 2. CH3Br 3. WK S S Dithiane alkylation (twice), then hydrolysis to the carbonyl compound. If hydrolyzed after one alkylation, then an aldehyde is obtained. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 4 Beauchamp 58 1. nBuLi 2. CH3CH 2Br 3. WK S S S S S 5 O Hg+2 / H2O S 24. Dianion Chemistry 1 O O O O 1. NaH or LDA 2. nBuLi O O O O O 2 O O Br O workup O O O 3 O O O O O 4 O 5 O H3O+ / H2O (-CO2) O 1. NaOH 2. LDA O O OH 7 A second alkylation can be performed using the normal ethyl acetoacetate synthesis, alcylating the position in between the two carbonyl groups. After ester hydrolysis and decarboxylation a disubstituted acetone is obtained with a alkylation on both sides of the carbonyl. O O CH3Br O O 1. O 2. workup Br The reaction can be run once, worked up and decarboxylated (shown in the next frame). In this case the same product could have been obtained using the normal ethyl acetoacetate synthesis. The same product as using the normal ethyl acetoacetate synthesis. O O O 6 O 1. 2. O O H3O+ / H2O (-CO2) To make dianion requires very strong bases. To simplify our reaction we will write 2 eqs of LDA to show formation of dianion. The second acidic site is the more reactive site in the alkylation. OH Dianions from carboxylic acid can be formed using a strong, nonnucleophilic base for the Cα-H position. The carbanionic site is the more reactive site and alkylation occurs there. The product will be an alkylated carboxylic acid, which can be esterified by making the carboxylate and doing an SN2 on an RX compound, as discussed earlier. C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide 59 O O 8 Beauchamp 1. NaOH OH OH Br 2. 25. Robinson Annelation 1 O O O O O O HO O 2 O i. Base makes enolate O O O O ii. conjugate addition to α,ß-unsaturated carbonyl O O 2. workup O OH 2 O 3 3 O 4 3 O 6 5 HO 6 O 4 O 1 5 iii. aldol condensation (-H2O), 1,6 atoms join together 1 O 2 O O β-hydroxycarbonyl (aldol product) OH 4 -H2O O O O β-hydroxycarbonyl 5 α,β-unsaturatedcarbonyl O O H3O O O O α,β-unsaturatedcarbonyl 6 -H2O ∆ HO O O - CO2 followed by tautomerization of enol HO O O O If ester group is hydrolyzed the acid will decarboxylate (-CO2) forming a cyclic ketone. (annelation = ring forming) O C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc