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Guide Beauchamp 1 Chem 316 / Beauchamp Reactions Review Sheet Name SN2 Reactions - special features: biomolecular kinetics Rate = kSN2[RX][Nu ], single step concerted reaction, E2 is a competing reaction o o o o relative order of reactivity: CH3X > 1 RX > 2 RX >> 3 RX (based on steric hinderance, no SN2 at 3 RX) allylic & benzylic RX are very reactive, adjacent pi bonds help stabilize transition state and lower TS energy (Ea) o complete substitution at Cα (3 RX) or Cβ (neopentyl pattern) almost completely inhibits SN2 reactions vinyl & phenyl are very unreactive, bonds are stronger and poor backside approach leaving group ability: OTs = I > Br > Cl in neutral or basic conditions (just like E2, SN1 adn E1), and neutral molecule leaving groups are good from protonated, cationic intermediates in conditions, + + + + -OH2 , -ORH , -OR2 , -NR3 , etc. we will consider all anions, , , and sulfides to be strong (favors SN2 and E2 reactions) in our course some electron pair donors are mainly nucleophiles (, , , 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, = DMF, acetonitrile = AN, , etc.) in our course some electron pair donors are mainly nucleophiles (sulfur, azide, cyanide, carboxylates) and we will consider neutral solvent molecules such as , and to be weak nucleophiles (favors SN1 and E1)

stereoselectivity: 100% inversion of configuration from backside atack

regioselectivity: reacts at with leaving group, completely unambiguous

chemoselectivity: N/A

The following list is designed to emphasize SN2 reactions. Other possibilities (E2) are not listed. a. primary RX (X = Cl, Br, I, OTs) Possible additional steps 1. make (HCl/H2O) 2. make acid (H2SO4/∆) N C 3. make (DIBALH) X N C 4. make (RMgBr) 5. make 1o (LiAlH4) Limitations o o SN2 at Me, 1 and 2 RX Possible additional steps 1. make cis (Pd/H2/quinoline) 2. make trans alkene (Na/NH3) 3. make (Pd/H ) R 2 4. make ketone (H SO /Η Ο) X R C C 2 4 2 5. make aldehyde (a.R2BH, b.H2O2) (from + NaNH ) 2 6. zipper reaction (NaNR2) Limitations alkyne (terminal or internal) o SN2 at Me and 1 RX Possible additional steps 1. make RX (SOCl2,PBr3,HI) 2. make tosylate (TsCl/py) H O 3. make aldehyde (PCC/no H2O) X OH 4. make acid (Jones/Η2Ο) 5. make alkoxide (NaH) Limitations o SN2 at Me and 1 RX

Possible additional steps 1. protonate in acid 2. stable in X R O OR (from alcohol + NaH) Limitations S 2 at Me and 1o RX ether N

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Possible additional steps O 1. hydrolyze in acid or base R 2. reduce with LiAlH4 X O O R 3. react twice with organometallics (from acid + NaOH) O Limitations S 2 at Me, 1o and 2o RX N

Possible additional steps 1. make thiolate with NaOH (good ) H S X SH (from NaSH) Limitations S 2 at Me, 1o and 2o RX N

Possible additional steps 1. can oxidize ro sulfoxide or R S X SR (from thiol + NaOH) Limitations S 2 at Me, 1o and 2o RX N

O O Possible additional steps imide 1. hydrolyze to 1o amine with N NaOH/H2O X N (or , H2NNH2) NaOH/H2O O O Limitations NH2 o o o S 2 at Me, 1 and 2 RX (from phthalimide + NaOH) 1 amine N

N3 Possible additional steps NNN 1. can by hydrogenated azide (reduced) to a 1o amines with X 2 Pd/H2 NNN Pd/H2

(from NaN3) NH2 Limitations azide o S 2 at Me, 1o and 2o RX 1 amine N

Possible additional steps P Ph Ph 1. make nucleophile with n-BuLi and react with P Ph X X = Ph P and to make 3 very specific alkyltriphenylphosphonium Limitations halide, this is used in S 2 at Me, 1o and 2o RX Wittig reactions N

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H Possible additional steps 1. makes RX center into H Al H Li alkane functionality X H

Limitations (LAH) S 2 at Me, 1o and 2o RX N

H Possible additional steps 1. makes RX center into X H B H Na alkane functionality H

Limitations S 2 at Me, 1o and 2o RX N

Possible additional steps 1. Couples two "R" parts from two different RX starting structures, one is made into an lithium, then a cuprate and coupled to Cu another RX compound, cuprates X Li are needed because this reaction organocuprate (from We will view cuprate + RX does not work with Mg or Li organolithium from as an SN2 reaction, eventhough reagents. free radicals may be involved Limitations RX compound) o o SN2 at Me, 1 and 2 RX

O Possible additional steps 1. LDA is made from diisopropyl amine and n-BuLi, usually in R CH2 Li R THF at room temperature and X from carbonyl the reaction run at compounds + lithium O -78oC diisopropyl amide (LDA), Limitations at very low temperatures, S 2 at Me, 1o and 2o RX many variations possible N special RX (allyl, benzyl, vinyl, phenyl, neopentyl) X X X X X

allyl RX benzyl RX vinyl RX phenyl RX neopentyl RX

exceptionally good electrophiles in SN2 reactions very poor electrophiles in SN2 reactions A good exercise would be to write out each reaction above with allyl and benzyl RX compounds.

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 4 b. secondary RX (X = Cl, Br, I, OTs)

Possible additional steps 1. see 1o RX, cyanide is not X N C N too basic for mainly SN2 at C o 2 RX, acid's pKa = 9

Limitations nitrile S 2 at Me, 1o and 2o RX N

Possible additional steps mainly E2 reaction 1. not useful at 2o RX, see 1o RX reactions, acdtylides X R C C are too basic for mainly SN2 at o 2 RX, acid's pKa = 25 2-E and 2-Z and 1- alkenes Limitations o SN2 at Me and 1 RX

OH Possible additional steps 1. not useful at 2o RX, see alcohol o X H O 1 RX reactions, messy product mixture (SN2 and E2), acid's pKa = 16 Limitations 2-E and 2-Z and 1- alkenes o SN2 at Me and 1 RX

OR Possible additional steps 1. not useful at 2o RX, see alcohol 1o RX reactions, messy X R O product mixture (SN2 and E2), acid's pKa = 16-18 Limitations 2-E and 2-Z and 1- alkenes o SN2 at Me and 1 RX

Possible additional steps O 1. see 1o RX, less basic carboxylates R are better behaved nucleophiles X O R O and give good yields for SN2 at 2o RX centers, conjugate acid's O pKa = 9 ester Limitations o o SN2 at Me, 1 and 2 RX

Possible additional steps 1. see 1o RX reactions H S X SH

thiol Limitations o o SN2 at Me, 1 and 2 RX

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 5 Possible additional steps 1. see 1o RX reactions X R S SR

Limitations sulfide o o SN2 at Me, 1 and 2 RX

O O Possible additional steps o N 1. see 1 RX reactions X N O O NaOH/H2O NH2 Limitations o o o SN2 at Me, 1 and 2 RX 1 amine

N3 Possible additional steps NNN o azide 1. see 1 RX reactions X 2 NNN Pd/H2

(from NaN3) NH2 Limitations o o o SN2 at Me, 1 and 2 RX 1 amine

Ph Possible additional steps Ph 1. see 1o RX reactions Ph P Ph P X Ph X Ph alkyltriphenylphosphonium triphenylphosphine halide, used in the Wittig Limitations o o reaction, SN2 at Me, 1 and 2 RX

Possible additional steps o H 1. see 1 RX reactions, We use LAH as nucleophilic H Al H Li hydride in this book. If X H we need basic hydride, we'll use , NaH. lithium aluminium hydride Limitations o o (LAH) SN2 at Me, 1 and 2 RX

Possible additional steps o H 1. see 1 RX reactions, We use NaBH4 as nucleophilic H B H Na hydride in this book. If X H we need basic hydride, we'll use sodium hydride, NaH. Limitations sodium borohydride o o SN2 at Me, 1 and 2 RX

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 6 Possible additional steps 1. see 1o RX reactions Cu X Li

Limitations organocuprate o o SN2 at Me, 1 and 2 RX

O Possible additional steps 1. see 1o RX reactions R CH2 Li X R

chemistry O Limitations o o SN2 at Me, 1 and 2 RX

Br O Intramolecular SN2 reaction. O O O

special RX (allyl, benzyl, vinyl, phenyl, neopentyl) X X X X X

allyl RX benzyl RX vinyl RX phenyl RX neopentyl RX

very poor electrophiles in S 2 reactions exceptionally good electrophiles in SN2 reactions N

SN reactions of 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 o o o favored reactivity: 3 RX > 2 RX > 1 RX (none at CH3X, need Cβ-H), o 1 RX 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 o complete substitution at Cα (3 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 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 RO- leaving group ability: OTs = I > Br > Cl in neutral or basic conditions (just like SN2/E2 reactions) anions whose conjugate acids have high pKa's (weaker acids have stronger bases) generally produce more E2 relative to o SN2, the two examples we will emphasize at 2 RX centers are carboxylates (SN2 > E2) vs hydroxide and alkoxides (E2 > SN2) and cyanide (SN2 > E2) vs terminal (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 CH2 will often be different, producing E or Z stereoisomer alkenes depending on o the anti conformations present, also a chiral 3 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 B At 1o RX S 2 is usually E2 H N H Cβ Nu B target H Cβ favored over E2, except if the sterically large and S 2 Cα N Cα X very basic potassium Nu H target t-butoxide is used. H Nu = B X perspective 1 perspective 2

o 2 RX template o Nu At 2 RX SN2 and E2, are in H competition, less basic electron H Cβ H Nu B pair donors tend to favor SN2 H and more basic electron pair Cα X C B H β Cβ donors tend to favor E2 reactions, Cα any feature that adds sterically H Cβ large groups pushes the reaction Nu = B X perspective 1 perspective 2 towards E2.

3o RX template Nu H H H Cβ H Nu B Only E2 reactions are expected Cβ C X at 3o RX when reactied with B H C α Cβ Cβ β strong electron pair donors. Cα H Cβ Nu = B perspective 1 perspective 2 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 C 6 5 2 1 3 interconvert in fast equilibrium C

possible reactions an axial "X" is necessary for a succesful possible E2 reaction and also works better for SN2 reactions ? ?

An example of some possible choices for SN2 versus E2 in reactions at a secondaryRXcenter having a chiral Cα,chiral Cβ and a betaCH2.

SN2 CH2CH3 E2 CH2CH3 OCH3 H CH CH H 2 3 OCH3 CH CH H Cβ H C H 2 3 Cβ β C Nu OCH3 B C OCH Cα I Nu C C I 3 H H H α Hb H C Ha Cβ b Hb Ha Cβ Ha Cβ CH3 H CH3 CH3 CH3 (2E,4S)-3-methoxy-2-hexene (3S,4S) (3R,4S)

E2 CH CH E2 2 3 CH CH OCH CH3CH2 OCH 2 3 H C 3 3 OCH H β C 3 H CH2CH3 H Cβ C B C I B C H α C C I OCH3 H α Hb H H C CH2CH3 CH C a β H C 3 b β H CH3 CH3 (3Z)-3-methoxy-3-hexene Ha (2Z,4S)-3-methoxy-2-hexene a. primary RX (X = Cl, Br, I, OTs), typically see mostly SN2and donot consider the E2 product, unless the base is potassium t-butoxide, then E2 is the major product

OH H O X or or Contrast with the reaction OR below. R O

mainly SN2

BUT O K X Contrast with the reaction above. mainly E2 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 less basic, mainly SN2 reaction more basic, mainly E2 reaction O N C R C C R H O R O O pK of conjugate acid = 16-18 pKa of conjugate acid = 9 pKa of conjugate acid = 25 pKa of conjugate acid = 5 a

E2 reactions of 2o RX (and a few 3o RX) compounds

Possible additional steps 1. many additional alkene reactions, are possible although in this H O or R O X reaction these would not be E2 products productive because too many different products are obtained OH (or OR) E2 requires Cβ-H and Cα-X Limitations bonds to be in anti conformation SN2 product SN2 and E2 products obtained

Possible additional steps 1. alkene reactions H O or R O

X only one hydrogen can be anti Limitations or three Cβ-H's mainly E2 product

CH3 only E2 reaction, t-butoxide is H C C O 3 K too big and bulky for SN2 CH3 reactions, an anti Cβ-H is Br possible on either side when the Br is axial

enantiomers

CH3 High pKa , sterically bulky base, H3C C O K should be only E2, but Br cannot CH3 significantly rotate to an axial Br No reaction position since the very large t-butyl group locks the ring into confromation having t-but yl equatorial.

o 6 Only E2 at a 3 RX with a strong base/nucleophile. There are three C 's but only C and the methyl 1 R N β 6 Br 3 allow the necessary anti 2 (DBU or DBN) conformation for E2 reactions. C2 cannot rotate its hydrogen anti.

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o 6 Only E2 at a 3 RX with a strong base/nucleophile. All three Cβ's F can rotate a hydrogen anti and 1 Br 3 form E2 product.

A C carbon is fully substituted CN β Br so SN2 reaction is greatly inhibited. There is an anti Cβ-H possibility on the other side so E2 can occur there.

H Br 5 6 4 S 2 and E2 reactions possible, 3 1 N 2 CH3O this is a good example for showing H H CH3 H See choices below. why you need o be able to draw and understand 3D drawings, this (3S,4S) Br example is comprehensively viewed CH 3 below. H H

SN2 reaction CH3O H OCH3 H SN2 H S Br R Br H S S H H

E2 reactions H H S Br H C-C S rotation H H H CH CH3O CH3O H CH O 3 CH 3 C-C 3 C-C H H rotation rotation H H H H H H CH3 Br H Br Br

E2a E2b E2c H CH3 H CH3 CH3 H H

CH3 H H H H H "Z" configuration "E" configuration "E" configuration

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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 competing reactions (usually SN1 dominates) o o o favored reactivity: 3 RX > 2 RX and we say none at a 1 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 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) X 2 2 X 2 2 H Nu transfer CX CNu Nu C H Nu C Nu H 4 4 4 3 3 3 4 3 "S" configuration "S" configuration attack can occur from either "R" configuration face of the flat carbocation to racemization (50/50 mixture for our course) ii. (cis ring cis/trans ring) or (trans ring cis/trans ring) R R R Nu H Nu H R proton H Nu transfer H Nu X trans ring cis ring trans ring X Nu H attack can occur from top or bottom of carbocation Br H H H Br H H = H first step for H H SN1/E1 reactions H H ROH H CH3 CH3 H CH3 only one anti C -H conformation changes of two chairs β allows any beta hydrogen to be lost "IF" E2 reaction. from the carbocation "IF" RO 1. rearrange 2. add Nu 3. lose beta-H (likely in this reaction S 2/E2 o + N because a 3 R can form)

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 12 via Our general rules are SN1 > E1, except for high temperature, acid dehydration of alcohols. Br H2O Rearrnagement here is not a E1 (minor) problem because nothing OH changes. No stereochemistry or regiochemistry to consider. S 1 (major) N

via Our general rules are SN1 > E1, except for high temperature, acid ROH dehydration of alcohols. Br Rearrnagement here is not a E1 (minor) OR problem because nothing changes. No stereochemistry or regiochemistry to consider. S 1 (major) N

via O Our general rules are SN1 > E1, except for high temperature, acid dehydration of alcohols. OH Br Rearrnagement here is not a O E1 (minor) problem because nothing O changes. No stereochemistry or regiochemistry to consider. SN1 (major)

via E1 (minor) H2O enantiomers Br Rearrangement of 2o OH OH carbocation is possible, SN1 (major) but not shown in this diastereomers problem. via E1 (minor) ROH enantiomers Br Rearrangement of 2o OR OR carbocation is possible, SN1 (major) but not shown in this diastereomers problem.

via E1 O (minor) enantiomers Br OH O Rearrangement of 2o O SN1 (major) carbocation is possible, ester on top diastereomers but not shown in this and bottom 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

H2O Br E1 (minor) Rearrangement is likely because a 3o S 1 (major) N OH carbocation can form from the originally formed 2o carbocation.

via

ROH Br E1 (minor) Rearrangement is likely because a 3o SN1 (major) carbocation can form from the OR o originally formed 2 carbocation.

via O

Br OH E1 (minor) O Rearrangement is likely because a 3o carbocation can form from the S 1 (major) O o N originally formed 2 carbocation.

via Rearangement is likely since a 3o carbocation can form, normally SN1 dominates over E1, with H2O Br racimization of a chiral center OH (stereogenic centers are drawn with a wiggly lines), however significant E1 is expected because the alkene is S 1E1tetrasubstituted. N

via Rearangement is likely since a 3o carbocation can form, SN1 will Br ROH dominate over E1, racimization of chiral center is expected OR (stereogenic centers are drawn with a wiggly line, only the most stable E1 alkene is shown. S 1E1 N

via Rearangement is likely since a 3o O carbocation can form, normally SN1 dominates over E1, with Br OH racimization of a chiral center O (stereogenic centers are drawn with a wiggly lines), however significant O E1 E1 is expected because the alkene is tetrasubstituted. SN1

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SN1, very good at benzylic even Br OH though primary can still occur H2O because of resonance stabilization of carbocation, E1 is not possible here because there is no Cβ-H to lose a hydrogen.

O Phenyl carbocation is VERY Br OH No reaction difficult to form in sp2 orbital.

+ SN1, very good at allylic R common intermediate via Br resonance, two different products formed from a or OR ROH commonintermediate having Br OR partial positive charge at two kinetic thermocynamic sites as shown by the product product resonance structures

Vinyl carbocation is VERY difficult to form in p orbital of sp hybridized H2O No reaction carbon. Carbocations that we typically Br see are empty p orbitals of a sp2 hybridized carbon.

SN1, acid protonates OH and makes + -OH2 . Water is a good leaving group HI o o OH I and when at 2 or 3 forms a carbocation. Mainly SN1 with HX acids. Nucleophile cis or trans adds from top and bottom. cis and trans

SO2 leaving group, HCl also OH SOCl2 Cl formed. View reaction as SN1 at 2o and 3o ROH. cis or trans cis and trans

Oxygen first does SN2 at phosphorous and then HOPBr2 is the leaving group OH PBr3 in second step (repeated two more Br o times). View reaction as SN1 at 2 and cis or trans o o cis and trans 3 ROH and SN2 at methyl or 1 ROH.

O Substitution reacton is at the sulfur = TsCl S Cl OTs and represents another way to make the OH into a good leaving group, as OH O cis goes to cis a tosylate (inorganic sulfur ester). N = and Pyridine added to sponge up (neutralize) the HCl generated in the reaction. trans goes to trans

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Dehydration of alcohols in strong acid, with heat, represents OH H2SO4 / ∆ our main E1 conditions. Rearrangement is possible, but cis or trans enantiomers not shown.

OH would protonate, but -OH + HBr 2 OH cannot leave from a phenyl carbon. No Reaction the empty sp2 orbital (NOT a p orbital!) is too unstable.

Just a reminder at 1o ROH, OH + HBr would protonate, but -OH2 OH Br 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) OH H2SO4 / ∆ major distill out. Tetrasubstitution is the E1 most stable alkene shown.

E1 product. The most stable H SO / 2 4 ∆ alkene is shown due to more substituted, trans and conjugated. HO

Oxygen first does SN2 at phosphorous OH Br and then HOPBr2 is the leaving group PBr3 in second step (repeated two more o times). View reaction as SN1 at 2 and o o 3 ROH and SN2 at methyl or 1 ROH.

1. makes tosylate (good leaving group) reaction occurs at sulfur, not carbon 1. TsCl, pyridine so no change in chiral center 2. NaBr 2. SN2 by bromide at carbon, chiral OH Br center inverts

SO2 leaving group, HCl also formed. View reaction as SN1 SOCl2 o o at 2 and 3 ROH and SN2 at Cl OH 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 Beauchamp 16 Reactions of Alkenes (and ) -

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.

Markovnikov addition, 1 Br Stereo = N intermediate carbocation Regio = Y HBr (can rearrange, add a nucleophile or lose a racemic beta hydrogen.

Markovnikov addition, 2 a. Hg(OAc) OH Stereo = N 2 Regio = Y intermediate carbocation H2O (or ROH) does not rearrange because of b. NaBH mercury bridge, NaBH reduces 4 racemic 4 off mercury to hydrogen

3 Markovnikov addition, OH Stereo = N Regio = Y intermediate carbocation can rearrange if more stable H2SO4 / H2O carbocation can form, if heated racemic the E1 alkene is the product

4 Stereo = Y anit-Markovnikov addition, (syn) a. BH3 OH borane forms trialkylborane, Regio = Y b. H2O2 / HO second step oxidizes boron position to an OH

5 Stereo = Y (syn) Same as above, but instead of a. BH Br 3 Regio = Y boron becoming an OH, it b. Br2 / CH3O becomes a Br

6 Br Stereo = Y Bromonium bridge prevents (anti) rearrangement, bromide adds Br Regio = N anti to first at more Br2 racemic partial postive carbon.

7 Stereo = Y Bromonium bridge prevents OH (anti) rearrangement, hydroxide adds anti to first bromine at more Br / H O Br Regio = Y 2 2 partial positive carbon. Similar to racemic above reaction.

8 Stereo = Y Product from #7 forms an O (anti, SN2) epoxide. Oxgen attacks from a. Br2 / H2O backside in anti conformation. b. NaOH Regio = N Can also be made directly from racemic (overall) 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 Stereo = Y 9 O (syn) Regio = N Reaction occurs in a single mCPBA racemic step via concerted mechanism.

10 a. mCPBA Net result of epoxidation followed OH Stereo = Y b. H3O / H2O (anti) by opening the epoxide in acid or or OH Regio = N base is anti addition of two vicinal b. HO / H2O alcohol groups. This is opposite to racemic the next reaction (syn addition).

11 Stereo = Y Dioxygenation occursinasingle OsO4 OH concerted step via syn addition, or (syn) OH Regio = N followed by aqueous to KMnO4 form a vicinal diol. This is opposite racemic to the above reaction (anti addition).

12 Stereo = Y (syn) The metal activates the hydrogen Regio = N and two hydrogen atoms add to H2 / Pd achiral the pi bond in a cis or syn manner.

Stereo = N 13 Ozone cuts pi bond in two and o H Regio = N 1. O3, -78 C OH workup leaves a carbonyl bond 2. CH3SCH3 or Zn at each carbon (aldehydes and/or O ketones are the products). H 14 Stereo = N Regio = N o Ozone cuts pi bond in two and 1. O3, -78 C workup reduces carbonyl bonds 2. NaBH4 OH HO CH3 at each carbon to alcohol groups.

Stereo = N 15 Ozone cuts pi bond in two and Regio = N workup oxidizes carbonyl bonds o OH 1. O3, -78 C OOH at each carbon to carboxylic 2. H2O2 acids or ketones if the alkene O = CO2 OH carbon is geminally substituted.

16 Stereo = N Bromine adds as in reaction6above. 1. Br2 Regio = N performs two E2 2. NaNH2 reactions and then deprotonates the 3. WK alkyne. Workup with acid protonates the sp carbanion to form an alkyne.

17 Stereo = Y The metal activates the hydrogen Regio = N H / Pd and two hydrogen atoms add to the 2 first pi bond in a cis or syn manner to form an alkene, which then reduces to the alkane.

18 Stereo = Y The metal activates the hydrogen Regio = N and two hydrogen atoms add to the H2 / Pd / quinoline first orbital 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 18 19 Stereo = Y An electron from sodium adds to Regio = N the LUMO orbital. the resulting Na / NH3 anion protonates. Another electron adds and the resulting anion protonates to form the more stable E alkene.

20 Stereo = N Markovnikov addition, intermediate Regio = Y carbocation (can rearrange, add a HBr Br nucleophile or lose a beta hydrogen. achiral, but cis/trans diastereomers

Stereo = N Markovnikov addition, 21 a. Hg(OAc) 2 Regio = Y intermediate carbocation H O (or ROH) 2 OH does not rearrange because of b. NaBH4 mercury bridge, NaBH4 reduces off mercury to hydrogen

22 Stereo = N Markovnikov addition, Regio = Y intermediate carbocation OH can rearrange if more stable H2SO4 / H2O carbocation can form, if heated the E1 alkene is the product

OH 23 Stereo = Y anit-Markovnikov addition, Regio = Y boron and hydrogen add syn, a. BH3 OH borane forms trialkylborane, b. H2O2 / HO second step oxidizes boron position to an OH 24 Br Stereo = Y Regio = Y Same as above, but instead of a. BH3 Br boron becoming an OH, it b. Br2 / CH3O becomes a Br

25 Br Stereo = Y Br Regio = N Bromonium bridge prevents Br Br 2 rearrangement, bromide adds Br anti to first bromine.

26 Br Bromonium bridge prevents Br rearrangement, hydroxide adds anti to first bromine at more Br2 / H2O OH partial positive carbon. Similar Stereo = Y, Regio = Y OH to above reaction.

27 Product from #7 formsan epoxide. Oxgen attacks from O O a. Br2 / H2O backside in anti conformation. b. NaOH Can also be made directly from Stereo = Y, Regio = N alkene with mCPBA.

28 Reaction occurs in a single O O step via concerted mechanism. mCPBA 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 Beauchamp 19

29 OH Net result of epoxidation followed a. mCPBA OH b. H3O / H2O by opening the epoxide in acid or or OH base is anti addition of two vicinal b. HO / H2O alcohol groups. This is opposite to Stereo = Y, Regio = N OH the next reaction (syn addition).

30 OH Dioxygenation occurs in a single OsO 4 OH concerted step via syn addition, or followed by aqueous hydrolysis to KMnO4 form a vicinal diol. This is opposite OH OH Stereo = Y, Regio = N to the above reaction (anti addition).

31 The metal activates the hydrogen and two hydrogen atoms add to H2 / Pd the pi bond in a cis or syn manner. Stereo = Y, Regio = N

O 32 Ozone cuts pi bond in two and 1. O , -78oC O workup leaves a carbonyl bond 3 H 2. CH3SCH3 or Zn at each carbon (aldehydes and/or ketones are the products).

33 OH o Ozone cuts pi bond in two and 1. O3, -78 C OH 2. NaBH workup reduces carbonyl bonds 4 at each carbon to alcohol groups.

34 O Ozone cuts pi bond in two and workup oxidizes carbonyl bonds 1. O , -78oC O 3 OH at each carbon to carboxylic 2. H2O2 acids or ketone if the alkene carbon is geminally substituted.

35 Bromine adds as in reaction 6 above. 1. Br2 Sodium amide performs two E2 2. NaNH2 reactions and then deprotonates the 3. WK alkyne. Workup with acid protonates the sp carbanion to form an alkyne.

36 The metal activates the hydrogen H / Pd and two hydrogen atoms add to the 2 first pi bond in a cis or syn manner to form an alkene, which then reduces to the alkane.

37 The metal activates the hydrogen and two hydrogen atoms add to the H2 / Pd / quinoline 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 38 An electron from sodium adds to the LUMO pi bond. the resulting Na / NH3 anionprotonates. Another electron adds and the resulting anion protonates to form the more stable E alkene.

39 Zipper reaction, -like 1. Na NR2 proton exchanges that move pi 2. workup bonds to the terminal position where anion is most stable (in sp orbital) as: R

40 1. Na NR2 Zipper reaction, R 2. O opens epoxide, workup protonates the alkoxide. 3. workup OH

41 1. Na NR2 2. Zipper reaction, R Br does SN2 on R-Br. 3. workup

Na NR 42 1. 2 Step one forms terminal sp carbanion 2. H2C=O OH nucleophile. Step 2 adds methanal H 3. workup (formaldehyde) as a one carbon electrophile. Workup protonates the alkoxide anion.

1. Na NR 43 2 O OH Similar to above except a generic 2. aldehyde is used as the carbon H H electrophile. Workup protonates the 3. workup alkoxide anion.

Markovnicov addition of water (H 44 O H2SO4 / H2O and OH) via most stable carbocation. H Forms enol which tautomerizes to HgSO4 methyl ketone when a terminal alkyne reacts.

45 O If a nonterminal alkyne is used, 2-hexanone H2SO4 / H2O reaction could occur from either O side, possibly producing different HgSO4 ketones probably in similar amounts. 3-hexanone

46 If some special feature makes O H2SO4 / H2O one side preferred (e.g. resonance) HgSO4 then a single ketone might be preferred.

Anti-Markovnikov addition of dialkylborane to 47 a terminal alkyne. Two large R groups are used O (9-BBN is common) so the addition only occurs H a. R2BH once to the skinny alkyne. Workup with H2O2 b. H2O2 / HO H 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. R BH If a nonterminal alkyne is used, 2 reaction could occur from either b. H O / HO O 2 2 side, possibly producing different 3-hexanone 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 22 Reactions of Alcohols (SN, E, oxidation, esterification, acetal/ketal formation, acid/base...)

There is and there are primary, secondary, tertiary, allylic, benzylic alcohols. Phenols (aromatic alcohols) are considered separately. R R H OH R C OH R C OH R C OH OH OH H3C OH H H R o methanol 1 ROH 2o ROH 3o ROH allylic alcohols benzylic alcohols phenols

1 HI No carbocations at primary OH I carbon. Mechanism is SN2.

2 Carbocations form at secondary SOCl2 Cl OH carbon. Mechanism is SN1.

3 Br Carbocations form at secondary OH PBr3 carbon. Mechanism is SN1.

4 E1 conditions, alkene would OH distill out and shift equilibrium major H2SO4 / ∆ towards products. Rearrangements are expected.

5 E1 conditions, alkene would OH distill out and shift equilibrium H2SO4 / ∆ towards products. Rearrangements are expected.

6 E1 conditions, alkene would OH distill out and shift equilibrium H2SO4 / ∆ towards products. Rearrangements major minor are expected.

7 Sodium hydride is only basic in our course. It is very useful for OH Na Na H O pulling off very weakly acidic . LAH and NaBH4 Na(s) metal can also be used a strong base/nucleophile can be nucleophilic in our course.

8 Sodium hydride is only basic in Na our course. It is very useful for OH Na H O pulling off very weakly acidic protons. LAH and NaBH4 Na(s) metal can also be used a strong base/nucleophile 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 Sodium hydride is only basic in Na OH Na H O our course. It is very useful for pulling off very weakly acidic protons. LAH and NaBH4 Na(s) metal can also be used a strong base/nucleophile can be nucleophilic in our course.

10 1. NaH The first reaction is acid/base and the second reaction is S 2. OH N 2. Br O This reaction would work in either direction of alcohol and RX compound.

11 1. NaH The first reaction is acid/base and the second reaction is S 2. OH O N 2. Br If the reaction were tried the other way around there would be consideralbe E2 product

The first reaction is acid/base 12 1. NaH OH O and the second reaction is SN2. If the reaction were tried the other 2. Br way around there would only be E2 product

O 13 tosyl The OH of an alcohol can be made S Cl chloride into a toslyate (an inorganic ester). OH OTs Tosyl group is a very good leaving O group in SN and E chemistry (similar o pyridine = proton sponge 1 tosylate, good leaving group to iodides).

14 O The OH of an alcohol can be made tosyl into a toslyate (an inorganic ester). S Cl OTs OH chloride Tosyl group is a very good leaving O group in S and E chemistry (similar o N pyridine = proton sponge 2 tosylate, good leaving group to iodides).

15 Ts-Cl = tosyl chloride The OH of an alcohol can be made OH OTs into a toslyate (an inorganic ester). N Tosyl group is a very good leaving group in S and E chemistry (similar o N pyridine = proton sponge 3 tosylate, good leaving group to iodides). Susceptible to E1.

O 16 Removing water shifts equilibrium TsOH (cat.) to the right and adding water shifts OH O OH (remove H2O) equilibrium to the left. Toluene sulfonic acid is a common catalyst. O Fischer esterification

O 17 O Removing water shifts equilibrium TsOH (cat.) to the right and adding water shifts OH OH (remove H2O) equilibrium to the left. Toluene O 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 Removing water shifts equilibrium 18 TsOH (cat.) to the right and adding water shifts OH O OH (remove H2O) equilibrium to the left. Toluene sulfonic acid is a common catalyst. Fischer esterification O o E1 possible at 3 RX, reducing yields.

Need OH and H on the same carbon 19 O CrO3 / pyridine / no H2O atom. Highly oxidized chromium strips OH PCC electrons from oxygen and base removes H proton in E2 reaction to form pi bond o aldehyde at 1 ROH between the carbon and the oxygen. 20 Need OH and H on the samecarbon CrO3 / pyridine / no H2O atom. Highly oxidized chromium strips OH PCC O electrons from oxygen and base removes proton in E2 reaction to form pi bond ketone at 2o ROH between the carbon and the oxygen. 21 Need OH and H on the samecarbon CrO / pyridine / no H O OH 3 2 atom. Highly oxidized chromium strips PCC No reaction at 3o ROH electrons from oxygen and base removes proton in E2 reaction to form pi bond between the carbon and the oxygen.

22 O In acid the aldehyde hydrates and OH and H are on the same carbon atom again. CrO3 / H2O / acid OH The second oxidation forms a carboxylic Jones reagent OH acid. acid at 1o ROH

23 No further reaction is possible on a CrO / H O / acid OH 3 2 O ketone because there is no hydrogen Jones reagent atom to allow the E2 reaction to occur. ketone at 2o ROH

24 Tertiary alchols do not react because OH CrO / H O / acid 3 2 No reaction at 3o ROH there is not hydrogen atom to allow Jones reagent the E2 reaction to occur.

O diol = ethylene glycol 25 Acetals are used to protect aldehydes. OH O O They are stable in neutral and basic H HO solution, but reactive in acid solution. toluene sulfonic acid = TsOH H aldehyde Removing water shifts equilibrium to acetal the right, adding it shifts to the left. (remove H2O)

O diol = ethylene glycol 26 Ketals are used to protect ketones. OH O O They are stable in neutral and basic HO solution, but reactive in acid solution. toluene sulfonic acid = TsOH Removing water shifts equilibrium to ketone ketal the right, adding it shifts to the left. (remove H2O)

Alcohols can be protected withDHP forming a THP acetal. There is a 27 enol ether OO disquised carbonyl and second OH hidden in the DHP and THP groups. TsOH acetal THP acetals are stable in neutral and OH O (remove H2O) basic solution, but reactive in acid OTHP solution. Removing water shifts DHP = dihydropyran equilibrium to the right, adding it shifts THP = tetrahydropyran 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 (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. H 1R 1R O O O 4S O 4S O 2R 2S 2S ethylene oxide (2R)-propylene oxide oxide (1R,2S,4S)-methylcyclohexene oxide (1R,2S,4S)-2,4-dimethyl- ethenoxirane (2R)-propenoxirane cyclohexenoxirane (1R,2S,4S)-methylcyclohexenoxirane cyclohexenoxirane

1 Opens trans or anti from backside + attack. Cannot tell in this simple O H2O / H3O OH epoxide. HO

2 Opens trans or anti from H H backside attack at the more O H O / H O+ 2 3 OH substituted, more partial HO 2R 2S positive carbon. Chiral center does invert, becomes S.

3 OH OH Similar to #1. Opens trans or + anti from backside attack. O H2O / H3O Enantiomers are formed in OH OH equal amounts (a racemic 50/50 mixture of enantiomers mixture).

4 OH OH Similar to #1. Opens trans or + anti from backside attack. O H2O / H3O Diasteromers are formed in OH OH unequal amounts. unequal mixture of diasteromers 5 In strong base/nucleophile conditions O attack is at the less hindered positon HO / H2O HO as expected in S 2-type reactions. OH N A chiral center at the more a strong base/nucleophile substituted position is not inverted.

6 In strong base/nucleophile conditions H HOH attack is at the less hindered positon O HO / H2O as expected in SN2-type reactions. 2R A chiral center at the more 2R HO substituted position is not inverted.

7 OH Similar to #5. Opens trans or anti from backside attack. O HO / H2O Enantiomers are formed in a OH 50/50 racemic mixture. racemic mixture of enantiomers

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 26 8 OH OH Similar to #5. Opens trans or anti from backside attack. O HO / H2O Diasteromers are formed in OH OH unequal amounts. unequal mixture of diasteromers

Similar to #5. Mg and Li reagents are 9 CH (MgBr) O 2 formed from the metals and an RX 2. workup HO compound. Cuprates are made from Grignard, lithium or lithium reagents and cuprous bromide cuprate organometallic (CuBr). Workup is necessary

OH 10 H CH (MgBr) H O 2 Similar to #6. 2. workup 2R Grignard, lithium or 2R cuprate organometallic

11 CH2 (MgBr) OH Similar to #7. O 2. workup Grignard, lithium or cuprate organometallic racemic mixture of enantiomers

12 OH CH2 (MgBr) Similar to #8. O 2. workup Grignard, lithium or OH cuprate organometallic unequal mixture of diasteromers

13 SN2 reaction at less hindered O H Na center. The is made HO 2. workup from a terminal alkyne + NaNH2. terminal acetylides

14 H HO Similar to #6. O H Na H 2. workup 2R 2R terminal acetylides

15 OH H Na Similar to #7. O 2. workup terminal acetylides racemic mixture of enantiomers

OH 16 H Na Similar to #8. O 2. workup terminal acetylides 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. X H H H C O CO HX CO CO X addition C C H Cα product H α H Cα H α

The addition is totally top/bottom or syn/anti addition is not relevant in our course, but addition could produce enantiomers, if the regioselective. Use a could lead to R/S stereochemistry (loss of "β H" is also possible) carbon with the OH group is the only chiral lone pair for electron resonance shows that the positive charge is spread over the carbon center...or could lead to diasteromers, if donation. In our course, and oxygen atoms, the first resonace structure is better with full there is one or more other chiral centers begin every carbonyl octets and an extra bond, but the second resonance structure is reaction in acid this way. very informative about the ultimate fate of the intermediate H H competing pathway, redrawn from CO CO above (keto/enol tautomerization) C enol structure X H α Cα

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 Remember a similar competition about where to donate the b. Basic attack at an adjacent hydrogen (Cα-H) 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.

HX Nu C O H Nu C O Nu C O addition C C product H α H Cα H α often all acidic protons are excluded neutralize, often as a to avoid protonating the nucleophile second workup step

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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 C O an electrophile, usually at carbon C O Cα C δ E α carbon electrophiles E often add at Cα B C O carbonyl with H Cα electrophile reaction with a proton, "keto" can occur at carbon or C O hydrogen usually tautomer oxygen () H C O equilibrates among Cα Cα-H's to carbonyl groups are more Cα all basic positions, acidic than typical C-H bonds due to H X preferred location resonance stabilization by oxygen in enolate depends on thermo- intermediate tautomerization "enol" the enolate conjugate base. tautomer dynamics though less stable contributors pKa (CH in alkane) = 50 further reactions may be more reactive at C or O pKa (CH α to C=O) = 20 are possible Reactions of Aldehydes and Ketones (mainly carbonyl addition reactions) O O O O O H O H propene 2S-methylbutanal 2-butanone 2R-methylpentan-2-one 4-methylcyclohexan-1-one 3R-methylcyclohexan-1-one

Hydration of a carbonyl. 1 Equilibrium favors the keto O + HO OH form. Very fast in acid or H2O / H3O base and very slow in neutral H H water. Keto/enol tautomeriztion is also possible.

2 O Same as #1. HO OH + H2O / H3O

3 Same as #1. + OH O H2O / H3O OH

Hydration of a carbonyl. 4 Equilibrium favors the keto O HO OH form. Very fast in acid or HO / H2O base and very slow in neutral H H water. Keto/enol tautomeriztion is also possible.

5 O HO OH Same as #2. HO / H2O

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 Same as #2. HO / H2O OH

7 OH Organometallic (from RX O 1. Li compound) adds to carbonyl electrophile. Racemic (R/S) H o 2. workup 2 benzylic ROH forms in this reaction.

8 O 1. CH3CH2 (MgBr) OH Organometallic (from RX compound) adds to carbonyl electrophile. Achiral 3o ROH 2. workup forms in this reaction. 9 1. Na Terminal acetylide adds to top O OH and bottom of carbonyl face. 2. workup Cis/trans diastereomers form. "OH" on top and bottom

10 Cyanide nucleophile forms O 1. Na CN OH cyanohydrin with carbonyls and slow addition of acid. Aldehydes H 2. workup C and less substituted ketones work N best. R/S is possible here.

o 1 RNH2 + aldehyde or ketone forms 11 . Removing water shifts O H2N equilibrium to right and adding water o N shifts it to left. Many 1 RNH2 TsOH derivatives react similarly. E/Z pH = 5 (-H2O) stereochemistry is possible but not shown.

o 12 Pyrolidine (2 amine) forms enamines H N with carbonyl compounds. Removing O N water shifts equilibrium to right and TsOH adding water shifts it to left. Makes Cα into a neutral nucleophilic carbon. pH = 5 (-H2O)

13 O Oxidizes via carbonyl hydrate. CrO , H O, H O+ O 3 2 3 OH (Jones) H H OH OH

14 O Zn, HCl Reduces C=O to CH2 in acid. Clemmenson Reduction 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 Beauchamp 30 15 Reduces C=O to CH2 in base. H2NNH2, KOH, ROH A hydrazone forms, there are a O (Wolff-Kishner Reduction) number of proton transfers, some resonance structures and loss of .

Acetals form (via hemiacetals). Removing water shifts equilibrium to right and adding water shifts it to left. Makes 16 O OH HO carbonyls unreactive under neutral and TsOH O O basic conditions (protects them), but are H reactive in acid to break down back to the (-H2O) H carbonyl.

Similar reaction with ketones. 17 O OH Ketals form (via hemiketals) and are HO used to protect ketones. Removing O O TsOH water shifts equilibrium to right (-H2O) and adding water shifts it to left.

Sodium borohydride only reduces 18 O aldehydes and ketones and opens 1. NaBH 4 epoxides. Workup protonates 2. workup H OH intermediate anion. An aldehyde o forms a 1 ROH.

Lithium aluminium hydride reduces all carbonyl compounds, 19 and opens epoxides. Workup H O 1. LiAlH4 protonates intermediate anion. A 2. workup OH ketone forms a 2o ROH. Cis/trans diastereomers form in this example.

1. 20 Wittig reactions form really specific O Ph alkenes. The Wittig salt is formed Ph P via RX + Ph3P. Nucleophilic carban H Ph is generated with nBuLi. 2. workup

21 1. Ph O Ph P Wittig reaction. Wittig salt formed via RX + Ph3P. Carbanion Ph generated with nBuLi. 2. workup

22 O HO Ketal formation (remove water). (diol) Hydrolyze ketal to ketone under HO O O same conditions, but add water. for carbonyls. TsOH, (-H2O)

o 23 Pyrolidine (2 amine) forms enamines O H N with carbonyl compounds. Removing water shifts equilibrium to right and N H TsOH adding water shifts it to left. Makes Cα into a neutral nucleophilic carbon. pH = 5 (-H2O)

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1o amines form imines with carbonyl 1. 24 pH = 5 (-H2O) compounds, which can be reduced to H2N H 2o amines by NaBH CN. 2o amines react O 3 N in an analogous way to form 3o amines 2. Na H3BCN H (see next example).

1. 25 pH = 5 (-H2O) 2o amines form iminium with H N carbonyl compounds, which can be O N o reduced to 3 amines by NaBH3CN. 2. Na H BCN (See examples above.) 3 Li and Mg organometallics prefer 1. OH 1,2 attack of α,β-unsatruated carbonyls. 26 O β Li Cuprates prefer attack at Cβ, called α conjugate addition or 1,4-addition. H Allylic/benzylic OH probably unstable α,β-unsaturated carbonyl 2. workup in this example.

O Li and Mg organometallics prefer 27 O 1. β 1,2 attack of α,β-unsatruated carbonyls. α Cu Cuprates prefer attack at C , called Li β conjugate addition or 1,4-addition. α,β-unsaturated carbonyl 2. workup is retained in this example.

More stable nucleophiles, like cyanide, prefer attack at Cβ, forming 28 O the more stable, thermodynamic O Na CN product, also called conjugate addition or 1,4-addition. Stabilized enolates, H O/ROH β α 2 C discussed later, react in a similar α,β-unsaturated carbonyl N 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 32 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 N C OH O Cl O NH2 propanoic acid propanoyl chloride propanoic anhydride ethyl propanoate propanamide propanenitrile

Which C=O groups are most reactive? Why? (The answers are found in steric, inductive and resonance effects.) Thiol (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 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 ). 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 . 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 C D E FGH

O O O O O O O O O 1 C C C C C C C C C R Cl R O R R SR R H R R R OR R NR2 R O

O O O O O O O O O 2 C C C C C C C C C RClR O R RSR RH RR ROR RNR2 RO

no additional resonance O O O O O O O 3 C C C C C C C RClR O R RSR ROR RNR2 RO

-7 (-10) +5 (+7) +7 (+10) +40 (+56) +50 (+70) +18 (+25) +37 (+52) +25 (+35) The first number represents the pKa of LG part of acyl group when protonated (the corresponding ∆G in pKa (∆G) parentheses in kcal/mole). This provides a measure of how stable the leaving group is on its own. of HCl

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 33 1 O There are a variety of ways to O S O transform a into Cl Cl an acid chloride. Two of these are OH Cl shown and use thionyl chloride or thionyl chloride oxalyl chloride.

O O O See #1. Acid chlorides are at the 2 Cl top of the reactivity hill and all Cl oxalyl OH chloride Cl of the other acid derivatives can O be made from them by using the appropriate nucleophile.

3 O O O O Carboxylates are even better nucelophiles and are easily HO O formed by neutralizing the acid. Cl anhydride

O O O 4 O Cl O OH anhydride

5 O O SH This would probably be a pretty stinky reaction. Cl S ethanethiol

O O o 6 Ester synthesis. Adding a 3 amine HO will neutrialize the HCl that also Cl O forms and protect an organic molecule that has other sensitive functionality. pyridine (proton sponge)

7 O O HO O Ester synthesis. Cl pyridine (proton sponge)

O 8 O Generally, we are doing everything in our power to Cl H2O OH avoid this reaction. It undoes the first two reactions above that made the acid chlorides.

9 O O Reaction with ammonia will form 1o amides. An extra Cl NH3 NH 2 equivalent is needed to neutralize the HCl formed.

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 Reaction with 1o amines O H N 2 will form 2o amides. An extra N equivalent is needed to neutralize Cl H the HCl formed.

11 O O o HN Reaction with 2 amines o Cl N will form 3 amides. An extra equivalent is needed to neutralize the HCl formed.

Reaction with diisobutyl aluminium 13 O 1. H Al O hydride (DIBALH) at very low -78oC temperature will form aldehydes, Cl H after acidic workup. Nitriles and DIBALH esters also form aldehydes with 2. workup DIBALH.

14 O O Cu Reaction with cuprates at very low Li temperature will form ketones. Cl cuprates o -78 C

15 O O O Amore complex anhydrideisprepared from a simpler anhydride. Ethanoic O O HO O anhydride (acetic anhydride) is readily available and commonly used in this O manner.

16 O Ester synthesis. A carboxylic acid O O HO also forms. If the molecule has other sensitive functionality then an amine O O base may be needed to neutrialize the acid.

Ester synthesis. DMAP is a 17 O O HO O common catalyst in these reactions.

O O (CH3)2N N N,N-dimethylaminopyridine (DMAP)

18 O O O Generally, we are doing H2O O 2 OH everything in our power to avoid this reaction.

o o o O 1 , 2 or 3 amide synthesis is possible 19 O O H2N in a manner similar to the acid chlorides o N above from ammonia, 1 amines or O 2o amines. Excess amine is needed to H pyridine (proton sponge) 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 Beauchamp 35 20 O O isolated Lithium aluminium hyhdride, (LAH) 1. LiAlH4 OH reduces all carbonyl functional groups, O 2. workup as well as nitriles. LAH supplies discarded nucleophilic hydride and workup OH supplies acidic (electrophilic) hydrogen. in workup

Fischer ester synthesis. Uses a catalytic 21 HO amount of acid and water is removed, O O which shifts the equilibrium to the ester side. Adding water under the same OH O conditions would hydrolyze the ester TsOH (cat.), (-H2O) back to an alcohol and a carboxylic acid.

22 O 1. LiAlH4 Lithium aluminium hyhdride OH OH 2. workup reduces all carbonyl functional groups, as well as nitriles.

23 1. NaOH Hydroxide neutralizes the carboxylic O acid. The carboxylate acts as a well 2. Br O behaved nucleophile to do SN2 OH o o O reactions at methyl, 1 and 2 RX compounds.

Amides are pretty hardyand require 24 O O pretty harsh acid or base conditions to hydrolyze them to carboxylic acids. N H2SO4 / H2O / ∆ OH In base the formation of a carboxylate drives the reaction and in acid complete H H3N protonation of the amine drives the reaction (no longer nucleophilic). The O target molecule could be either part (the O acid or the amine) or both of them. To 25 H OH extract the neutral acid into an ether layer 1. NaOH / H2O / ∆ a low pH extraction would be necessary, N H N 2. neutralize with acid while to get the amine into an ether layer a high pH extraction would be needed. after acidic workup

26 O A 3o amide generally forms 1. LiAlH4 o N 2. workup N a 3 amine when reduced with LAH.

26 O A 1o, 2o or 3o amide generally H 1. LiAlH H o o o N 4 N forms a 1 , 2 or 3 amine when 2. workup reduced with LAH, followed by H H acidic workup.

27 O 1. LiAlH4 N 2. workup N H H

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 36 O 28 1. LiAlH4 N N 2. workup

29 O O 1. 3o amindes + Grignard reagents N (MgBr) lead to ketones after hydrolytic workup. 2. workup

30 O O N 1o amindes can be dehydrated H C N S with thionyl chloride to form Cl Cl nitriles. H thionyl chloride

31 As with amides, nitriles require NH2 C C harsh acid or base conditions to N HCl / H2O / ∆ hydrolyze them to first amides, O then carboxylic acids. In base the formation of a carboxylate drives the reaction and in acid complete protonation of the ammonia 32 drives the reaction (no longer OH C nucleophilic). N C H2SO4 / H2O / ∆ O

33 OH C 1. NaOH / H O C N 2 2. workup O

Reaction with diisobutyl aluminium hydride (DIBALH) at very low 34 H Al H temperature will form aldehydes, -78oC C after acidic workup. Acid chlorides N DIBALH O and esters also form aldehydes with DIBALH.

Esters should have been placed up above carboxylic acid reactions. Esters are hydrolyzed back toa 35 O O carboxylic acid and an alcohol in aqueous acid. Either compound O H2SO4 / H2O / ∆ OH could be the desired target. Overall this is the reverse of Fischer ester HO synthesis.

Esters can also be hydrolyzed back 36 O O to a carboxylic acid and an alcohol in aqueous base. Either compound O NaOH / H2O / ∆ OH could be the desired target. This is sometimes called saponification HO (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 LAH reduces esters to 1o alcohols 37 O OH after acidic workup. Either product alcohol could be the desired target. 1. LiAlH4 O 2. workup While NaBH4 will reduce aldehydes discarded and ketones, it will not reduce esters HO in workup (no reaction).

from reduced carbonyl, discarded in workup 38 LAH reduces esters to 1o 1. LiAlH O 4 OH desired alcohols after acidic workup. 2. workup target Either product alcohol could O be the desired target. HO

Reaction with diisobutyl aluminium desired 39 O 1. H Al O discarded hydride (DIBALH) at very low -78oC target in workup temperature will form aldehydes, O H after acidic workup. Acid chlorides DIBALH and nitriles also form aldehydes with 2. workup HO DIBALH.

Esters react twice with Mg and Li organometallics o 40 O forming 3 ROH after acidic workup. Two of the R OH groups of the 3o ROH are the same, being added o O 1. CH3CH2 Li from the organometallic. Benzylic, 3 ROH would 2. workup 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 Beauchamp 38 Reactions of Aromatic Compounds

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 NR2 N X O O R = alkyl phenols ethers esters R amines (except in amides R halogen comounds (X = F, strong acid where Cl, Br, I), while ortho/para they are protonated) directing, these substituents are deactivating

1 Nitration conditions (HNO3/H2SO4) make HNO3 / H2SO4 nitroaromatic compounds. Here with an NO2 faster than ortho/para activating substituent. Ortho product expected, but not shown. A small amount of meta product is also likely.

2 Sulfonation conditions (H SO /SO , oleum), SO / H SO 2 4 3 3 2 4 makes aromatic sulfonic acids. Mainly SO H faster than 3 ortho/para product with methyl substituent. benzene

3 Halogenation (FeX3/X2), (Cl2 and Br2), FeCl3 / Cl2 halogenates (chlorine or bromine) faster than Cl aromatic compounds. Mainly benzene ortho/para product with methyl substituent. 4 Friedel Crafts alkylation (RX/AlX3), forms carbocations and rearrangements AlCl / Cl 3 are likely, adds alkyl groups to aromatic faster than ring, which makes the aromatic ring more benzene activated and likely to react again.

Friedel Crafts acylation (RCOCl/AlCl ), 5 O 3 forms a resonance stabilize carbocation (an acylium ) so no rearrangement is AlCl / Cl O 3 expected, makes aromatic ketones, which faster than deactivate the ring and make it less likely benzene 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 O O O O C C C C C H R OH OR NR2 amides aldehydes ketones acids esters

O O X S X N NR3 C X O O X sulfonic acids, amides, positively charged sp3 carbon with nitro groups groups, like esters, X = OH, NR2, OR strongly withdrawing ammonium ions groups attached

6 Nitration conditions (HNO /H SO ) make NO2 3 2 4 HNO3 / H2SO4 nitroaromatic compounds. Here with an meta deactivating substituent. Meta is the O2N slower than O2N main product expected and a slow reaction benzene is likely.

7 SO3H Sulfonation conditions (H SO /SO , oleum), SO / H SO 2 4 3 3 2 4 makes aromatic sulfonic acids. Mainly O N 2 slower than meta product with a nitro substituent. O2N benzene

8 Br Halogenation (FeX3/X2), (Cl2 and Br2), FeCl3 / Cl2 halogenates (chlorine or bromine) O2N slower than aromatic compounds. Mainly O2N benzene metal product with a nitro substituent.

9 Friedel Crafts alkylation (RX/AlX3), forms carbocations and rearrangements AlCl3 / Cl O2N No reaction are likely, but the reaction is rarely does not typically work with successful with only deactivating deactivated aromatic rings substituents present.

10 O Friedel Crafts acylation (RCOCl/AlCl3), forms a resonance stabilize carbocation so AlCl / Cl O2N 3 No reaction no rearrangement is expected, but the reaction does not typically work with is rarely successful with only deactivating deactivated aromatic rings substituents present.

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 40 2. Nucleophilic reactions (addition/elimination), diazonium chemistry (Ar-N2+) from following sequence: nitro Æ amino Æ diazonium salts

HNO3 NaNO2 / HCl o H2SO4 Fe / HCl (makes HONO) T > 5 C O N 2 H2N N N reduce nitro diazonium salt, stable below aromatic ring is group 5oC, decomposes to carbocation the electrophile ! O (or free radical ) above 5oC, possible reactions see reactions below at meta position(s) Cl O reactions are more controlable with less activating amide than amine, N possible reactions at ortho/para position(s), H can hydrolyze amide back to the amine to continue the reaction sequence towards the diazonium chemistry

1

HNO3 / H2SO4 First step to diazonium salt is O2N nitration of an aromatic ring.

2 Fe / HCl or Meta groups might be added at this stage before the nitro group is reduced O N SnCl2/HCl 2 H2N to an amine. A metal in a reduce state reduce nitro donates electrons and an acid donates group the protons.

3 O O If additional substitution at this stage is H N 2 Cl N desired, the amine group is usually protected as an amide to reduce its basicity H and activating power. All available positions (o + p) might be substituted or the amine 4 O might be protonated and turned into a meta + H3O / H2O director. If the amine is protected as an amide or N H2N it must be hydrolyzed in acid or base to get NaOH / H2O back the amine functionality H

5 is the electrophile and the aromatic amine group is the nucleophile, NaNO2 / HCl H2N (makes HO-N=O) N N which joins two nitrogen atoms together, followed by some proton transfers, loss of water and resonance.

diazonium salt is stable below 5oC, it 6 decomposes to an unusual carbocation in 2 o that the empty orbital is sp , (some reactions N N T > 5 C may proceed by a free radical intermediate), aromatic ring is a variety of nucleophiles can be added at the electrophile ! this point, see reactions below 7 Ipso substitution (same position), T > 5oC reactions are called Sandmeyer reactions, N N Cl CuCl 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 o Ipso substitution (same position), Copper T > 5 C reactions are called Sandmeyer reactions, N N CuBr Br the bromine put on in this reaction is backwards to the way it was put on above, nucleophilic bromide adds here. 9 T > 5oC Ipso substitution (same position), Copper N N NC reactions are called Sandmeyer reactions, CuCN cyanide is nucleophilic in this reaction, the aromatic ring is the electrophile.

10 T > 5oC Ipso substitution (same position), iodide N N I KI is the nucleophile.

11 T > 5oC Ipso substitution (same position), N N HO H2O water is the nucleophile.

12 T > 5oC Ipso substitution (same position), a fluoride from tetrafluoroborate is the N N F BF4 nucleophile.

13 o Ipso substitution (same position), T > 5 C hypohphosphorous acid is a very N N H unusual ACID hydride donor. A H3PO2 possible reaction sequence is shown below.

H H lose H OH2 proton H O P H Electrophile H Electrophile O P O P O OH OH 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 toaddat 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

OH The nitro substituent is electron O NCl O2NOHwithdrawing and can stabilize 2 H2O negative charge by resonance and chloride is a good leaving group, attack by a nucleophile can displace 2 Br CH3O the chloride, the reaction is somewhat like a substitution reaction on a OCH3 O N vinylogous acid halide. 2 CH3OH O2N

O O O N O N N O O Br Br Nu 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 verystrong base (often some sortofsodium 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 Nu: adds at either position N N Br N(CH3)2

HN(CH3)2 meta and para benzyne intermediate products obtained Nu: adds at 2 Cl either position ortho and meta N N N(CH3)2 products obtained

HN(CH3)2

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 43 4. Miscellaneous side chain reactions

1 O Clemmenson reduction (HCl/Zn), CH2 R reduces aromatic ketone to methylene R HCl / Zn carbon (CH2) under acid conditions. The Zn supplies the electrons and the HCl supplies the protons. Wolff Kishner reduction (H NNH /RO /∆), 2 O 2 2 reduces aromatic ketone to methylene CH R 2 carbon (CH2), under base conditions. R H2NNH2/RO /∆ -like structure forms, acid/base proton transfers, tautomer-like changes and ultimately loss of nitrogen gas. 3 O Pd/H2 reduction, reduces aromatic ketone CH2 R to methylene carbon (CH2) because it's R Pd / H2 benzylic, reduces, reaction occurs under neutral conditions unlike Clemmenson's (acidic) or Wolff-Kishner (basic). 4

CrO3/∆ HO2CCO2H CrO3/∆ or KMnO4/∆ oxidations, very harsh conditions, no sensitive groups tolerated, oxidizes any carbon side chain 6 with a benzylic hydrogen to a carboxylic acid, a quaternary benzylic carbon will KMnO4/∆ HO2C either not react or if really pushed the aromatic ring is oxidized away, leaving a carboxylic acid in place of the ring.

7

KMnO4/∆ HO2C forcing conditions

8 Br Free radical substitution (Cl2 or Br2 and light, hν), chain reaction mechanism Br2 / hν +HBr 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 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 H3CCH3

Typical free radical substitution mechanism 1. initiation hν and/or ∆ Br 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 depends on H rxn difference in C-H H Br HBr and H-Br bond energies. 2o > 1o

b. abstraction of Br - carbon free radical abstracts Br from Br2 molecule (very weak bond).

H ∆Hrxn is always H favorable because Br Br Br Br-Br bond is so Br weak. 3 termination - two free radicals diffuse near one another and quench each other in bond formation.

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 Br HBr Use of HX acids (HCl, HBr, HI).

2 OH Cl

SOCl2 Use of thionyl chloride.

3 OH Br PBr3 Use of phosphorous trichloride (PCl3, PBr3 or P/I2).

OH a. O b. a. b. 4 S Cl OTs I Make tosylate followed by an SN2 Na I O reaction (Me, 1o, 2o RX) with a

N sodium halide salt

b. Synthesis of RX compounds from alkenes

5 HX acids (Markovnikov addition) HBr Br

a. a. b. CH3 b. 6 CH H 3 i. BH ii. H O /HO 2. Br / CH O 3 2 2 1. BH3 2 3 R H (anti-Markovnikov & B "syn" addition) Br R

2. Synthesis of alcohols

a. Synthesis of alcohol compounds from RX compounds 1 NaOH S 2 at Me, 1o with NaOH Br OH N

2 o o 1. CH3CO2Na SN2 at Me, 1 , 2 with CH3CO2Na, Br 2. NaOH OH followed by base hydrolysis to form the alcohol and acetate which is (via ester) discarded.

o o 3 Br OH SN1 at 2 , 3 RX with H2O, 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 1. HgX2 / H2O minimizes rearrangement. Borohydride 2. NaBH4 reduces mercury off and substitutes hydrogen on.

2 OH Aqueous acid forms carbocation + H3O / H2O intermediate which can rearrange

3 1. O / -78oC 3 CH3OH Ozonolysis cuts double bond in 2. NaBH two forming carbonyls and sodium 4 lost in OH borohydride workup reduces aqueous carbonyls to alcohols. workup

4 Anti-Markovnikov and "syn" addition 1. BH3 OH of borane, BH , followed by oxidation 2. H2O2 / HO 3 with perioxide to form an alcohol,

c. Synthesis of alcohol compounds from RMgX & RLi organometallics reacted withaldehydes, ketones, esters (twice) and epoxides (all followed by acid workup) 1. Mg 1 2. O Organomethallics + aldehydes and o ketones makes 1 (from CH2=O), Br H 2o (from RCH=O) or 3o (from R C=O) OH 2 3. WK alcohols.

1. Mg (2 eqs.) 2 2. O Br Organomethallics + esters (react o OCH3 twice) makes 3 alcohols. 3. WK OH

3 1. Li 2-like 2. O Organomethallics + epoxides, SN Br reaction at less hindered side of the 3. WK OH 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 withaldehydes, ketones, esters and acids(twice & only with LAH) and epoxides (all followed by acid workup)

1 O 1. NaBH4 Sodium borohydride (or LAH) + 2. workup aldehydes and ketones makes H OH 1o or 2o alcohols after workup.

2 O 1. LiAlH Only lithium aluminium hydride 4 OH 2. workup works on esters, reacts twice to make OCH3 1o alcohols after workup. (+ CH3OH, discarded)

3 O 1. LiAlH4 Only lithium aluminium hydride works on esters, reacts twice to make OH 2. workup OH 1o alcohols after workup.

4 OH NaBH or LiAlH + epoxides, S 2-like O 1. NaBH 4 4 N 4 reaction at less hindered side of the 2. workup epoxide, workup protonates the (R) (R) alkoxide.

e. Acid or base hydrolysis of esters forms a carboxylic acid and an alcohol (either or bothcould be the desired result).

O O 1 1. H O / HO OCH 2 OH Base hydrolysis of esters is often 3 2. WK called saponification (soap making) CH3OH (discard ?)

O 2 O Acid hydrolysis of esters is the H O+ / H O reverse of Fischer ester synthesis. 3 2 OH O Water is added instead of removed. (discard ?) HO

3. Synthesis of ethers from alcohols and alkenes 1 Make an alcohol into a stronger OH 1. NaH O 2. nucleophile by removing proton Br with hydride (strong base). SN2 works OK at methyl and primary RX centers.

2 conc. o o OH O An SN1 reaction at 2 adn 3 ROH H2SO4 (could have E1 complications), and cold o an SN2 reaction at 1 ROH.

Markovnikov addition of an alcohol at an alkene. Rearrangement is minimized by bridging mercury atom, which gets reduce off with hydride 3 1. HgX2 (free radical intermediate). Note that OH O the alcohol used in this reaction could 2. NaBH have been made by a similar procedure 4 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 48 4. Synthesis of epoxides from alkenes

Br 1 First, a halohydrin is made from an 1. Br2 H alkene. Products in this example are H2O OH enantiomers. (d / l)

H In a second reaction, the alkoxide is 2 Br formed and does an S 2 on the NaOH N H O vicinal bromide to form the epoxide. Products in this example are CH OH (d / l) 3 enantiomers.

3 H meta-chloroperoxybenzoic acid (mCPBA) accomplished the same mCPBA O transformation in a single step. The products in this example is H meso (achiral with chiral centers).

5. Synthesis of alkenes

1 OH These are E1 conditions. H SO / ∆ 2 4 Rearrangements are possible. (dehydration) (major)

2 K This represents our only productive O conditions for E2 at a primary center Br and is due to the sterically bulky and very basic potassium t-butoxide.

3 Strong base/nucleophile and a 3o RX Br NaOH mean an E2 reaction. Only the more stable alkene is shown.

4 O 1. Ph3P=CH2 Wittig reaction, generally the best bet (from CH3X) to get the exact alkene you are looking 2. WK for.

5 Pd / H2 Poisoned Pd catalyst stops at the cis quinoline alkene. (Lindlar's cat.)

6 Na / NH (l) Birch reduction of alkyne mostly 3 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 Beauchamp 49 Birch reduction of aromatic ring puts 7 two pi bonds opposite one another. Na / NH3(l) ROH If an electron donating substituent is present, it will be at one of the sp2 (Birch) positions.

8 Complete reduction of an alkyne Pd / H2 to an alkane for comparison.

6. Synthesis of alkynes

1 1. NaNH2 Terminal acetylide carbanion works Br 2. well at methyl and primary RX.

SN2

Br Double elimination product (plus loss of 2 1. excess terminal sp C-H under the reaction NaNH 2 conditions. Workup protonates or an 2. WK electrophile could be added. The starting Br dibromide can be made from an alkene + Br2.

3 The Zipper reaction moves a triple 1. excess bond through any number of CH2's until NaNH2 the termial position is found, where the 2. WK sp C-H is lost, forming the most stable anion in the pot.

7. Synthesis of amines O O 1. NaOH Gabriel amine synthesis, starts with 1 phthalimide, removes proton on N H N 2. Br nitrogen, does an SN2 reaction on an RX and hydrolyzes off the two o O SN2 O carbonyl portions to obtain a 1 RNH2. O 2 N NaOH 1o amines NH2 1o amines O

3 O 1. H Reductive alkylation of imine with NH2 N sodium cyanoborohydride to make H 2. NaBH3CN o o 3o amines 2 or 3 amines. 3. WK H

4 1. N Reductive alkylation of imine with O H N sodium cyanoborohydride to make o 2. NaBH3CN 3 amines 2o or 3o amines. H 3. WK H

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 50

5 O o o o 1. LiAlH4 LAH reduction of 1 , 2 and 3 amides 2. WK NH2 makes 1o, 2o and 3o amines. NH2

6 N 1. LiAlH4 LAH reduction of nitriles makes o C 2. WK NH2 1 amines after workup.

8. Synthesis of ketones

1 OH O CrO3 PCC or Jones at 2o ROH. (no H2O or H2O)

2 O Nitriles + RLi compounds, followed by N Li hydrolysis form ketones. C 2. WK

3 + +2 O Hydration of an alkyne. Markovnikov H3O /Hg H O additon, forms enol, which tautomerizes 2 to ketone.

4 Ozonolysis of alkene, DMS workup. o 1. O3, -78 O Many other workup conditions are 2. CH3SCH3 2 possible. For best results here, it would be nice to have a symmentrical alkene.

5 Cuprates + acid chlorides form O (CH3)2Cu O ketones. Cuprates come from Cl Li organolithium compounds which come from RX compounds.

6 S 1. nBuLi S Dithiane alkylation (twice), then 2. CH3Br hydrolysis to the carbonyl compound. 3. WK If hydrolyzed after one alkylation, then S S an aldehyde is obtained.

7 S 1. nBuLi S 2. CH3CH2Br 3. WK S S

8 S O +2 Hg / H2O S

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 51 9 2 eqs. O 2 eqs.RLi + carboxylic acid, forms a O double alkoxide because of the power CH Li 3 of the organolithium nucleophile, which OH 2. WK hydrolyzes to a ketone in the workup.

O 10 O Friedel Crafts Acylation, makes aromatic ketones, deactivating substituents inhibit Cl the reaction. Only reacts one time because keto group is a deactivating, meta director. AlCl3

9. Synthesis of aldehydes

1 O PCC OH CrO3 (no H O 2 ) H

2 1. DIBAH O Nitriles + DIBALH, followed by N hydrolysis form aldehydes. C -78oC 2. WK H

3 hydroboration of an alkyne, then H2O2/HO 1. BH3 O 2. H2O2./ HO H

4 Ozonolysis of alkene, DMS workup. o O 1. O3, -78 Many other workup conditions are 2. CH SCH 3 3 2 H possible. For best results here, it would be nice to have a symmentrical alkene.

5 O 1. DIBAH Cuprates + acid chlorides form O -78oC ketones. Cuprates come from Cl 2. WK organolithium compounds which H come from RX compounds.

6 S Dithiane alkylation (once), then 1. nBuLi S 2. CH3CH2Br hydrolysis to the carbonyl compound. An aldehyde is obtained. S 3. WK S

7 S O +2 Hg / H2O S H

8 O 1. DIBAH O o DIBAH + ester at low temperature -78 C makes aldehydes after hydrolysis. O 2. WK H

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 52 9 O C O Vilsmeier reaction on activated aromatics (many variations) to make aromatic HCl H aldehydes. AlCl3

10. Protection of aldehydes and ketones

Protection of aldehyde or ketone 1 with ethylene glycol. Acid catalysis O HO and removal or water forms acetal N O C OH N O or ketal. Carbonyl becomes inert TsOH (-H2O) C to many strong nucleophiles that would otherwise react with it.

2 O Run the desired reaction, an organo- O 1. CH3Li O N O O metallic reaction here. It is possible C 2. mild WK to do a mild workup and not hydrolyze the ketal, or a more vigorous workup, as in the next frame could deptrotect 3 the ketal at the same time as the other O OO reaction is worked up. O O + H3O / H2O

11. Synthesis of acids 1 O Jones conditions oxidize 1o ROH to CrO3 carboxylic acids and 2o ROH to OH (H O) 2 OH ketones.

2 Ozonolsis with oxidative workup, o O i. O3 / -78 C 2 using H2O2, forms acid if alkene ii. H2O2 /HO carbon has a hydrogen and ketones OH if alkene carbon is geminally disubstituted.

3 O N H2SO4 Full acid hydrolysis of a nitrile. C H2O / ∆ OH

4 1. H O/HO 2 O N ∆ Full base hydrolysis of a nitrile. C 2. WK OH

5 O aqueous O acid or base Aqueous hydrolyisis of acid derivatives. OR OH

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 53 6 O O aqueous Aqueous hydrolyisis of acid derivatives. Cl acid or base OH

7 O OO aqueous acid or base Aqueous hydrolyisis of acid derivatives. O OH

8 O O Full acid hydrolysis of a amide. H2SO4 NH2 H2O / ∆ OH

9 1. Mg reacted with carbon O dioxide, then workup. Br 2. CO2 3. WK OH

12. Synthesis of acid chlorides

1 O O A few ways to make an acid chloride SOCl2 from a carboxylic acid: thionl chloride, OH oxalyl chloride and phosphorous thionyl chloride Cl trichloride.

O 2 O Cl Cl O OH O Cl oxalyl chloride

3 O O PCl3 OH Cl phosphorous trichloride

13. Synthesis of anhydrides

1 O OO A couple ways to make an OO unsymmetrical anhydride from O a carboxylic acid and either OH O another anhydride or an acid chloride.

O OO 2 O OH O Cl

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 54 14. Synthesis of esters

1 O 1. NaOH O 2. Br Make a good carboxylate nucleophile o o OH O then ract with a methyl, 1 or 2 RX compound.

2 O O OH Fischer ester synthesis, acid catalysis TsOH and remove water to from ester. Use (-H2O) O opposite conditions to hydrolyze ester OH (acid catalysis and lots of water).

3 O OH O A tertiary amine is sometimes used to make the reaction work faster and Cl O better.

4 OO OH O A tertiary amine is sometimes used to make the reaction work faster and O O better.

O 5 O Cl O O Another use of mCPBA is to oxidize O H ketones to esters. Called the mCPBA O Baeyer Villegar Rxn.

15. Synthesis of amides

1 N O Milder conditions hydrolyze nitriles C HCl to amides, harsher conditions H2O NH2 hydrolyze nitriles to carboxylic acids.

2 O O Acid chlorides + ammonia, 1o or 2o amines makes 1o, 2o or 3o amides. NH3 Cl NH2

O 3 O Anhydrides + ammonia, 1o or 2o N N o o o H amines makes 1 , 2 or 3 amides. Cl

O 4 OO Anhydrides + ammonia, 1o or 2o N N amines makes 1o, 2o or 3o amides. O H

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 55 16. Synthesis of nitriles

1 Br N Na C SN2 reactions of cyanide with o o N C methyl, 1 or 2 RX compounds

2 O N SOCl2 C Dehydration of primary amide with NH thionyl chloride. 2 (-H2O)

17. Enamine Chemistry

Start with carbonyl, make enamine, 1 NH alkylate enamine, hydrolyze back O to carbonyl compound with extra N pH = 5 R group added (methyl, allyl or (-H2O) benzyl in our course).

Hydrolyze alkylation product via this intermediate 2 1. Br N 2. WK = aq. hydrolysis O N H2O

18. Synthesis of β-hydroxycarbonyl and α,β-unsaturated carbonyl

O α of two carbonyls, 1 H O O usually the same one. Base is used to Na RO make an enolate which then attacks OH H H β another carbonyl to form a β-hydroxy β-hydroxy carbonyl carbonyl structure that can be isolated or dehydrated to an α,β-unsatruated O carbonyl shown in the next frame. this O often done with acid, but in this book 2 α α H we will indicate the next step with the H symbol for heat, ∆. acid. hydrolysis β + β OH H3O / H2O / ∆ α,β-unsatruated carbonyl

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 56 19. Malonic ester synthesis (produces mono and di- substituted acetic acids)

OO 1 1. CH3CH2O Malonic ester synthesis. Remove OO acidic proton with alkoxide base 2. Br O O then alkylate with electrophile O O 3. WK (RX, epoxide or another carbonyl). Can hydrolyze ester at this point, decarboxylate (-CO2) to obtain a OO O monoalkylated ethanoic acid 2 + (acetic acid), or repeat the reaction O O H3O / H2O OH a second time and then decarboxylate (-CO2) to obtain a dialkylated ethanoic acid (acetic acid). It's also possible to do product from 1 monoalkylated acetic acid similar chemistry by using the dianion OO of ethanoic acid or using a simple OO ethanoate ester and LDA to generate 3 1. CH3CH2O the ester enolate and perform an O O 2. Br alkylation at low temperature (-78oC) O O 3. WK product from 1

OO O 4 + O O H3O / H2O OH (-CO2) product from 3 dialkylated acetic acid

20. Ethyl acetoacetate synthesis (produces mono and di- substituted )

1. CH CH O OO Acetoacetic ester synthesis. Remove 1 OO 3 2 2. acidic proton with alkoxide base Br O then alkylate with electrophile O 3. WK (RX, epoxide or another carbonyl). Can hydrolyze ester at this point, decarboxylate (-CO2) to obtain a OO O monoalkylated 2-propanone (acetone), or repeat the reaction a second time 2 + O H3O / H2O and then decarboxylate to obtain a (-CO2) dialkylated 2-propanone (acetone). It's also possible to do similar product from 1 monoalkylated acetone chemistry by using a simple ketone and LDA to generate OO the ketone enolate and perform an 1. CH CH O OO 3 3 2 alkylation at low temperature (-78oC) O 2. Br O 3. WK product from 1

OO O 4 + O H3O / H2O (-CO2) product from 3 dialkylated acetone

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 57 21. Cuprate chemistry

1 Organolithium reagents come Li Br Li from RX compounds + Li metal. RX compound organolithium reagent

Cuprates are prepared from organo- 2 lithium reagents + CuBr (cuprous Li Cu salt) in a 2 to 1 ratio. 0.5 eq CuBr Li There are three choices for a cuprate organocuprate in our course.

O 1. conjugate addition to an 3 O Cu α α,β-unsaturate carbonyl α,β-unsaturate Li β carbonyl organocuprate

2. Cuprate coupling reaction with an RX compound. Remember the cuprate 4 comes from an organolithium, which Cu Br comes from another RX compound. It hard to tell which bond was formed Li and in what direction the atoms were organocuprate RX compound used because there are a lot of possibilities 3. Cuprate substitution of chlorine in 5 O Cu O an acid chloride to make a ketone. There are two possible ways you could Li Cl consider joining the acid chloride and organocuprate acid chloride cuprate.

22. Conjugate addition – stable anions often add at the C-β carbon

O O O OO O Na + H3O / H2O N C O O (-CO2) C N

23. Dithiane Chemistry – see aldehydes and ketones above 1 S Dithiane alkylation (once), then 1. nBuLi S hydrolysis to the carbonyl compound. 2. CH3CH2Br An aldehyde is obtained. S 3. WK S

2 S O +2 Hg / H2O S H

3 S 1. nBuLi S Dithiane alkylation (twice), then 2. CH3Br hydrolysis to the carbonyl compound. 3. WK If hydrolyzed after one alkylation, then S S 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 Beauchamp 58

4 S 1. nBuLi S 2. CH3CH2Br 3. WK S S

5 S O +2 Hg / H2O S

24. Dianion Chemistry

To make dianion requires verystrong 1 OO OO bases. To simplify our reaction we will 1. NaH or LDA write 2 eqs of LDA to show formation 2. nBuLi O O of dianion. The second acidic site is the more reactive site in the alkylation.

OO The reaction can be run once, O 2 worked up and decarboxylated OO (shown in the next frame). In Br OOworkup this case the same product could O have been obtained using the O normal ethyl acetoacetate synthesis. 3 OO + O H3O / H2O The same product as using the (-CO2) normal ethyl acetoacetate synthesis. O

OO A second alkylation can be 4 1. OO O performed using the normal ethyl acetoacetate synthesis, alcylating 2. CH Br O O 3 the position in between the two carbonyl groups. After ester hydrolysis and decarboxylation 5 OO O a disubstituted acetone is obtained + H3O / H2O with a alkylation on both sides of the carbonyl. O (-CO2)

Dianions from carboxylic acid can 6 O O 1. NaOH be formed using a strong, non- 2. LDA nucleophilic base for the Cα-H OH O position. The carbanionic site is the more reactive site and alkylation occurs there. The product will be an O alkylated carboxylic acid, which 7 O can be esterified by making the Br 1. OH carboxylate and doing an SN2 on O an RX compound, as discussed 2. workup earlier.

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc Organic Reaction Guide Beauchamp 59 O O 8 1. NaOH OH OH 2. Br

25. Robinson Annelation 1 i. Base makes enolate OO OO O O HO O

O O O ii. conjugate addition to 2 OO α,ß-unsaturated carbonyl O O 2. workup O

2 OH O 3 iii. (-H O), 3 O 1 2 3 4 2 O O 4 1,6 atoms join together O 1 6 5 5 HO β-hydroxycarbonyl O 6 O O (aldol product) OH

4 O -H2O O α,β-unsaturatedcarbonyl O O β-hydroxycarbonyl O O

5 O H3O HO -H2O O O α,β-unsaturatedcarbonyl ∆ O O If ester group is hydrolyzed the acid will decarboxylate (-CO ) forming a cyclic ketone. 6 2 - CO2 followed by (annelation = ring forming) HO tautomerization of enol

O O O

C:\Documents and Settings\butterfly\My Documents\classes\316\special handouts\org_rxns_study_list_for_web.doc