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Home , Carbanion

in Chem 315 – making carbanion

Allowed sources of to make other organic molecules. Br CH4 Br NaCN CO2

Bromoalkanes made from above

Br Br Br Dashed lines below indicate a new Br carbon-carbon bond formed via / reaction. H3C

Magnesium, and copper in beginning organic chemistry

poor results with RBr Br Br Li R Br R Li R R Li good rxns with C=O Li Li organolithium O bromohydrocarbons discard reagents good rxns with

Br +2 Mg Br R Mg Br poor results with RBr R R R Br good rxns with C=O Mg (MgBr) bromohydrocarbons Mg R Grignard reagents good rxns with O (organomagnesium reagents) simplistic mechanism for cuprate formation

Cu Br good results with RBr (SN2) Cu R R Cu reacts with acid chlorides, forms ketones R R Li Li R Li reacts with ,-unsaturated C=O at C transmetallation dialkyl cuprates 

Simplistic mechanisms for forming Mg and Li reagents.

Li Br Mg Br Li Br R R (MgBr) R R Li Li magnesium organometallics lithium organometallics discard (Grignard reagents)

Mg and Li reactions with C=O (C=O strategy has “OH” and “R” on the same carbon.)

1. make 2. 3. H O O H Li 1 eq. H O H O C H C H R H H CH2 R workup R electrophile nucleophile (methanal / formaldehyde) tetrahedral intermediate (TI) 1o

1. make H 2.O O 3. H O Li 1 eq. H O H C H3C C H H C CH R 3 H R CH R 3 electrophile workup nucleophile (TI) 2o alcohol (simple aldehydes) 3. H H 1. make 2. O O O H O H Li 1 eq. C H3C C CH3 H C C 3 CH3 R CH3 R R workup CH3 nucleophile electrophile (ketones) (TI) 3o alcohol

2. 3. H H 1. make O O O 2 eqs. CH3 O O (MgBr) (MgBr) H O H C CH3 H3C C O C R C CH3 C H3C O CH R 3 R CH R R R 3 R workup R nucleophile electrophile ketone > ester o (TI) (TI) 3 alcohol (esters) 1. make 2. 3. H H O O O O O (MgBr) 2 eqs. (MgBr) H O H C H3C C Cl C R C CH3 C R H3C Cl CH R 3 R CH R R 3 nucleophile electrophile R workup R (TI) o (acid chlorides) (TI) 3 alcohol 1. 2. 3. H O Li O O C H O H C C R O H H3C O R O electrophile nucleophile () carboxylates workup carboxylic acids

1. make 2. 3. H H N N H C N H H Li H O H N H3C C C H O H R H3C R H3C R C electrophile workup H3C R nucleophile (nitriles) OH H 2 H2O H NH4 H H H H H H N N N H C R H3C R 3 H3N C C C C C H3C R H3C R H3C R O O O H O O H H ketones H H OH2

2. H 1. make O 3. H H O O HOH2 O H Li C H O H H3C NR2 H C C NR H C C NR 3 2 3 2 H3C C NR2 R R workup R nucleophile electrophile R (3o amides) (TI) H O H O H C C R N R N H C 3 2 H3C R R ketones R H resonance

1. make 2. O O 3. acid Li H Li Li O Li base HOH O H C C 2 O CH O C CH3 3 O CH3 O C CH R 3 carboxylic workup R only happens with R nucleophile acids + R Li counter (TI) H2O H H H H O OH2 O OH2 O O C CH H 3 O C CH O C CH C 3 H2O H 3 R CH3 R resonance H H ketones R R

Mg and Li reactions with epoxide electrophiles (epoxide strategy has “OH” and “R” on the adjacent .)

1. make 2. 3. H Li O O H O H O R R R H electrophile Li nucleophile workup (epoxides,SN2) 1. make 2. 3. H R (MgBr) O O H O H O R R R H R nucleophile electrophile Li (epoxides,S 2) workup N

Comparison of cuprate reactions with Li/Mg reagents (make cuprates from 2 x RLi + CuBr)

1. make Li Li CuBr R Br 2 Cu eqs. R R R cuprates good SN2 1. make Li Br poor R result

2. O 1. make O O Li R CuBr C Cu H C C Cl Li H3C Cl 3 C 2 R R CH3 eqs. R R cuprates reaction stops react once (TI) at ketone

1. make 2. 3. H H O O O Li O O (MgBr) H O H C H3C C Cl C R C CH3 C R H3C Cl CH R 3 R CH R R 3 nucleophile electrophile R workup R (TI) o (acid chlorides) RLi reacts twice (TI) 3 alcohol 2. 3. H R O 1. make O Li R  R O Li CuBr  H O H 2 Cu eqs. R R cuprates electrophile workup "R" adds at C (1,4) (,-unsaturated C=O) (conjugate addition) 1. make 2. R 3. H O R R  H  O H O H O Li

electrophile workup (,-unsaturated C=O) "R" adds 1,2 at C=O

LDA / -78oC reactions with C=O and epoxides (reactions at “H” over reactions at “C”)

O O 1. make O D S 2 D N Li N H3C C C H C C Br H C C R R S 3 H3C CH2 H R H2C C H2 LDA CH H ketones ketone 2 bigger o H2C -78 C H3C ketones CH3

1. make H O O O N Li R H C H R C Br H3C C LDA C SN2 H C C R 3 H C CH2 H C S H C C H2 3 H 2 -78oC 2 CH bigger CH3 ketones ketone 3 H C enolates Ha C ketones 2 CH3 Hb O O 1. make O D S 2 D N N RO C C H Li C C Br RO C R R S RO CH2 H R H2C C H2 LDA CH bigger H ester 2 esters o esters H2C -78 C enolates H3C CH3

1. make H O O O N Li R H C H R C Br RO C LDA C SN2 RO C H C S R H RO CH2 H2C C 2 H2 -78oC CH esters CH3 bigger 3 ester H C H2C a esters enolates CH3 Hb 1. make O O 2 eqs. O O N Li D N H C H D LDA R R SN2 HO C R R O C C H C C Br H C LDA 2 o O O CH2 H R H2C C Li -78 C H2 3. Wk o H carboxylic acids -78 C CH2 dianions bigger H2C H3C carboxylic acids CH3

1. make O H O O O 2 eqs. N Li N H H C H LDA R R HO C C H C C Br S 2 R R O C O C LDA N H O CH2 H C S H C C 2 o H2 H 2 Li -78 C o 2 R -78 C 3. Wk CH3 carboxylic acids CH3 H C H2C dianions a bigger CH3 carboxylic acids Hb 1. make N D N N Li N SN2 C D C H R R C C Br C C LDA CH2 H R H2C H2 Li CH2 H o bigger nitriles -78 C H C nitriles H2C nitrile 3 CH enolates 3

1. make H N N Li N N R H C H R C Br C LDA C SN2 C CH H C S C H 2 H2C 2 o H2 R -78 C Li CH CH3 3 H C Ha C bigger 2 nitrile nitriles CH enolates 3 Hb

LDA reaction with epoxides (E2-like)

2. 1. make 3. H H H CH2 C O Li H H C O CrO3 C CH C O H O H H2C N H C C H pyridine O o H C C 2 H -78 C 2 H 2 (PCC) H R R H C 2 LDA 2 workup allylic ,-unsaturated epoxides carbonyls 1. make 2. H H 3. H H CH2 H H Li C O C C O C O H O H H2C C o H C H CrO N O -78 C H2C CH 2 CH 3 CH pyridine R R CH3 epoxides CH (PCC) ,-unsaturated LDA H C CH3 workup 3 3 carbonyls allylic alcohols 1. make 2. 3. H H O O O O Li H O H H CrO3 H pyridine N o (PCC) R R -78 C workup LDA epoxides allylic alcohols

Sulfur ylids + C=O compounds make epoxides

H H 2 Ph H2C C SN2 Ph H C Br C CH3 Ph S Br H H H S C 2 S CH2 Ph H H CO Ph H Ph given RBr compounds ylid H3C carbonyl compounds Ph H C O Ph S 2 CH S CH2 Ph O SN2 Ph C H3C epoxides H C H 3 H Br 2 H2C C carbonyl Ph H Ph H C CH3 Ph compounds H2 SN2 S C S C Br S CH2 H R H H Ph H2C Ph CO Ph CH2 CH3 H3C ylid salt given H2C RBr compounds CH3 Ph Ph O S CH2 H2C S O CH Ph C SN2 Ph H H2C H2C CH3 epoxides CH3

Phosphorous ylids + C=O compounds make Z or E

Br H2 H2C C Ph D Ph D carbonyl C CH3 Ph compounds SN2 H Ph P C Br Ph P C 2 Ph P CD H D 2 Ph D D Ph D Ph CO given RBr compounds ylid salt H3C

Ph Ph Ph D2C D2 concerted C Ph P CD elimination P 2 Ph P HC CH Ph CH3 3 C CH3 Ph C Ph alkenes (usually Z, Ph O but can be E with H O H one additional step) oxaphosphatanes betaine

Br H2 H2C C Ph H Ph H C CH3 Ph H SN2 H Ph P C Br Ph P C 2 Ph P C H H H Ph Ph H3C CH3 Ph H C CO given ylid salt 3 RBr compounds H3C CH3 H H CH Ph Ph H C Ph 3 CH3 concerted C elimination Ph P C Ph P C Ph P CH CH3 3 C CH Ph C Ph Ph 3 H alkenes (usually Z, O but can be E with H O H one additional step) oxaphosphatanes betaine

Extra step to make Z alkenes into E alkenes. add 1 eq. CH CH H Ph 3 of acid Ph 3 Ph H2 H CH3 H C C A 2 Ph P C Ph P C Ph P C C CH H 3 CH3 CH3 CH H2 3 Ph C Ph C Ph C -78oC H H H O O betaine O at -78oC add extra equavilent of n- CH BuLi to epimerize the center next to 3 H H the phosphorous, forms the more Ph concerted C stable configuration with larger group elimination Ph H3C C Ph P trans in the oxaphosphatane ring C CH Ph P C Ph 3 CH3 O H Ph oxaphosphatanes H E alkenes

Ohira-Bestmann modification of the Seyferth-Gilbert reaction (makes terminal from aldehydes)

Overall reaction from aldehyde to the terminal – simplified Ohira-Bestmann reaction O O O O H O O K P R OMe K N R P R H OMe R N O O OMe N OMe aldehydes given terminal N alkynes

Possible mechanism O O O O O O P P R R OMe O OMe R OMe OMe O O N N P N given N OMe OMe N

O O O O O N

O R P R P OMe R H OMe H O P H OMe OMe OMe N N OMe N N

R H R H C C H C C C N C N resonance R N N

N N

rearrangement = N2 leaves, H migrates across

Cyanide reactions with RBr, C=O and epoxides electrophiles

SN2 N C Br N C

Nucleophilic cyanide attacks RBr o o comounds in SN2 reactions at methyl, 1 and 2 RBr

H R R R H O H N C C O N C CO N C COH R Acidic protons are added R to shift equilibrium to the R Nucleophilic cyanide attacks right, but slightly less than electrophilic carbonyl compounds T.I. intermediate a stoichimetric amount so cyanohydrin (aldehydes > ketones) we don't make deadly HCN.

H H

H2C O H O H H C O N C H2C 2 O N C CH 2 N C CH2 H2C acid/base SN2 at less hindered carbon

Terminal acetylide reactions with RBr, C=O and epoxides electrophiles

SN2 R C C Br R C C

Nucleophilic acetylide attacks RBr o comounds in SN2 reactions at methyl and 1 RBr

H R R R H O H R C C C O R C C CO R C C COH

R R Acidic protons are added R Nucleophilic acetylide attacks to protonate the alkoxide electrophilic carbonyl compounds T.I. intermediate oxygen. cyanohydrin (aldehydes > ketones)

H H H2C O H O H R C C H2C H2C O O R C C CH2 R C C CH2 H2C Acidic protons are added to SN2 at less hindered carbon protonate the alkoxide oxygen.

Dithiane reactions with RBr, C=O and epoxides electrophiles Can react 1x to make aldehydes or 2x to make ketones (after hydrolysis with HgCl2/H2O)

1. alkylate 1x followed by 2. hydrolysis makes aldehydes Li RBr compounds Li Br Hg+ S S H C Br Hg+2 2 S S S S C S S C C C H H H 2. workup H 1,3-dithiane H Li SN2

S S S

+ Hg Hg Hg+ Hg+ S S S S O S C C C H H C O H O O H O H H H H H H H H H H H aldehydes S C resonance C C Hg O O H H O S O H H

1. alkylate 2x followed by 2. hydrolysis makes ketones epoxides Li O S S 2. workup S S S S H2C C Li C C H S 2 O N HOH Li 2

Hg+ Hg+2 S S S S Hg+ C S S C C 2. workup H O OH O H H OH

S S S S OH Hg+ H O Hg Hg 2 Hg+ C S C S S S O C C H O H H O O resonance OH OH H H H OH

C O O H O C H 2 H O

Skeletal targets with an “X” .

1C 2C 3C 4C X allowed starting structures. X X b c d X X a b a CH4 H3C X o o o o * Br methyl 1 1 2o 1 X 3o X 1 2o 5C a c e g 1o b d f h X X ** X Br CO2 NaCN X * X X X o o o 1 2o 2 1o 3o 2o 1o 1 neopentyl X * = chiral centers, too complicated forus 6C b c de f X a X * * * X * o X o 1o 2o 2o X 1 3o 2 X 6C m g h i j X k l X X

* * * X o o o o X X 2o 1 X 1 2 3 1o 1o neopentyl 6C n o p q categories of RX compounds: X methyl 1o = primary neopentyl allyl 1o = primary o benzyl * * 2 = secondary neopentyl X o vinyl 2 = secondary 3o = tertiary neopentyl X o o o phenyl 2o neopentyl 1 X 1 3 3o =tertiary a c 7C b X d X ef * * * X X o X 1 o o o o 2 2o 2 X 1 3 7C g h k X X i j X lmX * * * ** X * o o X 2o 2o 2o X 1o 1 2o 3 7C X o p X q r s t n X * * * * * * * X * o o o o o 2o 2 1 1 X X 1 neopentyl 2 X 2o 7C u v w x y X z aa X bb * * * * X * * o o o o o 1 X X 1o o 3 2o 1 X 1 X 1 3 X X X 7C cc dd ee ff gg hh ii jj X

* * X X X X o X o 3 2o 1o 2o 1o neopentyl 1o 2 3o

7C kk ll mm X

X X o o 1o neopentyl 3 1 o Extra patterns to know (allylic and benzylic RX are very fast SN2patterns)(1 neopentyl, vinyl and phenyl RX patterns are unreactive). a X a X b X c X b X X X X benzylic benzylic

allylic allylic allylic 1o neopentyl vinyl X phenyl X

Simple combinations from 1-3 carbon organometallic nucleophiles with 1-3 carbon electrophiles.

H3C 1 make organometallic H C (MgBr) H3C Li 2 H2C (MgBr) Na 2. add electrophile H3C H C Li Na H3C C 3. workup H 2 H3C OH OH OH O OH OH OH

C H H

OH OH O OH OH OH OH

C H3C H

OH OH O OH OH OH OH

H3C C C H H2

OH OH OH OH OH OH O

C

H3C CH3

OH OH OH OH OH O OH

epoxides

OH O OH OH OH OH OH

epoxides

O OH OH OH OH

C R not used in not used in H O our course our course esters (adds 2x)

O OH OH OH OH not used in C R not used in our course our course H C O 3 esters (adds 2x)

O OH OH OH OH

H C C R not used in not used in 3 our course C O our course H 2 esters (adds 2x)

OH OH O OH OH not used in not used in R C R our course our course O O carbonate (adds 3x) O O O O O C not used in not used in our course our course OH OH OH OH O carbon dioxide

N O O O O C not used in not used in H3C our course our course nitriles

O O O O N not used in H C C not used in 3 our course C our course H2 nitriles Products from reactions of carbon nucleophiles and carbon electrophiles used in our course: Carbon and hydrogen nucleophiles Ph R Ph Al H N HS S R Li R (MgBr) P Li AlH R Cu Li Na CN RCC Na Ph 4 Li Carbon 2 H C R Li cyanide acetylides 2 Na BH4 lithium diisopropy- electrophiles organolithium organolithium cuprates ylid (LAH) diisobutylaluminium dithiane reagents reagents Wittig reagents hydride (DIBAH) amide (LDA), -78oC anion H C Br SN2, 3 not useful not useful 2 RX coupling nitrilesalkynes not useful alkyls not useful not useful methyl RX hydrolysis reaction makes C=O SN2, R Br not useful not useful 2 RX coupling nitriles alkynes not useful alkyls alkyls not useful not useful hydrolysis primary RX reaction makes C=O R SN2, 2 RX coupling nitriles alkyls hydrolysis not useful not useful E2 not useful alkyls not useful not useful makes C=O R Br reaction (aldehydes secondary RX &ketones) O epoxide 1o ROH 1o ROH 1o ROH 1o ROH not useful 1o ROH o not useful not useful 1o ROH 1 ROH addition nitriles alkynes O o o o epoxide 2o ROH 2o ROH o 2 ROH o not useful 2 ROH 2 ROH not useful E2, make 2 ROH 2 ROH addition nitriles alkynes allylic alcohols propylene oxide O

o o o o E2, make 3 ROH 3 ROH 3o ROH 3 ROH 3o ROH not useful 3o ROH 3 ROH not useful epoxide allylic alcohols addition nitriles alkynes isobutylene oxide

O C=O o o o specific methanol C 1 ROH 1 ROH not used cyanohydrin 1 ROH not useful not useful addition in our course alkenes H H alkynes methanal

O

specific o C=O 2o ROH o cyanohydrin o 1 ROH 1o ROH not useful C 2 ROH not useful 2 ROH alkenes chemistry addition R H alkynes simple aldehydes O cyanohydrin specific enolate C=O C 3o ROH 3o ROH not useful unless o 2o ROH 2o ROH 3 ROH alkenes not useful chemistry addition R R sterically simple ketones hindered alkynes O o o 3 ROH 3 ROH not used enolate not used C R not useful not useful not useful 1o ROH not useful aldehydes (Nu: twice) (Nu: twice) in our course chemistry in our course R O simple esters O ketones acid/base not used C acid/base acid/base acid/base acid/base acid/base acid/base enolate use 2 equivalents no net rxn not useful no net rxn chemistry in our course R OH no net rxn no net rxn no net rxn no net rxn no net rxn simple (B: once HCN = danger carboxylic acids Nu: once) O

C=O C o o E2, make 3 ROH 3 ROH not useful not useful o o R Cl ketones not useful 1 ROH 1 ROH aldehydes substitution (Nu: twice) (Nu: twice) ketenes simple acid chlorides o R C N 1 amines aldehydes ketones simple nitriles ketones enolate not used not useful not useful not useful not useful not useful (also amines chemistry in our course RCONR'2 (also aldehydes o ketones ketones 3 amides fromamides) from3o amides) ketones O CO use 2 equivalents carboxylic not used not useful not useful carboxylic not useful not useful not useful not useful not useful (B: once acids acids in our course carbon dioxide Nu: once) O not used C conjugate not used o o conjugate not useful alcohols 3 ROH 3 ROH addition not useful alcohols not useful in our course R addition in our course , -unsaturated ketones + WK = normal workup to neutralize the reaction conditions. For the basic reactions (like above) above this would require mild acid neutralization (H3O ). NR = no reaction or no productive result or not emphasized