Chem 315 Reactions Through Topic 11

Web pages Beauchamp 1

Propose synthetic reactions for the indicated target structures from the given starting materials. Show the starting material (methane, ethane and propane), a reaction arrow with the reagent and a product for each synthetic step of your synthesis. If a compound has been prepared earlier you do not need to remake it (just refer to the part where you made it). Common organic reagents may be used as needed. Additional “carbon” compounds available include bromobenzene, cyclohexane, carbon dioxide and sodium cyanide.

1. Given starting material = methane,(CH4)

Target molecules (the part from methane has the “C” written out). 6 1 2 3 4 5 N 7 89 O H C NH H C SH C O H3C Br H3C OH 3 2 3 CH H C H3C 3 CH 3 H3C 3 methane + Br /hνa. 1 + ester (S 2) 2 N 1. 1 + O 2 + HBr (2 ways) b. ester + NaOH a. propyne + NaNR2 (2 ways) 2 + PBr3 + 1 + NaCN (SN2) 31 + H3O , H2O N b. bromomethane 2 + SOBr2 RO + RBr (S 2) a. 31+HgX /H O a. 40 + NaNR2 N 2 + a. TsCl/py 2 2 1 + NaSH (SN2) b. NaBH b. bromomethane b. NaBr 4 (SN2) O a. 13 + NaBH4 2. NaOH b. WK

10 11 O 12 O 13 O 14 O 15 O O CH3 CH3 C CH3 C C C H O H O H O H O (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) RO + RBr (SN2) RCO + RBr RO + RBr (SN2) RCO2 + RBr RCO2 + RBr RCO2 + RBr 2 (S 2) (S 2) (S 2) ROH + RBr (S 1) N (SN2) N N N RCOCl + ROH RCOCl + ROH RCOCl + ROH RCOCl + ROH (acyl substitution) (acyl substitution) (acyl substitution) (acyl substitution)

OH OH 20 OH 21 OH O 23 16 O 17 O 18 19 22

C C H3C OH H3C H3C OH H3C CH3 H H H OH H3C H3C a. 1 + Mg (or Li) 2 + CrO /py 2 + CrO /H O a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) 3 3 2 a. 1 + Mg (or Li) b. CO (PCC) (Jones) b. methanal b. ethanal b. propanal b. propanone 2 b. alkyl methanoate c. WK c. WK c. WK c. WK c. WK c. WK

24 OH 25OH 26 27 28 O 29 O OH OH H3C H C H3C 3 H3C H3C H3C CH3 CH3 acid chloride + cuprate a. 1 + Mg (or Li) acid chloride + cuprate a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) b.3C epoxide b. propanenitrile b. alkyl propanoate b. 2C epoxide b. ethanenitrile b. alkyl ethanoate c. WK c. WK propanoic acid + c. WK c. WK ethanoic acid + 2 eqs methyl lithium 2 eqs methyl lithium

O 36 O 30 31 32 33 34 35 CH3 CH3

H3C H3C H3C H3C

(2 ways) (2 ways) (2 ways) (2 ways) 1. ketone + LDA cuprate + RBr cuprate + RBr cuprate + RBr CH3 cuprate + RBr (2 ways) 2. RBr (compound 1) cuprate + enone cuprate + RBr (conjugate addition) a. enamine + 1 b. H2O (hydrolysis)

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2. Given starting material = ethane,(CH3CH3) 8 1 2 3 4 5 6 7 9 N O O NH C Br OH 2 SH a. 1 + ester (S 2) 1 + O ethane + Br /hν N 1. (2 ways) (2 ways) 2 b. ester + NaOH a. 40 + NaNR a. propyne + NaNR2 2 + HBr + 2 31 + H3O , H2O N 1 + NaSH (SN2) 1 + NaCN (SN2) b. bromoethane 2 + PBr3 b. bromoethane RO + RBr (S 2) a. 31+HgX /H O N 2 + SOBr2 2 2 2 + a. TsCl/py b. NaBH4 (SN2) O b. NaBr a. 13 + NaBH4 2. NaOH b. WK

11 O 13 O 14 O 15 O 10 12 O O

R O O O O (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) RO + RBr (SN2) RO + RBr (SN2) RCO + RBr RCO + RBr RCO2 + RBr RCO2 + RBr 2 2 (S 2) (S 2) (S 2) ROH + RBr (S 1) (SN2) N N N N RCOCl + ROH RCOCl + ROH RCOCl + ROH RCOCl + ROH (acyl substitution) (acyl substitution) (acyl substitution) (acyl substitution)

16 O O O OH O 17 18 19 20 OH 21 OH 22 23

OH O H OH OH (2 ways) a. 40 + R2BH 2 + CrO3/H2O (Jones) a. 1 + Mg (or Li) RCO + RBr b. H2O2 / HO a. 1 + Mg (or Li) 2 a. 1 + Mg (or Li) a. 1 + Mg (or Li) b. CO2 a. CH3Br/Mg b. methanal (SN2) a. 1 + Mg (or Li) b. propanal b. propanone c. WK + b. CO2 c. WK RCOCl + ROH 40 + H3O /H2O b. ethanal c. WK c. WK (acyl substitution) c. WK c. WK 5 + H2SO4/H2O 2 + CrO3/py (PCC) ethanenitrile + H2SO4/H2O/∆

OH OH 26 OH 28 24 25 27 29 O OH OH

acid chloride + cuprate a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) b.3C epoxide b. ethanenitrile b. alkyl methanoate b. alkyl ethanoate b. alkyl propanoate b. 2C epoxide c. WK c. WK ethanoic acid + c. WK c. WK c. WK 2 eqs ethyl lithium O O 30 O 31 32 33 34 35 36 37

acid chloride + cuprate (2 ways) (2 ways) a. 1 + Mg (or Li) (2 ways) (2 ways) (2 ways) 1. ketone + LDA b. propanenitrile cuprate + RBr cuprate + RBr cuprate + enone ethanoic acid + cuprate + RBr cuprate + RBr cuprate + RBr (conjugate addition) 2. RBr (compound 1) 2 eqs propyl lithium a. enamine + 1 b. H2O (hydrolysis)

38 39 40 41 42 43 O Br Br HO Br OH OH 1 + K+ t-butoxide 38 + mCPBA 38 + OsO Br a. 39 + NaNR2 4 2 Br2 / H2O (or KMnO ) 2 + H2SO4/∆ b. WK 41 + NaOH 4

Wittig = methanal + ylid

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3. Given starting material = propane,(CH3CH2CH3) a.

1 2 3 5 8 9 10 4 N O C O O OH Br NH2 SH a. 1 + ester (S 2) N 1 + O propane + Br2/hν b. ester + NaOH 1. 2 + HBr 31 + H O+, H O (2 ways) (2 ways) (2 ways) 2 + PBr 3 2 N 1 + NaCN (SN2) 3 a. 31+HgX /H O 2 + SOBr 2 2 RO + RBr (S 2) RO + RBr (SN2) 2 1 + NaSH (SN2) RO + RBr (SN2) N b. NaBH4 2 + a. TsCl/py (SN2) O b. NaBr a. 13 + NaBH4 ROH + RBr (S 1) ROH + RBr (SN1) 2. NaOH ROH + RBr (SN1) N b. WK

11 O O 14 15 OH OH 12 13 16 OH 17 O

OH R O (2 ways) (lots of ways) ROH + RBr (S 1) RCO + RBr 2 + CrO3/H2O N 2 a. 1 + Mg (or Li) (Jones) a. 1 + Mg (or Li) (SN2) b. methanal a. 1 + Mg (or Li) a. 1 + Mg (or Li) RCOCl + ROH 2 + CrO /py b. ethanal b. propanal b. propanone 3 c. WK c. WK (acyl substitution) (PCC) c. WK c. WK + 33 + H3O /H2O ...and more O O 18 19 OH 20 21 22 23 24 O OH Li OH OH Cu

a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) b.3C epoxide cuprate acid chloride + cuprate acid chloride + cuprate b. CO2 b. alkyl methanoate b. 2C epoxide c. WK a. 1 + Mg (or Li) a. 1 + Mg (or Li) c. WK c. WK c. WK 2RLi + CuBr b. ethanenitrile b. propanenitrile ethanoic acid + ethanoic acid + 5 + H2SO4/H2O 2 eqs propyl lithium 2 eqs propyl lithium

25 26 29 O O 27 28 30 31

1. ketone + LDA (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) 2. RBr (compound 1) cuprate + RBr cuprate + RBr cuprate + RBr cuprate + RBr cuprate + RBr cuprate + enone (conjugate addition) a. enamine + 1 b. H2O (hydrolysis)

33 34 37 32 35 36 O Br Br HO OH Br OH a. 32 + NaNR 31 + mCPBA + 2 31 + Br2/H2O 31 + H2O2 / HO 1 + K t-butoxide 31 + Br2 b. WK 34 + NaOH

38 O 41 42 all from 39 O 40 43

H (lots of ways) 1. R2BH a. NaNR2 39 + Na / NH3 39 + Pd / H2 39 + Pd / H2 b. H2O2 / HO 2 + CrO3/H2O b. CH3-Br quinoline (Jones) 2 + CrO3/py (PCC) + 33 + H3O /H2O ...and more

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4 1 2 3 5 N 6 7 C SH NH2 Br OH 1. O 2 + HBr 1 + NaOH (SN2) 1 + NaCN (S 2) 2 + PBr 1 + NaSH (SN2) N 1 + NaCCH (SN2) 1 + NaCCCH3 (SN2) 3 31 + a. BH3 N 2 + SOBr 2 b. H2O2, HO 2 + a. TsCl/py (S 2) b. NaBr N O 2. NaOH

11 O 8 9 10 12 O O O O R O (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) RO + RBr RO + RBr RO + RBr RO + RBr RCO2 + RBr (both S 2) (both S 2) (both SN2) N N (both SN2) (SN2) RCOCl + ROH (acyl substitution)

13 O 14 O 15 O 16 O 17 O 18 O

O O O O H OH (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) (2 ways) 2 + CrO3/py RCO + RBr RCO2 + RBr RCO2 + RBr RCO2 + RBr 2 (PCC) 2 + CrO3/H2O (S 2) (SN2) (SN2) (SN2) N 33 + a. R BH (Jones) RCOCl + ROH RCOCl + ROH RCOCl + ROH RCOCl + ROH 2 b. H O , HO nitrile + H2SO4/H2O (acyl substitution) (acyl substitution) (acyl substitution) (acyl substitution) 2 2

OH OH OH OH 19 20 21 22 23 OH 24

OH a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) b. methanal b. ethanal b. propanal a. 1 + Mg (or Li) c. WK b. alkyl methanoate c. WK c. WK b. propanone c. WK a. 1 + Mg (or Li) c. WK b. alkyl ethanoate c. WK 25 OH 26 O 27 28 O OH 29 OH OH (2 ways) a. 1 + Mg (or Li) a. 1 + Mg (or Li) a. 1 + Mg (or Li) acid chloride + cuprate a. 1 + Mg (or Li) b. 2C epoxide b.3C epoxide b. alkyl propanoate a. 1 + Mg (or Li) b. ethanenitrile b. CO2 c. WK c. WK ethanoic acid + 2 eqs propyl lithium c. WK c. WK

5 + H2SO4/H2O

35 30 O 31 32 33 34

(2 ways) (2 ways) (2 ways) (2 ways) acid chloride + cuprate (2 ways) cuprate + RBr a. 1 + Mg (or Li) b. propanenitrile cuprate + RBr cuprate + RBr cuprate + RBr cuprate + RBr ethanoic acid + 2 eqs propyl lithium

36 O O 37

(2 ways) 1. ketone + LDA cuprate + enone 2. RBr (compound 1) (conjugate addition) a. enamine + 1 b. H2O (hydrolysis)

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Group 1 O N

Br OH O O NH2 C SH

1 2 3 4 567 8

(MgBr) Li R S S H H C C Cu H3C CH3 13 H3C CH3 Li 11 12 14

9 10 O 1 2 3 3 4 5 6 O 1. Br /hν O Na 2 O O 1. Na (S 2) N H H N K OH Na O water (S 1) O N (SN1) potassium t-butoxide (S 2) phthalimidate O (make) 2. NaOH (acyl substitution) N (make) (make) (make) (an imidate) 2. NaOH (acyl substitution) 7 8 9 10 11 12 13 Na S Li O 14 Na 1. Li CN Li Mg Li R-Cu-R / Li (make) H 2. 1/2 eq. CuBr H S (cuprate) cyanide S CH Grignard organolithium 2 make react cuprates with rxn reagents cuprates RX, RCOCl, α,β-unsat C=O dithiane anion (make) ketone enolates (make)

1. Group 2 H O N C R OH O O NH2 C C Br

1 234 5 6 7 O SH R (MgBr) S S Li H C CH H3C CH2 3 2 Cu C C Li H H2 8 2 10 11 14 9 12 13

5 1 2 3 4 O 6 7 Na O 1. Na O Na (S 2) N O O N CN Na K H Na Na O cyanide potassium t-butoxide (S 2) (S 2) phthalimidate (SN2) N N O (make) (make) (an imidate) (SN2) 8 9 10 2. NaOH (acyl substitution) 13 S Li O 11 12 14 Na 1. Li Li R-Cu-R / Li (make) Mg Li 2. 1/2 eq. CuBr H S H (cuprate) S CH 2 Grignard organolithium make react cuprates with rxn reagents cuprates RX, RCOCl, α,β-unsat C=O dithiane anion (make) ketone enolates (make) Group 3

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O O O Na O O OH H OH 1 2 3 5 4 6 Ts O Br Cl

78 9

1 2 3 4 5 6 9 7 (four ways) 8 ( four ways) 1. O HBr HCl CrO3 / H2O CrO3 / H2O H Ts-Cl / py H2SO4/∆ Na H Na PCl (Jones) (Jones) (acyl substitution) PBr3 3 (-H2O) sodium sodium SOBr SOCl (E2) 2 2 rearrangement (E2) hydride Cl hydride a. TsCl/py a. TsCl/py possible (acyl substitution) (acid/base) b.NaBr b.NaCl (E1) 2. Br (SN2 & SN1) (SN2 & SN1) (SN2) last approach avoids SN1 (& rearrangements)

2. Group 4 O Ts OH O O Na O O Br Cl

123 5 6 7 8 4

1 2 2 3 4 5 6 7 (four ways) 8 ( four ways) 1. O HBr HCl CrO3 / H2O CrO3 / H2O H Ts-Cl / py H2SO4/∆ Na H Na PCl (Jones) (Jones) (acyl substitution) PBr3 3 (-H2O) sodium sodium SOBr SOCl (E2) 2 2 rearrangement (E2) hydride Cl hydride a. TsCl/py a. TsCl/py possible (acyl substitution) (acid/base) b.NaBr b.NaCl (E1) 2. Br (SN2 & SN1) (SN2 & SN1) (SN2) last approach avoids SN1 (& rearrangements)

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3. Group 5 R Br OH O Br OH Br Br Br (R,S) (R,S) (R,S)

1 2 5 34 67 Br OH O 8 OH R (R,S) (R,S) O O OH CH O (R,S) 2 CBr2 OH (R,S) O HO O H CH2 CH3 C OH 9 10 12 11 OH 14 15 16 13 Rg = regioselectivity (Markovnikov, anti-Marrkovnikov or not applicable) St = stereoselectivity (syn, anti or random addition)

1 (two ways) 2 (two ways) 3 4 5 67 + 1. HgX / ROH HBr 1. BH3 1. BH3 Br2 Br / H O + 1. HgX2 / H2O ROH2 , ROH 2 2 2 H3O , H2O 2. NaBH rearrangements 2. NaBH4 rearrangements 2. H2O2, HO 2. Br2, CH3O rearrangements 4 possible no rearrangements possible no rearrangements anti-Markovnikov anti-Markovnikov Rg = NA Rg = Y possible St = Y, anti Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y St = Y, anti Rg = Y Rg = Y St = N St = N St = N St = Y, syn St = Y, syn (convert to St = N St = N 1. hydroboration epoxide in NaOH) 10 11 12 13 2. oxidation 9 16 8 mCPBA 1. O , -78oC o o 14 15 3 1. O3, -78 C 1. O3, -78 C OsO4 Br / ROH or 2. CH SCH CHBr3 2 or 3 3 2. NaBH4 2.H2O2 / HO Pd / H CH2I2 1. Br /H O 2 K+ t-butoxide KMnO 2 2 Zn (Cu) 4 2. NaOH Rg = NA Rg = NA Rg = NA Rg = Y Rg = NA St = Y, anti St = NA St = NA St = NA Rg = NA Rg = NA Rg = NA Rg = NA St = Y, syn St = Y, syn St = Y, syn St = Y, syn St = Y, syn catylic dihydroxylation epoxidation ozonolysis reduction

4. Group 6 Br R OH Br R OH O OH Br Br Br Br O R,S R,S R,S R,S R,S 6 7 8 1 4 2 3 (enantiomers) (enantiomers) (enantiomers) 5 (enantiomers) (enantiomers) (enantiomers) (enantiomers) (enantiomers) (2S,3S) OH (2S,3S) (2S,3S) OH H (2R,3R) (2R,3R) (2R,3R) O C OH H C CH OH 3 O 2 CBr2 O CH3 HO O 9 10 C O (meso) (meso) H 11 12 14 15 16 (2R,3S) (2R,3S) 13 (meso) (meso) Rg = regioselectivity (Markovnikov, anti-Marrkovnikov or not applicable) OH St = stereoselectivity (syn, anti or random addition) (2R,3S) (2R,3S)

1 (two ways) 3 2 (two ways) 4 5 67 + 1. HgX / ROH HBr 1. BH3 1. BH3 Br2 Br / H O + 1. HgX2 / H2O ROH2 , ROH 2 2 2 H3O , H2O 2. NaBH rearrangements 2. NaBH4 rearrangements 2. H2O2, HO 2. Br2, CH3O rearrangements 4 possible no rearrangements possible no rearrangements anti-Markovnikov anti-Markovnikov Rg = NA Rg = Y possible St = Y, anti Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y St = Y, anti Rg = Y Rg = Y St = N St = N St = N St = Y, syn St = Y, syn (convert to St = N St = N 1. hydroboration epoxide in NaOH) 10 11 12 13 2. oxidation 9 16 8 mCPBA 1. O , -78oC o o 14 15 3 1. O3, -78 C 1. O3, -78 C OsO4 Br / ROH or 2. CH SCH CHBr3 2 or 3 3 2. NaBH4 2.H2O2 / HO Pd / H CH2I2 1. Br /H O 2 K+ t-butoxide KMnO 2 2 Zn (Cu) 4 2. NaOH Rg = NA Rg = NA Rg = NA Rg = Y Rg = NA St = Y, anti St = NA St = NA St = NA Rg = NA Rg = NA Rg = NA Rg = NA St = Y, syn St = Y, syn St = Y, syn St = Y, syn St = Y, syn catylic dihydroxylation epoxidation ozonolysis reduction

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5. Group 7 R OH Br R O OH O OH Br Br R,S R,S R,S R,S R,S 7 Br 8 1 2 4 6 Br Br 3 (enantiomers) 5 (enantiomers) OH (enantiomers) (enantiomers) (enantiomers) (enantiomers) (meso) (enantiomers) (2S,3R) OH (2R,3S) (2R,3S) (2S,3R) O H CH CBr2 (2R,3S) C OH 2 9 H3C O HO O (enantiomers) O CH3 O OH 10 16 C 15 (2S,3S) (enantiomers) 12 (2R,3R) H 14 11 13 (enantiomers) (enantiomers) Rg = regioselectivity (Markovnikov, anti-Marrkovnikov or not applicable) OH (2S,3S) (2S,3S) St = stereoselectivity (syn, anti or random addition) (2R,3R) (2R,3R)

1 (two ways) 2 (two ways) 3 4 5 67 + 1. HgX / ROH HBr + 1. HgX2 / H2O ROH2 , ROH 2 1. BH 1. BH H3O , H2O 3 3 2. NaBH rearrangements 2. NaBH4 rearrangements 2. H O , HO 2. Br , CH O Br2 Br / H O rearrangements 4 possible 2 2 2 3 2 2 no rearrangements possible no rearrangements anti-Markovnikov anti-Markovnikov possible Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y Rg = NA Rg = Y Rg = Y St = N St = N St = N St = Y, anti St = Y, anti St = N St = N St = Y, syn St = Y, syn

9 10 16 8 11 12 13 14 15 mCPBA o o o CHBr Br2 / ROH OsO4 1. O3, -78 C 1. O3, -78 C 1. O , -78 C CH I 3 or 3 Pd / H 2 2 + or 2. CH SCH 2 K t-butoxide 3 3 2. NaBH4 2.H2O2 / HO Zn (Cu) KMnO 1. Br2/H2O Rg = Y 4 Rg = NA 2. NaOH Rg = NA Rg = NA Rg = NA Rg = NA Rg = NA St = Y, anti St = Y, syn Rg = NA St = NA St = NA St = NA St = Y, syn St = Y, syn St = Y, syn Rg = NA St = Y, syn

6. Group 8 OH O Br Br OH Br Br Br R

R Br OH O 12 3 4 5 6 7 achiral achiral achiral achiral achiral (enantiomers) 8 (enantiomers) (enantiomers) O OH OH OH C O H C H2 C O H CH2 H2 CBr C C 2 OH O OH C 9 10 11 O 12 13 OH (meso) (meso) achiral achiral 14 15 16 Rg = regioselectivity (Markovnikov, anti-Marrkovnikov or not applicable) achiral achiral (meso) (meso) St = stereoselectivity (syn, anti or random addition)

1 (two ways) 2 (two ways) 3 4 5 67 + 1. HgX / ROH HBr + 1. HgX2 / H2O ROH2 , ROH 2 1. BH 1. BH H3O , H2O 3 3 2. NaBH rearrangements 2. NaBH4 rearrangements 2. H O , HO 2. Br , CH O Br2 Br / H O rearrangements 4 possible 2 2 2 3 2 2 no rearrangements possible no rearrangements anti-Markovnikov anti-Markovnikov possible Rg = Y Rg = Y Rg = Y Rg = NA Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y St = N St = N St = N St = Y, anti St = Y, anti St = N St = N St = Y, syn St = Y, syn

9 10 16 8 11 12 13 14 15 mCPBA o o o Br / ROH OsO 1. O3, -78 C 1. O , -78 C 1. O , -78 C CHBr3 2 4 or 3 3 Pd / H CH2I2 or 2. CH SCH 2 K+ t-butoxide 3 3 2. NaBH4 2.H2O2 / HO Zn (Cu) KMnO 1. Br2/H2O Rg = Y 4 Rg = NA 2. NaOH Rg = NA Rg = NA Rg = NA Rg = NA Rg = NA St = Y, anti St = Y, syn Rg = NA St = NA St = NA St = NA St = Y, syn St = Y, syn St = Y, syn Rg = NA St = Y, syn

Other alkenes to consider.

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7. Group 9 R Br Br R O O Br Br Br O Br O

Br Br H 12 3 4 5 Br Br enol ether 6 7 O ketones can be hard to control aldehydes can be hard to control 8 via enol via enolate OH HO OH HO H 12 OH OH O not as good 9 CO2 10 11 on terminal alkynes 13 14 15 16 17 Rg = regioselectivity (Markovnikov, anti-Marrkovnikov or not applicable) St = stereoselectivity (syn, anti or random addition)

1 2 3 4 5 6 789 1. R BH Br2 / ROH KMnO4 H O+, H O ROH +, ROH HBr HBr 2 3 2 2 2. H O , HO Br2 Br2 (hot) (Hg+2 cat.) (Hg+2 cat.) (1 eq) (2 eqs) 2 2 (1 eq) (2 eqs) anti-Markovnikov Rg = NA Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y Rg = NA Rg = NA St = Y, syn St = N St = N St = mixed St = mixed St = mixed St = N St = N St = Y, syn harsh conditions

10 12 16 17 11 13 14 15 18 Na / NH3 Pd / H2 Pd / H2 + + + + (Birch) 1. Na H N 1. Na H2N 1. Na H2N 1. Na H N quinoline 1. Na+ H N 2 2 2 O 2. O 2. 2. can continue using Rg = NA Lindlar's Cat. 2. O zipper reaction 2.H2CO St = Y, syn (makes E, not good Br Rg = NA with terminal alkynes) 3. WK complete St = Y, syn H reduction 3. WK 3. WK 3. WK 3. WK (makes Z)

8. Group 10 R O Br Br Br R O O Br Br Br O

Br Br H

12 3 4 56 78Br Br O

OH HO OH HO OH OH O 91210 11 13 14 15 16 17 Rg = regioselectivity (Markovnikov, anti-Marrkovnikov or not applicable) St = stereoselectivity (syn, anti or random addition)

1 2 3 4 5 6 789

Br / ROH KMnO4 H O+, H O + 1. R2BH 2 3 2 ROH2 , ROH HBr HBr Br2 Br2 +2 2. H O , HO (hot) (Hg cat.) (Hg+2 cat.) (1 eq) (2 eqs) 2 2 (1 eq) (2 eqs) anti-Markovnikov Rg = NA Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y Rg = Y Rg = NA Rg = NA St = Y, syn St = N St = N St = mixed St = mixed St = mixed St = N St = N St = Y, syn harsh conditions

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Chemical Catalog of Reagents

Nucleophiles / Bases - electron pair donors Electrophiles / Lewis Acids - electron pair acceptors Br R + Br H O Na H S Na+ Br Br hydroxide hydrogen H C Br RX = 3 R Br (buy) sulfide R R R R methyl primary secondary tertiary allylic benzylic + O Na S Na+ alkoxides alkyl sulfides R Br (make) (make) R Br Br O These 3 examples are mostly unreactive in SN and E reactions. R O K+ 1o neopentyl vinyl phenyl Na+ O R t-butoxide carboxylates O N O O O O O N (make) (make) C C C R O C C C O C + NaH H H R H R R R R aldehydes nitriles & methanal aldehydes ketones α,β-unsaturated carbon dioxide imines C=O N N N N ketones

Na+ azide O O O O O O O phthimidate (buy) (make) O C C C C C R C C + X R Cl R O R R O R NR2 R OH R CCNa + carboxylic acids acid chloride amides (1o,2o,3o) carboxylic acid NCNa terminal anhydrides esters cyanide & derivatives acetylides (X = leaving group) (buy) (make) O O O S Ph epoxides O O O O Li Ph PCH2 O

R CH2 S Li Ph enolates dithiane Wittig ylid (make) carbanions (make) (make) Strong Mineral Acids O

H2SO4 H Cl H I SOH Li H Br HNO3 H3O ROH2 R Li hydrochloric R (MgBr) sulfuric hydrobromic hydroiodic nitric acid R Cu R acid acid O Grignard acid acid organolithium lithium toluenesulfonic acid reagents reagents (make) dialkyl HgX (make) (make) Other Lewis Acids PCl3 2 O cuprates FeX BH mecuric SOCl2 O Cl phosphorous 3 3 thionyl chloride trichloride feric trihalide borane ion SCl C C LiAlH4 NaBH4 R PBr3 BF3 O SOBr AlX3 LAH A H 2 Cl O phosphorous R2BH boron toluenesulfonyl chloride (buy) sodium thionyl bromide aluminium lithium borohydride oxalyl chloride tribromide trihalide dialkylborane trifluoride R aluminium (buy) DIBAH Oxidizing Reagents hydride diisobutyl Reducing Reagents OsO CrO3 / H2O H / Pd 4 Jones aluminium Na / NH 2 o o o 3 catalytic 1. O3, -78 C 1. O3, -78 C 1. O3, -78 C (RO)3AlH Li hydride KMnO CrO / pyridine Birch Conditions hydrogenation 2. CH SCH 2. NaBH 2. H O / HO 4 3 lithium trialkoxy (buy) 3 3 4 2 2 PCC aluminium hydride H2 / Pd / quinoline Br2 Cl2 H2O2 CuBr (buy) (Lindlar's Cat.) bromine chlorine peroxide cuprous bromide Always act as Bases 1. Na R N Li LDA 2 N Na+ H K+ H 2. workup lithium sodium hydride potssium hydride sodium amide diisopropylamide (buy) (buy) (buy) (make)

Neutral Nucleophiles / Bases - electron pair donors (lone pairs and pi bonds) O N P S O R R R Ph Ph H2S C H2O R H R H R OH R2N O R Ph hydrogen enamines thiols alkynes enol ethers amines phosphines sulfide alkenes o o o water alcohols carboxylic acids aromatics (1 ,2 ,3 ) Available organmetallics, can act as nucleophiles or as bases (organolithium reagents, for now, later magnesium and copper reagents too) Li H Li 2 H Li C C CH2 Li H3C C CH3 Li H3C CH CH Li H C C C CH 3 3 H 3 H2 2 CH3 H2C methyl lithium n-butyl lithium sec-butyl lithium t-butyl lithium vinyl lithium phenyl lithium

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Always available: CH4

Br HO Ph Br

= Ph Ph = phenyl Provided for now: =

Br HO Br Br Br

Make (propose a synthesis for RBr - possible from 1. R-H, 1. Br /hν, free radicals 2 Br Br 2. R-OH, 2. many ways (see below) make 3. alkenes 3. addition of HBr Br phenylethyne Br Br Br Br Ph H3C Br Br Br Br Br

Br make Br make ethyne propyne Make (propose a synthesis for ROH - possible from R-Br, alkenes, esters, C=O, epoxides) OH OH OH OH H3C OH OH OH OH OH

OH OH 1. S 2 or S 1 OH N N 2. ester hydrolysis 3. carbonyl reduction 4. open epoxides

Make (propose a synthesis for esters - possible from R-Br + carboxylate, acid chlorides + alcohols, carboxylic acids + alcohols) OAc OAc OAc OAc OAc OAc H3C OAc OAc OAc

O OAc OAc Ac R OAc = C R O H C O 1. RBr = SN2 or SN1 3 OAc = acetate (ester) 2. acyl substitution 3. Fischer ester synthesis Make (propose a synthesis for ROR' - possible from 1. R-Br, 2. alkenes) R R O O O R O R O H C R 3 O R O R R O O R R O O R O O R R O = Ph R = Ph 1. RBr = SN2 or SN1 2. alkene addition reactions

Make (propose a synthesis for ROTs from ROH, make alkyl tosylates from alcohols using TsCl/py = toluenesulfonyl chloride/pyridine) OTs OTs OTs OTs OTs H3C OTs OTs OTs OTs elimination is a common side rxn OTs OTs O Ts-Cl = S Cl pyridine = N

"OTs" ≈ "I" as a leaving group from RX O

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o o o Make (propose a synthesis for RNH2 - possible from R-Br + phthalimide,= SN2 at methyl, 1 , 2 RX, but not 3 RX)

NH2 NH2 NH2 NH2 NH2 NH2 H3C NH2 NH2 NH2 not possible O this way

NH2 NH2 NH2 N H

phthalimide O

o o o Make (propose a synthesis for thiol - possible from R-Br + NaSH = SN2 at methyl, 1 , 2 RX, but not 3 RX) SH SH SH SH SH SH H3C SH SH

SH not possible this way SH SH SH SH Thiols are very = = SH stinky compounds, Ph SH Ph = Ph and often biologically active.

Make (propose a synthesis for alkene from 1. RBr = E2 reaction or 2. ROH = E1 reaction)

1. RBr + K+ t-butoxide 2. ROH + H2SO4/∆ E2: from 1-bromobutane

+ Make (propose a synthesis for alkyne from RBr2, 1. double E2 reaction using R2N Na 2. workup) aldehyde ketone from: alkene (E/Z) from: 1,1-dibrompropane alkane 1,1-dibromoethane 1,2-dibromopropane other rxns possible 1,2-dibromoethane 2,2-dibromopropane

o o o R Make (propose a synthesis for alkyne from RBr + terminal acetylides = SN2 at methyl, and 1 , but not 2 RX and 3 RX) R R Ph Ph H3C R R R R = H from ethyne or CH3 from propyne R

The zipper reaction can move an internal triple bond to the terminal position through a sequence of (CH2)s.

H2 H2 C C CH3 1. R N Na H2 H2 H2 2 C C C C C C H2 H2 R N-H R C C C C 2 H H 2 2 C R 2. workup internal triple bond terminal alkyne H

o o o Make (propose a synthesis for nitrile from RBr + NaCH = SN2 at methyl, 1 , 2 RX, but not 3 RX)

N N C C C C C C N N H3C N N

N N N C amides C C carboxylic acids C N aldehydes N C Ph ketones 1o amines

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Make (propose a synthesis for aldehyde from primary alcohol, oxidation = PCC) O O PCC = CrO3/pyridine (no water) O O O O H H H Ph

H H H H H O

Make (propose a synthesis for ketone from secondary alcohol, oxidation = 1. PCC or 2. Jones) O 1. PCC = CrO /pyridine O O 3 O (no water)

2. Jones = CrO3/acid (with water)

Make (propose a synthesis for carboxylic acid from primary alcohol, oxidation = Jones) O O Jones = CrO3/acid (with water) O O O O OH OH OH Ph H OH OH OH OH O O Make (propose a synthesis for acid chloride from carboxylic acid + SOCl2 [thionyl chloride], acyl substitution) O O O O O Cl Cl Ph H Cl Cl Cl Cl (not stable) Cl O

Make (propose a synthesis for primary amide from acid chloride + ammonia or an amine = acyl substitution) O O O O O NH 2 NH2 Ph NH2 NH NH 2 NH2 2 O Make (propose a synthesis for alkyl ester from acid chloride and alcohol, ROH, acyl substitution, O or also see above = SN2 with RBr + carboxylate, and also Fischer esterification = carboxylic acid + alcohol, remove water) O O R O O O O R O R O Ph R H O R R R not from O O O acid chloride O Make (propose a synthesis for ketones from propanone and methyl, primary and secondary RBr, enolate SN2) O O O O O

Ph 1. ketone 2. LDA / -78oC O O O O O 3. RBr 4. workup

Ph Ph

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Make (propose a synthesis for alkyl dithiane from dithiane and methyl, primary and secondary RBr, SN2) S

S S S S 1. dithiane 2. n-BuLi S 3. RBr S 4. workup S S S S Ph

S S S S S Ph S S S S S

S Ph

Make (propose a synthesis for RCl from ROH - four ways: 1. HCl, 2. PCl3, 3. SOCl2, 4. a. TsCl/pyridine, b. NaCl, also possibilities for "Br" and "I" below) Cl Cl Cl Cl Cl Cl H C 3 Cl Cl

1. S 2 1. S 2 1. S 2 1. S 2 1. SN2 N N N N 1. SN1 1. SN1 1. SN1 2.. S 2 2.. S 2 2.. S 2 2.. S 2 2.. SN2 N N N N 2.. SN1 2.. SN1 2.. SN1 3.. S 2 3.. S 2 3.. S 2 3.. S 2 3.. SN2 N N N N 3.. SN1 3.. SN1 3.. SN1 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. b. S 2 b. S 2 b. S 2 b. S 2 b. SN2 N N N N b. SN2 b. SN2 b. SN1 Cl 1. ROH + HCl 1. ROH + SOCl Cl 2 Cl Cl also HBr, HI also SOBr2

SN2 or SN1 SN2 or SN1

1. SN1 1. SN1 1. S 1 1. S 2 N N 1. ROH + PCl 1. ROH + TsCl/pyridine 2.. SN1 2.. SN1 2.. S 1 2.. S 2 3 N N (acyl substitution) 3.. SN1 3.. SN1 3.. S 1 3.. S 2 N N also PBr 2. NaCl 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. 4a. acyl subst. 3 b. S 2 b. S 2 (SN2) N N b. SN2 b. SN2 SN2 or SN1 also 2. NaBr or 2. NaI

Special Reaction: form epoxide from bromohydrin in NaOH O O O O Na H Br Na H Br OH OH given for now epoxide given for now epoxide

Strong nucleophiles reacting with epoxides (SN2-like reaction) Na 1. Na 1. C OH C O OH C O N (buy) N (buy) C N (R) N 2. workup (R) 2. workup SN2 attack either side SN2 attack less hindered side

1. Na 1. Na 1. Na OH O OH (make) OH O (make) O 2. workup (make) 2. workup S 2 attack either side S 2 attack either side N SN2 attack either side 2. workup N

1. Na 1. Na OH 1. Na OH (R) OH O O O (make) (R) (make) 2. workup (R) (make) (R) (R) (R) S 2 attack less hindered side2. workup S 2 attack less hindered side S 2 attack less hindered side N N 2. workup N

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H 1. 2 1. H2 C C C C H3C C H C C H 3 OH O 2 Li O (S) H2 Li n-butyl lithium OH n-butyl lithium (S) (buy) (buy) 2. workup S 2 attack either side 2. workup N

1. 1. O Na (S) OH O Na OH OH HO OH HO (buy) (buy) (S) S 2 attack either side 2. workup N 2. workup SN2 attack less hindered side

H H (R) OH (S) O O HO HO H O H H O H OH H O H H O H attack either side SN1-like, attack at better δ +, but from opposite face

1. Na 1. OR Na R OH (S) R OH O (make) O OR O (make) O 2. workup (S) SN2 attack either side 2. workup SN2 attack less hindered side

H H (S) (R) O R OH O R O H HO R R O H O O R O H R O H attack either side SN1-like, attack at better δ +, but from opposite face

Strong nucleophiles reacting with carbonyl groups (carbonyl addition reactions, aldehydes and ketones)

Na Na 1. Na 1. 1. OH O OH O OH O C (make) C (make) C (make) H H H H H H 2. workup 2. workup 2. workup

Na Na 1. Na 1. 1. OH O OH O OH O C (make) C (make) C (make) H3C H H3C H H3C H 2. workup 2. workup 2. workup

Na Na 1. Na 1. 1. O OH O O OH C OH (make) C (make) C (make) H3C CH3 H3C CH3 H3C CH3 2. workup 2. workup 2. workup

1. 1. 1. Na Na Na C C OH O C O O C N C OH N N (buy) N C OH (buy) C N (buy) C C N H H cyanohydrin H3C H 2. workup 2. workup H3C CH3 2. workup

1. H 1. H2 1. H2 2 C CH C CH2 C CH2 2 H C C H C C O H3C C O 3 O 3 H H2 H2 2 Li Li n-butyl lithium Li C n-butyl lithium OH C n-butyl lithium C OH (buy) (buy) H C H (buy) H3C CH3 H H 3 OH 2. workup 2. workup 2. workup

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O O O 1. C 1. C 1. C Na H H Na Na HO OH HO OH H3C H HO OH OH OH OH H3C CH3 2. workup 2. workup carbonyl hydrate (buy) carbonyl hydrate (buy) carbonyl hydrate (buy) 2. workup

O O O 1. C 1. R C R 1. C R Na H H Na Na O OH H3C H OR OR O OH OR H3C CH3 O OH 2. workup 2. workup (buy) (buy) hemiacetal (buy) 2. workup hemiacetal hemiketal

Lithium aluminium hydride (LiAlH4 = LAH) and sodium borohydride (NaBH4) nucleophiles reacting with various electrophiles (LiAlD4 and NaBD4 used in examples below so you can see where the hydride went.)

Reactions with RX electrophiles D D D D D D H3C D D D

D D D

== Ph D Ph

(S) O D O Li D 1. Na 1. OH OH D B D D Al D D D 2. workup 2. workup (S) D (buy) D (buy)

H O H Li D O H Na D O Li D O O 1. O 1. 1. C C C D Al D D B D D Al D H H H C H H3C CH3 H C H 3 H3C C H H3C C CH3 D 2. workup D 2. workup D 2. workup (buy) (buy) D (buy) D D

More reactions will be added.

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Commonly encountered nucleophiles and electrophiles thus far O O O X = leaving O O C group C C R X R X Important R H R R Me, 1o, 2o, 3o, esters, acid chlorides, anhydrides, electrophiles aldehydes, ketones = amides, carboxylic acids = allylic, benzylic epoxides C=O addition reactions acyl substitution reactions Important (C vs. H competition) (C vs. H competition) (C vs. H competition) (C vs. H competition) nucleophiles (can also be bases) methyl, SN2 only 1o RX, S 2 > E2 (except) H O Na N (Both Nu: /B: reactions are possible) 2o RX, S 2/E2 depends (SN > E) hydroxide N 3o RX, E2 only (buy)

R O Na (S > E) N (Both Nu: /B: reactions are possible) alkoxides (S vs E depends on (make) N RX and Nu: /B: ) O

C Na (SN > E) (No useful reactions for us) R O

carboxylates (SN vs E depends on (acetate) (make) RX and Nu: /B: )

N C Na (SN > E) (mainly Nu: reactions) cyanide (SN vs E depends on (buy) RX and Nu: /B: )

R C C Na (SN > E) (mainly Nu: reactions) terminal acetylides (SN vs E depends on (make) RX and Nu: /B: )

O Li C (SN > E) (mainly Nu: reactions) R H C 2 (SN vs E depends on enolates (make) RX and Nu: /B: )

Li H3Al H lithium (mainly Nu: reactions) (SN > E) aluminum hydride (SN vs E depends on (buy) RX and Nu: /B: )

Na H3BH (mainly Nu: reactions) sodium borohydride (SN > E) (S vs E depends on (buy) N RX and Nu: /B: ) Many of these reactions require a workup step to neutralize the strongly basic (nucleophilic) conditions. Always a base in our course: Li N Li CH2CH2CH2CH3

Na H Na NH2 (make) n-butyl lithium sodium hydride sodium aminde a very strong base and a very strong nucleophile (buy) (buy) lithium diisopropylamide (LDA) (buy or make)

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