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314 Arrow Pushing practice/Beauchamp 1

Electrophile = loving = any general electron pair acceptor = Lewis acid, (often an acidic )

Nucleophile = nucleus/positive loving = any general electron pair donor = Lewis , (often donated to an acidic proton)

Problems - In the following reactions each step has been written without the formal charge or lone pairs of and curved arrows. Assume each follows the normal octet rule, except hydrogen (duet rule). Supply the lone pairs, formal charge and the curved arrows to show how the electrons move for each step of the . Identify any obvious and electrophiles in each of the steps of the reactions below (on the left side of each reaction arrow). A separate answer file will be created, as I get to it. Let me know when you find errors.

RX reactions

Examples of important patterns to know from our starting points (plus a few extras).

methyl and primary secondary tertiary special

H3C X very good very poor SN2 patterns SN2,E2,SN1,E1 X X X X X vinyl allylic X X X X

X X

X benzylic X phenyl

X X There are many X variations. X

1o neopentyl

1. SN2 and SN2 a b

I Br Br N C I I C I N

2. SN2 and E2 a b H Br H O HC C H I HC C Br OH I

3. SN2 and SN2 a Na b Na Na Br S HC C Br Br O O S Na Br R R

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4. SN2 and acyl substitution O O Na Na Br further reaction with NaOH N N

Br H2N acyl substitution alkyl imide primary amine make O O mech. - not shown

make imidate O O O H Na N H N

O Na O

5. E2 and SN2 a H b H2O O O I

H O Br Br E2 > SN2 I SN2 > E2 O O R S

6. E2 reactions a H b H H2O O I

H O Br E2 >> S 2 I Br N O E2 >> SN2

7. E2 and SN2 a b K K K K Br I

Br H3C O O I SN2 O E2 >> SN2 make potassium t-butoxide K K

H H O O potassium hydride (always a base)

8. Nucleophilic hydride = sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4 = LAH), [deuterium is used below to show reaction site] – SN2 reaction D a D B D b D Al D Na Br D Li D B D D I D D Al D Br D D I Na Li D D

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9. Alkyl carbanions (lithium and magnesium) are poor nucleophiles with RX compounds, [cuprates work well] a b

H2 H2 C CH2 C CH2 H C C Br poor yields, too Br poor yields, too 3 many side reactions H3C C H2 H2 many side reactions Li Li

10. E2 and E2 and acid/base R2N Br Br Br Br R N H Br Na 2 Na H H C H C C C H C H C C H C NR2 H NR2 H H NR H H H NR2 Na 2

11. E2 and E2 and acid/base R N 2 R2N H Br Br Br Br Br Na Na CH Na H C H C 3 CH3

C CH3 C CH3 H NR2 H H NR H H H NR2 NR2 2

12. SN1 and E1 possibilities (1. rearrangement, 2. add nucleophile, 3. lose beta proton) Br H H

Br H H O H H E/Z H H H H H H

O H H H H

E/Z H O O H H H H

O H2O

H H R/S O

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Alcohol Reactions

Examples of important patterns to know in our course (plus a few others).

methyl and primary secondary tertiary special

H3C OH OH OH vinyl - enol is OH OH OH unstable, allylic keto tautomer preferred OH OH OH OH OH OH benzylic OH OH phenyl

OH OH There are many variations. OH OH

1o neopentyl

13. HX + ROH (SN2 at methyl and primary ROH and SN1 at secondary, tertiary, allylic and benzylic ROH in our course) Br H H H Br O O O + H3O H Br H H

+ Br H H H3O O H H O O R H Br H Br Br H R,S

Br H H + H3O O H H H O O R H H H Br H H Br Br

SN1 and E1 are possible here, but H not shown. H Br E1 + SN1 no R/S

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14. Thionyl chloride = acyl-like substitution, then SN2

synthesis of an alkyl chloride from an alcohol + thionyl chloride (SOCl2) [can also make RBr from SOBr2] O H O O Cl 2 S C Cl H 2 S R O H S C Cl R O R O Cl Cl H

H Cl

O No rearrangement Cl O Cl because no R+. S 2 at methyl and S H2 N C S primary alcohols O Cl Cl CH2 R O R H Cl

15. Thionyl chloride = acyl substitution, then SN1

synthesis of an alkyl chloride from an alcohol + thionyl chloride (SOCl2) [can also make RBr from SOBr2] O

O Cl O S Cl S O Cl H S O R O Cl Cl R H Cl R H

O O Cl S SN1 at secondary and Cl S tertiary alcohols O Cl O H H R R/S H Cl

16. Phosphorous tribromide (PBr3) = SN2, then SN2 (at methyl and primary ROH)

Br Br Br

H P P P O Br Br O Br O Br Br reacts S S Br H S twice H more

17. Phosphorous tribromide (PBr3) = SN2, then SN1 (at secondary, tertiary, allylic and benzylid ROH)

Br Br Br

P H P P Br Br O Br O O Br reacts R R Br H twice H Br H more

Br R,S

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18. Cr=O addition, acid/base and E2 to form C=O ( and )

O N H O O N O H H Cr O Cr O O O O O Cr H3C C O O H3C C H3C C C H C H H H C H 2 H 2 H H 2 H primary alcohols N

PCC = pyridinium chlorochromate oxidation of primary alcohol to an (no water to O hydrate the ) O O N H Cr O H3C C C H H2 aldehydes

19. Cr=O addition, acid/base and E2 to form C=O (aldehydes and ketones)

O N H O O N O H H Cr O Cr O O O O O Cr H3C C O O H3C C H3C C C CH3 C CH3 H H C CH3 2 H 2 H H 2 H secondary alcohols N

O PCC = pyridinium chlorochromate oxidation O O of primary alcohol to an aldehyde (no water to Cr hydrate the carbonyl group) N H O H3C C

C CH3 H2 ketones

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20. Cr=O addition, acid/base and E2 to form C=O, then hydration of C=O and repeat reactions H O O O O O H O H Cr O H H Cr O O O H H O O Cr H3C C O O H3C C H3C C C H C H H H C H 2 H 2 H H 2 H primary alcohols Jones = CrO3 / H2O / acid H primary alcohols oxidize to carboxylic acids (water hydrates the carbonyl group, O which oxidizes a second time ) H H H H O O O O O O Cr H H H C C O H3C C H3C C 3 C H C H C H H H2 H2 2 hydration of the aldehyde aldehydes (cont. in water)

O H H H H H O O O H H H H O H O Cr H O O O O O H H H3C C O H3C C O Cr C H3C C O H H C O O 2 H H H C 2 H H H2 H second oxidation of the carbonyl hydrate

H O O O O O Cr O H H Cr O O O

H3C C H H C C O H C O 3 H C 2 H H2 H O carboxylic acids H H O H H

21. Formation of alkoxide from ROH + NaH or KH (acid/base reaction)

Na H H Br Na Br

H O H O O Na R R R

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22. Dehydration to alkene (E1) from ROH + H2SO4/∆ (possibility of rearrangements) H O H H O O O H O S OH H H O S OH H O H O H

H O H H H O O Water ends up as O + O S OH HO SO H3O in H2SO4. H H O O

O H H O S OH O O H H R R H O H H H O H O O S OH

H O

O H H H O Water ends up as O HO SO H O + O S OH H3O in H2SO4. O Only the major O S OH H O alkene is shown. O

23. Formation of from ROH + acid chlorides O Cl O O

H O O O Cl R R Cl R H H

O There are many variations of ROH and RCO2H joined together by oxygen. O H Cl R

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24. Formation of tosylates from ROH + TsCl (toluenesulfonyl chloride = tosyl chloride), SN/E chemistry is possible O Cl O O Cl S S H Cl S O O O O R O R O H N N H HCl

compare Cl separate step O

Cl 1. TsCl/pyridine Cl S O R,S 2. NaCl (racemic) + Cl O (prevents R formation S and any rearrangement) Na alkyl tosylate = RX compound

Epoxide reactions

Examples of important patterns to know from our starting materials.

O O O O O

O

25. We can make epoxides from alkenes using 1. Br2/H2O, 2. NaOH. (Later from mCPBA too.)

step 1 - make bromohydrin Br bromohydrin Br Br Br Br H Br O H H Br O O O O H H H H H H H step 2 - make epoxide by O H reacting with HO Br Br

O O O H H

epoxide synthesis from bromohydrin

Br Br mild base

S S O O S O O H O H H H epoxides bromohydrins

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26. SN2 like attack at less hindered epoxide carbon, and workup (overall addition) 2. workup H Na H O Na O O 2 O

O H OH H OH2 R R R hydroxide

Na 2. workup H Na O O O H2O O O H OH2 O R alkoxides R R (ethoxide)

2. workup H Na H2O Na O O O

H OH2 CCH R terminal R R acetylide

2. workup H Na H2O Na O O O N N H OH2 C CN C R cyanide R R

Li O H O O H2O H2 2. workup H2C C C CH R 3 R H2 Li H OH2 R n-butyl lithium

27. Nucleophilic hydride = sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4 = LAH), [deuterium is used below to show reaction site] Na H D O 2. workup H2O O O

D B D D D R H OH2 Na R D R sodium borodeuteride sodium borhydride

Li D Li H O H O O 2. workup O 2 D Al D D D R D R H OH2 R lithium aluminium deuteride lithium aluminium hydride (LAH)

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28. Epoxide reactions in acid conditions. H

H O H O H O OH OH H H O O R S H O H S R H O H H (compare to base reaction)

H

O H H O CH3 O OH OH H C H3C 3 O O R S H O H S R H O CH3 H (compare to base reaction)

29. Our only E2 reaction for epoxides. Uses very basic, sterically bulky LDA (always a base). Li Li 2. workup H N O N H H O H O H O H

LDA = lithium allylic alcohols diisopropylamine (always a base)

Aldehyde and reactions

Examples of important patterns to know.

O O O O O O

C H H H H H H H methanal (formaldehyde) O

O O O O

H

We can make aldehydes and ketones from alcohols and alkynes (for now).

30. C=O addition with organolithium reagent, and workup Li H O O O H2O H2 2. workup H2C C

C CH3 H H2 Li H OH2 n-butyl lithium aldehyde R/S 2o alcohol

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H Li O O Li O 2. workup H2O

CH3 CH3 CH3 H OH2 organolithium or Li organomagnesium Cl aldehydes or ketones reagents Cl 2o or 3o alcohols

31. C=O addition with cyanide forming cyanohydrin O Na 2. workup H H2O O Na O C CH H OH2 C CH H CCH H Li Cl H Cl aldehyde or ketone terminal propargylic acetylide alcohols

32. C=O addition with cyanide forming cyanohydrin O Na 2. workup H H2O O Na O C N H OH2 C N H CN H Li H Cl aldehyde or ketone Cl cyanohydrins

33. Nucleophilic hydride = sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4 = LAH), [deuterium is used below to show reaction site] H O Na D O O 2. workup D B D D H H2O H D H OH2 Na 1o alcohol aldehyde D sodium borodeuteride H Notice: D was nucleophilic hydrogen sodium borhydride and H (on O) was electrophilic hydrogen

H O Na D O O 2. workup D D B D H2O D H OH2 Na 2o alcohol ketone D sodium borodeuteride R/S Notice: D was nucleophilic hydrogen sodium borhydride and H (on O) was electrophilic hydrogen

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34. Hydration of C=O in acid or base conditions (also tautomerization conditions, competing reactions)

Hydration of C=O is similar to making acetals and ketals and hydrolysis of esters H H H H O O O O O H H resonance O

H H H O H H O H H H acid conditions O O

H O O O H H H H O O O

O O base conditions H H

35. Ketone to hemi-ketal to ketal and aldehyde to hemi-acetal to acetal (protects C=O as ether during other reactions conditions)

Making a ketal (acetals are similar) TsO H H H O H H O H OTs O O O OH resonance HO OH OH

O O OTs functional H group = ______ketone hemi-ketal H H common name = ______O H H H H O O H H H O

H H H O OH O O O O O O O O resonance

water controls the direction of equilibrium common name = ______Remove H2O shifts equilibrium to the ______

Adding H2O shifts equilibrium to the ______

36. Deprotection of ketal (acetal) to regenerate ketone or aldehyde, SN1 reaction, then E1 reaction to form C=O (deprotection of a ketone or aldehyde)

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l Hydrolysis of a ketal back to a ketone and ethylene glycol (acetals are similar and go back to aldehydes and ethylene glycol)

H H H H O O O O O O O O O OH H H O O

H H (H2SO4/H2O) O H H common name = ______O H H O H O H H O H H H H H H O O O O OH OH H H O O O O O H H H O H functional group = ______H H Remove H2O shifts equilibrium to the ______

Adding H2O shifts equilibrium to the ______

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Carboxylic acids and derivatives – reactions

Examples of important patterns to know.

O O O O O O O C H OH OH OH OH OH Ph methanoic acid Ph OH OH (formic acid)

O O O O O O O C H OR OR OR OR OR Ph methanoate esters Ph OR OR (formic esters)

O O O O O O O R C R R R R N R Ph R H N N N N H H H Ph N N H H H methanamides H (formamides)

O O O O O methanoyl O chloride is not stable Cl Cl Cl Cl Ph Ph Cl Cl

We can make carboxylic acids from alcohols, aldehydes and nitriles (for now).

37. Base hydrolysis of esters

base hydrolysis = saponification Na Na O Na O OR OH R O C R R C O O R O C H H H O R O ester H

H O O H R O O O H H resonance alcohol C H C R O C R O 2. workup R O Na carboxylic acid (neutralize carboxylate)

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38. acid chloride + ROH = esters (notice two different R groups joined together by an oxygen) ester synthesis from acyl substition at an acid chloride with an alcohol O

O O C R R R O R O C O R C O C R H R Cl R O H Cl H acid chloride O O Cl H H R H R

o 39. acid chloride + RNH2 = 2 amides (notice two different R groups joined together by a nitrogen) O secondary amide synthesis from acyl substition at an acid chloride with a primary amine

O C R O R O R R N C H N R C N H C R R Cl R N H H Cl H H acid chloride H Cl H2N R H3N R

40. Synthesis of acid chlorides, acyl substitution, twice

synthesis of an acid chloride from an acid + thionyl chloride (SOCl2) O Cl O Cl O Cl resonance O O S S S Cl Cl Cl O O O C H S R O Cl Cl C H C H C H Base R O R O R O

O Cl

O S O Cl Cl resonance O S Cl S O Cl O C R O C R C O R C O R O C Cl R O acylium H Base

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41. acyl substitution, then two elimination reactions o synthesis of a nitrile from an 1 amide + thionyl chloride (SOCl2)

O Cl O Cl O Cl

O O S S S Cl Cl Cl O O O C H S resonance resonance R N Cl Cl C H C H C H Base R N R N R N H H H H O Cl O O S Cl Cl O H Cl S S O Cl O C R N R C N R C N H R C N H C Cl resonance resonance R N H

H Base H

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42. (hydration) to imidate, tautomers to amide, acyl substitution to carboxylic acid

HCl / H O hydrolysis of a nitrile to an amide (in H SO / H O hydrolysis continues on to a carboxylic acid) 2 2 4 2 H

H H C N N H 3 H N C C resonance N C H3C H O H C H3C O H3C H O H H H H

O

H H H H H

H C N H3C N 3 H3C N H H C N H H C 3 C C C H resonance resonance O O O O H O H H H H H H hydroxamic acid O H O H H H H H H H H C N 3 H H C H3C N O H C N H 3 H C C H O H O H O H O O o 1 amides H H H H see resonance structures stop here in HCl/H2O directly above O (continue on in H2SO4/H2O) H H H H H H C H H3C N 3 O H C N H C N C H H 3 H C O H O O O H O H H H O H H H

resonance H H H H H3C O H C H3C N 3 N C H C O C O H H

H resonance H O most stable cation drives O O H equilibrium to completion H H carboxylic acids (in H2SO4/∆)

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Alkene and Alkyne reactions

Examples of important patterns to know.

other patterns showing regioselectivity and stereoselectivity

alkynes

We can make alkenes from RX and ROH and alkynes from RX2 (for now).

43. C=C addition reaction with H-Cl (H-Br and H-I are similar), Markovnikov addition forms most stable carbocation H H H H H Cl H Cl

CH3 Cl CH3 CH3

44. C=C aqueous acid hydration reaction, goes via top/bottom addition (hydration of an alkene) There isn't any lone pair, so you have to use the pi electrons as the nucleophile. H H H O H H H OH H3C C H3C C H C C 3 C CH C CH H O H 3 2 C CH3 H2 H2 H H2

H O H

hydration of an alkene with aqueous acid H form most stable carbocation H H ( rearrangements are possible ) O

H3C C H O H C CH3 H2

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45. C=C addition reaction (hydration of an alkene), with rearrangement There isn't any lone pair, so you have to use the pi electrons as the nucleophile. H H H H H H H3C C H H3C C H C C 3 C CH3 CH CH H O H 2 C CH3 OH

CH3 CH 3 CH3

hydration of an alkene with aqueous acid H H H H form most stable carbocation ( rearrangements are possible ) H3C C H3C C C CH3 C CH3 H3C H C H H 3 O O H H H O H O H H

46. C=C addition reaction (ether synthesis from an alkene by addition of alcohols)

There isn't any lone pair, so you have to use the pi electrons as the nucleophile. CH3 H H O H H H OCH3 H3C C H3C C H C C 3 C CH C CH H O CH 3 2 3 C CH3 H2 H2 H H2

(CH3OH / TsOH) H O CH3

hydration of an alkene with aqueous acid CH3 form most stable carbocation H H ( rearrangements are possible ) O

H3C C H O CH3 C CH3 H2

47. C=C addition reaction (ether synthesis from an alkene by addition of alcohols), with rearrangement There isn't any lone pair, so you have to use the pi electrons as the nucleophile. H H H H H H H3C C H3C H3C C H C C 3 C CH3 CH CH H O CH 2 3 C CH3 OH

CH3 CH3 CH3 (CH3OH / TsOH)

ether synthesis from an alkene with alcoholic acid H H H H form most stable carbocation ( rearrangements are possible ) H3C C H3C C C CH3 C CH3 H3C H C H H 3 O O CH3 CH H C O 3 H3C O H 3 H

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48. Hydration of alkynes (Markovnikov addition forms most stable carbocation), enol intermediate tautomerizes to keto tamtomer.

There isn't any lone pair, so you have to use the pi electrons as the nucleophile. H H H H H C C C C H 3 H H C C C H O H H C H C O H 3 3 O H H H

H O H H H H H H H H3C C H H H3C C H C C C H 3 H C C H O H H C C 3 H O resonance C H O O H H H O H O O H H H

49. Bromination of alkenes, goes via anti addition a little tricky, Br Br Br requires 3 arrows to make bridge Br

bridging cation Br Br prevents rearrangement, attack at more partial positive carbon

C=C addition reaction

Br Br Br

Br

CH3 Br CH3 CH3 Br no rearrangement alkenes / alkynes bromide attacks at because of bridging more partial positive stereoselective = anti addition Br cation carbon regioselective = none

50. Bromhydrin formation from alkenes, goes via anti addition

a little tricky, Br Br requires 3 arrows Br Br Br Br

O O H H O H O H H H OH2 bridging cation prevents rearrangement, H H attack at more partial water attacks at more bromohydrins form positive carbon partial positive carbon epoxides in mild base

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C=C addition reaction stereoselective = anti addition Br regioselective = Markovnikov Br Br Br Br Br CH 3 CH3 CH H 3 CH3 O O O alkenes / alkynes H H no rearrangement H because of bridging water attacks at more O H Br cation partial positive carbon H H

51. Hydroboration of alkenes = anti-Markovnikov addition (opposite regioselectivity to normal hydration conditions)

anti-Markovnikov addition to C=C (hydration makes alcohols), two steps: 1 BH3 2. H2O2/HO step 1 = concerted addition to C=C by borane

H H R B H H twice more B B H R H trialkylborane alkenes

step 2 = oxidation by hydrogen peroxide and rearrangement to anti-Markovnikov alcohol

R O R O H R R B B B R R O O trialkylborane OH O H R R twice B more R R B H OH O O O H O O anti-Markovnikov alcohol H H

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52. Hydroboration of alkynes = anti-Markovnikov addition (opposite regioselectivity to normal conditions)

anti-Markovnikov addition to CC (hydration makes aldehydes), two steps: 1 R2BH 2. H2O2/HO step 1 = concerted addition to CC by dialkylborane H R B H R

R B R R = sterically large group alkenes so addition only occurs once

step 2 = oxidation by hydrogen peroxide and rearrangement to anti-Markovnikov aldehyde

H R H R R R B B H B R R O H O H O trialkylborane O O O H

R R R R B H B H O H OH H O

O O O H H enolate = resonance

H H O

O

H anti-Markovnikov aldehyde

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53. SN2

54. SN2

55. SN2

56. SN2

57. SN2

58. SN2

59. SN2

60. SN2

61. SN2

62. SN2

63. SN2

64. SN2

65. SN2

66. SN2

67. SN2

68. SN2

69. SN2

70. SN2

71. SN2

72. SN2

73. SN2

74. SN2

75. SN2

76. SN2

77. SN2

78. SN2

79. SN2

80. SN2

81. SN2

82. SN2

83. SN2

84. SN2

85. SN2

86. SN2

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