electrophile nucleophile problemspsbeauchamp/pdf/315_mechs.pdf · electrophile = electron loving =...

314 Arrow Pushing practice/Beauchamp 1

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Electrophile = electron loving = any general electron pair acceptor = Lewis acid, (often an acidic proton) Nucleophile = nucleus/positive loving = any general electron pair donor = Lewis base, (often donated to an acidic proton) Problems - In the following reactions each step has been written without the formal charge or lone pairs of electrons and curved arrows. Assume each atom 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 reaction mechanism. Identify any obvious nucleophiles 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).

XH3C

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

methyl and primary secondary tertiary

allylic

benzylic

vinyl

phenyl

1o neopentyl

special

very good SN2 patterns

very poorSN2,E2,SN1,E1

XThere are many variations.

1. SN2 and SN2

I BrIBr CNI

IC

N

a b

2. SN2 and E2

Br

OHBr CHCI

I

a b

OH

H

CHC H

3. SN2 and SN2

a b

OBr

OR R

BrNa Na

CHC

Na

Br

Na BrS

S



4. SN2 and acyl substitution

Br

Br

N

O

Omake

N

O

O

further reaction

with NaOH

H2N

primary aminealkyl imide acyl substitution mech. - not shown

N

O

O

make imidate nucleophile

N

O

O

H

O H

Na

Na

NaNa

5. E2 and SN2

O Br

Br I

IO

a bH H2OO

O OH

SN2 > E2E2 > SN2 R S

6. E2 reactions

O Br

Br I

I

a bH H2OO

O

HE2 >> SN2 E2 >> SN2

H

7. E2 and SN2

Br

Br

H3CI

I

a b

E2 >> SN2O O SN2 O

K KK K

make potassium t-butoxide

OH H

K

potassium hydride(always a base)

O

K

8. Nucleophilic hydride = sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4 = LAH), [deuterium is used below to

show reaction site] – SN2 reaction

Br

DI

I

a b

BD

D

D

DNa

Na

BrAlD

D

D

DLi D

BD D

D

AlD D

D

Li



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

H3C

H2C

CH2

CH2

Li

Br poor yields, too many side reactions H3C

H2C

CH2

CH2

Li

Br poor yields, too many side reactions

10. E2 and E2 and acid/base

Br

CC

Br Br

HH

HH NR2

Na

CC

Br

HH

H

R2N

NR2H

CH

CH

CH

C

Na

Na

NR2H

BrR2N H

NR2

11. E2 and E2 and acid/base

Br

CC

Br Br

CH3

H

HH NR2

Na

CC

Br

CH3

H

H

R2N

NR2H H

CH3Na Na

NR2H

CH3

Br

R2N H

NR2

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

Br

HO

H

H

Br

H H H

O

H

H

HO

H

H

O

H

HH

H

HH

H

H H

E/Z

R/S

O

H

H

O

H

E/Z

H2O



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

OHH3C

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

methyl and primary secondary tertiary

allylic

benzylic

vinyl - enol is unstable,

keto tautomer preferred

phenyl

1o neopentyl

special

There are many variations.OH

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

OH

H Br

OH

H

Br

OH

H

Br

OH

H Br

OH

H

Br

Br

OHH

HBr

R

R,S

OH

H Br

OH

H

BrO

HH

H

Br

R

no R/S

H

H

H

Br

H

HBr

H3O+

H3O+

H3O+

SN1 and E1 are possible here, but not shown.

E1 + SN1



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

R OH S

Cl

O

Cl

H2C

R O

S

O Cl

Cl

OS

Cl

O

H

H2C

R O

SCl

O

Cl

CH2

R

Cl

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

SN2 at methyl and primary alcohols

No rearrangement because no R+.

H

Cl

ClH

H2C

R O

SCl

O

15. Thionyl chloride = acyl substitution, then SN1

OH S

Cl

O

ClO

S

O Cl

Cl

OS

Cl

O

H

O

SCl

O

HH

ClSN1 at secondary and tertiary alcohols

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

O

SCl

O

H Cl

ClH

RR

R

RR/S

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

OH

OP

H

Br

BrP

Br Br

Br

Br

Br

OP

H

Br

Br

reacts twice more

S S S

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

Br

HBr

R,S

OH

OP

H

Br

PBr Br

Br

Br

Br

OP

H

Br

Br

reacts twice more

R R



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

H3CCH2

CH

OH

H

Cr

O

OO H3CCH2

CH

OH

H

Cr

O

O

O

H3CCH2

CH

O

H

Cr

O

O

ONN H

N

H3CCH2

CH

OCr

O

O

O

N H

PCC = pyridinium chlorochromate oxidation of primary alcohol to an aldehyde (no water to hydrate the carbonyl group)

primary alcohols

aldehydes

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

PCC = pyridinium chlorochromate oxidation of primary alcohol to an aldehyde (no water to hydrate the carbonyl group)

H3CCH2

CCH3

OH

H

Cr

O

OO H3CCH2

CCH3

OH

H

Cr

O

O

O

H3CCH2

CCH3

O

H

Cr

O

O

ONN H

N

H3CCH2

CCH3

OCr

O

O

O

N H

secondary alcohols

ketones



20. Cr=O addition, acid/base and E2 to form C=O, then hydration of C=O and repeat reactions

H3CCH2

CH

OH

H

Cr

O

OO H3CCH2

CH

OH

H

Cr

O

O

O

H3CCH2

CH

O

H

Cr

O

O

O

H3CCH2

CH

OCr

O

O

O

Jones = CrO3 / H2O / acid primary alcohols oxidize to carboxylic acids

(water hydrates the carbonyl group, which oxidizes a second time )

primary alcohols

aldehydes (cont. in water)

HO

HH

OH

H

HO

H

H

H3CCH2

CH

OH

H3CCH2

CH

OH

HO

H

H3CCH2

C

OH

O

H

H

H

HO

HH3C

CH2

C

O

O

H H

HO

H

H

Cr

O

OO

H

H3CCH2

C

O

O

H H

H Cr

O

O

O

HO

H

H3CCH2

C

O

O

H H

Cr

O

O

OH

OH

H

HO

H

H3CCH2

C

O

OH

HO

H

H

Cr

O

O

O

hydration of the aldehyde

second oxidation of the carbonyl hydrate

H

O

H

resonance

carboxylic acids

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

OR

O

Br

OR R

Br

Na

Na

H

H

Na HH



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

SO

O

O

OH

H

OH

H

SO

O

O

OH

OH

H

H

SO

O

O

OH

OH O

H

H

H

H H

Water ends up as H3O+ in H2SO4.

HH

S O

O

O

HO

H

OR

HSO

O

O

OH

H

OR

H

H

OH

H

H

H H

H

SO

O

O

OH

S O

O

O

HO

H

OH

H

H

SO

O

O

OHSO

O

O

OH

HWater ends up as H3O+ in H2SO4. Only the major

alkene is shown.

23. Formation of esters from ROH + acid chlorides

OR

O

R

H

Cl

O Cl O

H

O

ClH

O

O

O

ClH

R

R

There are many variations of ROH and RCO2H joined together by oxygen.



24. Formation of tosylates from ROH + TsCl (toluenesulfonyl chloride = tosyl chloride), SN/E chemistry is possible

OR

OR

HS

Cl

H

Cl

SCl

O

O

O

O

N

OS

Cl O

O

N H

OS

O

O

Cl

Na

separate step

Cl

HCl

ClR,S

(racemic)S

1. TsCl/pyridine2. NaCl(prevents R+ formation and any rearrangement) alkyl tosylate = RX compound

compare

Epoxide reactions Examples of important patterns to know from our starting materials.

O OO

OO

O

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

Br BrBr

BrO

HH

OH H

Br

OHH

OH

Br

OHH

HBr

O H

step 1 - make bromohydrin bromohydrin

step 2 - make epoxide by reacting with HO

O

Br

O

Br

OHH

epoxide synthesis from bromohydrin

OO

H

O

Br

bromohydrinsH O

H H

O

Br

mild base

epoxides

S SS



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

OH2H

OO O

HH2ONa Na

hydroxide

O H OH

R RR

2. workup

OONa Na

alkoxides(ethoxide)

O O OH2H

H2O

R RR

O

O

H

C CH

2. workup

OO O

HNa Na

terminal acetylide

R

H2O

OH2H

RR

C N

2. workup

OO

CN

O

CN

HNa Na

cyanide R

H2O

OH2H

RR

R

n-butyl lithium

H2CCH2

H2C

CH3

O

RLi

OLi

2. workup

OH2H R

O H2OH

27. Nucleophilic hydride = sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4 = LAH), [deuterium is used below to show reaction site]

2. workupOO

Na

sodium borodeuteridesodium borhydride

R

H2O

OH2H

RR

BD

D

D

D Na

D

O

D

H

2. workupOO

lithium aluminium deuteridelithium aluminium hydride (LAH)

R

H2O

OH2HR

R

AlD

D

D

D

Li

D

O

D

HLi



28. Epoxide reactions in acid conditions.

O

R

OH

H

H

OH H

O

R

H

OHO

H

HOH H

OHO

HS

S(compare to base reaction)

O

R

OH

H

CH3

OH CH3

O

R

H

OHO

H3C

HOH H

OHO

H3CS

S(compare to base reaction)

29. Our only E2 reaction for epoxides. Uses very basic, sterically bulky LDA (always a base).

OOH

H

HN

Li

H

LDA = lithium diisopropylamine(always a base)

N HO

Li 2. workup

OH

allylic alcohols

Aldehyde and Ketone reactions Examples of important patterns to know.

CH H

O

H

O

methanal(formaldehyde)

H

O

H

O

H

O

H

O

H

O O O

O

O

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

30. C=O addition with organolithium reagent, and workup

O

Hn-butyl lithium

H2CCH2

H2C

CH3

Li

O

Li

2. workup

OH2H

O H2OH

aldehyde 2o alcoholR/S



O

CH3

LiO

CH3

Li 2. workup

OH2H

O

CH3

H

H2O

Cl

LiClaldehydes or ketones 2o or 3o alcohols

organolithium ororganomagnesium

reagents

31. C=O addition with cyanide forming cyanohydrin

H

O Na

H

O

C

2. workup

OH2H

H2O

ClLi

ClC CH

CH

Na

H

O

C CH

H

aldehyde or ketone propargylicalcohols

terminalacetylide

32. C=O addition with cyanide forming cyanohydrin

H

O Na

H

O

C

2. workup

OH2H

H2O

ClLi

ClC N

N

Na

H

O

C N

H

aldehyde or ketone cyanohydrins

33. Nucleophilic hydride = sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4 = LAH), [deuterium is used below to show reaction site]

2. workupNa


H2OOH2H

BD

D

D

D Na

O

H

O

DH

O

D

H

H

Notice: D was nucleophilic hydrogen and H (on O) was electrophilic hydrogen

aldehyde 1o alcohol

R/S

2. workupNa


H2OOH2H

BD

D

D

D Na

O O

D

O

D

H

Notice: D was nucleophilic hydrogen and H (on O) was electrophilic hydrogen

ketone 2o alcohol



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

O

OH

OH O

H

OH

OHH

HH

OH

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

resonance

HO

H H

OH

OH

acid conditions

O

OH

O

O

OH

H

H OH

OHbase conditions

OH

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

O

HOOH

OTsH OH

OTs

OH

O

OH

TsO H

OH

O

OH

HOH

O

O

H

O OH

O O

H

OHH

OHH

H

common name = ________________

common name = ________________Remove H2O shifts equilibrium to the _________________

Adding H2O shifts equilibrium to the _________________

functional group = _____________

H

OH

O

OH

OH

O

O

H

ketone

hemi-ketal

Making a ketal (acetals are similar)

resonance

resonance

water controls the direction of equilibrium

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)



O

OO

OH

OH

O

OH

OH

O

OH

H

O

OOO

HO O

H

OHHO

HH

H

common name = ________________

Remove H2O shifts equilibrium to the _________________

Adding H2O shifts equilibrium to the _________________

functional group = _____________

H

OH

O

OH

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

(H2SO4/H2O)

O

O

H

OHH

OHH

HO

HO

HH

OHH

HH

OHH

H



Carboxylic acids and derivatives – reactions Examples of important patterns to know.

CH OH

O

OH

O

methanoic acid(formic acid)

OH

O

OH

O

OH

O

Ph OH

O

OH

O

Ph

CH OR

O

OR

O

methanoate esters(formic esters)

OR

O

OR

O

OR

O

Ph OR

O

OR

O

Ph

CH N

H

O

NH

O

methanamides(formamides)

NH

O

NH

O

NH

O

Ph NH

O

NH

O

PhR R R R R

RR

Cl

O

methanoyl chloride

is not stable Cl

O

Cl

O

Cl

O

Ph Cl

O

Cl

O

Ph

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

37. Base hydrolysis of esters

NaO H

RC

O

O

HO

H

R

HO

H

CR

O

O

R

OH

RC

O

OH

O R

HO

R

RC

O

O2. workup(neutralize carboxylate)

RC

O

OH

H

ester

alcohol

carboxylic acid

Na Na

NaRC

O

O

ester base hydrolysis = saponification

resonance



38. acid chloride + ROH = esters (notice two different R groups joined together by an oxygen)

RC

O

Cl

R

O

H

CR

O

O

R

Cl RC

O

OR

acid chloride

ester synthesis from acyl substition at an acid chloride with an alcohol

H

HCl

RC

O

OR

RO

H RO

H

H

39. acid chloride + RNH2 = 2o amides (notice two different R groups joined together by a nitrogen)

RC

O

Cl

R

N

H

CR

O

N

R

Cl

RC

O

NR

acid chloride

secondary amide synthesis from acyl substition at an acid chloride with a primary amine

H

HCl

RC

O

NR

RH2N

H H

H

H

RH3N

40. Synthesis of acid chlorides, acyl substitution, twice

CR

O

OH S

Cl

O

Cl CR

O

OH

S

O Cl

Clresonance

CR

O

OH

S

O Cl

Cl

CR

O

OH

S

O Cl

Cl

Base

CR

O

O

S

O Cl

Cl

BaseH

CR

O

O

SCl

O

Cl

OS

ClO

CR OCR O

resonance

CR

Cl

O

synthesis of an acid chloride from an acid + thionyl chloride (SOCl2)

acylium ion



41. acyl substitution, then two elimination reactions

CR

O

NH S

Cl

O

Cl CR

O

NH

S

O Cl

Cl

resonanceC

R

O

NH

S

O Cl

Cl

CR

O

NH

S

O Cl

Cl

Base

CR

O

N

S

O Cl

Cl

BaseH

CR

O

N

SCl

O

Cl

OS

Cl

O

CR NCR N

resonance

HH H H

H

H

H HCR N

ClH

synthesis of a nitrile from an 1o amide + thionyl chloride (SOCl2)

resonance

resonance



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

H3CC

N

H3CC

N CNH3C

O

HH

CN

H

H3C

OH

OH

H

H

CN

H

HH3C

OH

CN

H

HH3C

OH

CN

H

HH3C

O

HO

H

HCl / H2O hydrolysis of a nitrile to an amide (in H2SO4 / H2O hydrolysis continues on to a carboxylic acid)

H

O

H

H HH3C

CN

H

OH H

H

H

O

H

CN

H

HH3C

OH

O

H

H H

stop here in HCl/H2O(continue on in H2SO4/H2O)

O

H

H HC

N

H

HH3C

OH

see resonance structuresdirectly above

H

O

HC

N

H

HH3C

OH

O H

H H

O

H

CN

H

HH3C

OH

O

HO

H

H H

CN

H

HH3C

OH

O

H

HC N

H

HH3C

OH

H

H3CC

OH

O

H

H3CC

OH

O

H

N

H

H

H H3CC

OH

ON

H

H

H

H

most stable cation drivesequilibrium to completion

resonance

resonanceresonance

resonance

resonance

hydroxamic acid

1o amides

OH

carboxylic acids (in H2SO4/∆)



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

CH3

ClH

H

H

CH3Cl

H

H

Cl

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.

HC

CH2

CH2

H3C CCH2

CH3

H3C

H

CCH2

CH3

H3C

HO

H

H

CCH2

CH3

H3C

HO

H

O

H

H H

O H

OH H

O

H

H HH

hydration of an alkene with aqueous acidform most stable carbocation

( rearrangements are possible )



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.

HC

CH CH2

H3C CC CH3

H3C

H

CC CH3

H3C

O

H

H H

O HO

H

H H

H



CH3 CH3

H

HH

CH3

CC CH3

H3C

HH

O

HH

H3C

OH

H

CC CH3

H3C

HH

OH

H3C

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


HC

CH2

CH2

H3C CCH2

CH3

H3C

H

CCH2

CH3

H3C

HO

H

CH3

CCH2

CH3

H3C

HO

CH3

O

H

H CH3

O CH3

OH CH3

O

H

H CH3 H



(CH3OH / TsOH)

47. C=C addition reaction (ether synthesis from an alkene by addition of alcohols), with rearrangement


HC

CH CH2

H3C CC CH3

H3C

H

CC CH3

H3C

O

H

H3C H

O HO

H

H CH3

H3C

ether synthesis from an alkene with alcoholic acidform most stable carbocation


CH3 CH3

H

HH

CH3

CC CH3

H3C

HH

O

HCH3

H3C

OH3C

H

CC CH3

H3C

HH

OCH3

H3C

(CH3OH / TsOH)



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

H3CC

CH

OH

H

H H3CC

C

H

HO

H

HC

C

H

HH3C

O

H

O

H

H

H

CC

H

HH3C

OH

OH

H

HCC

H

HH3C

OH

H

CC

H

HH3C

OH

H

CC

H

HH3C

O

H

OH

H

HH

OH


resonance

49. Bromination of alkenes, goes via anti addition

bridging cation prevents rearrangement,

attack at more partial positive carbon

BrBrBr

Br

Bra little tricky,requires 3 arrowsto make bridge

Br

Br Br

alkenes / alkynes

C=C addition reaction

Br

stereoselective = anti additionregioselective = none

no rearrangement because of bridging

Br cation

Br

Br

BrCH3 CH3

CH3

bromide attacks atmore partial positivecarbon

50. Bromhydrin formation from alkenes, goes via anti addition

BrBr Br

O

Bra little tricky,requires 3 arrows

HH

HO

H

Br

OH

OH2H

Br

bridging cation prevents rearrangement,

attack at more partial positive carbon

bromohydrins form epoxides in mild base

water attacks at more partial positive carbon

HO

H



Br Br

alkenes / alkynes

C=C addition reactionBr

stereoselective = anti additionregioselective = Markovnikov

no rearrangement because of bridging

Br cation

Br

Br

OCH3 CH3

CH3

water attacks at more partial positive carbon

HO

H

H

H

Br

O

CH3

HH

OH

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

OH

BH

H

H

alkenes

H

B

H

H

twicemore B

R

R

trialkylborane

B

R

R

trialkylborane

OO

HB

R

RO

OH

B

O

R R

B

O

R R

OH

B

O

R R

OH

twicemore

OH H

OH

anti-Markovnikov alcohol

step 1 = concerted addition to C=C by borane

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



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

OH

BH

R

R

alkenes

H

B

R

R

B

R

R

trialkylborane OO

H

B

R

RO

O

B

O

R R

B

O

R R

OH

B

O

R R

OH

OH H

O

anti-Markovnikov aldehyde

step 1 = concerted addition to CC by dialkylborane

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

R = sterically large groupso addition only occurs once

H H

H

H

H

enolate = resonance

O

H

OH H

H

H



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

electrophile nucleophile problemspsbeauchamp/pdf/315_mechs.pdf · electrophile = electron loving =...

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