Organic Reactions Summary For Use as a Study Guide …

Typical First Year Organic Reactions

Beauchamp

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Organic Reactions Summary For Use as a Study Guide Beauchamp

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Typical First Year Organic Reactions

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Important acid/base reactions used in the examples below. Write out every one of these easy mechanisms.

H2

C

H

R

S

thiols

sodium hydroxide Na OH

Keq =

Ka(RSH) Ka(H2O)

Keq =

10-8 10-16

= 10+8

H2 Na C

R

S

thiolates

thiolates are good nucleophiles, SN2 > E2 at Me, 1o and 2o RX,

and strong bases, E2 > SN2 at 3oRX.

H N

diisopropylamine

n-butyl lithium Li n-Bu

Keq =

Ka(HNR2) Ka(H-C4H9)

Keq =

10-37 10-50

= 10+13

Li N

LDA is a very strong base that is also very sterically hindered, it always acts as a base in our course.

LDA = lithium diisopropylamide

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Typical First Year Organic Reactions

Beauchamp

O

R

C

H

O

C

R2

esters

O

H

C

H

O

C

R2

carboxylic acids

N

C

H

C R2 nitriles

LDA = lithium diisopropylamide

Na NR2

O

Keq =

Ka(ROCOCH3) Ka(HNR2)

Keq =

10-25 = 10+12 10-37

R

C

O

CR2 Na

ester enolates

LDA = lithium diisopropylamide

2 eqs. Na NR2

Keq = Keq =

Ka( O2CCH3) Ka(HNR2)

10-25 = 10+12 10-37

O

Na

C

Na

O

CHR2

acid dianion

LDA = lithium diisopropylamide

2 eqs. Na NR2

Keq =

Ka( O2CCH3) Ka(HNR2)

Keq =

10-30 10-37

= 10+7

N Na C CR2

nitrile enolate

3

enolates are good nucleophiles, SN2 > E2 at Me, 1o and 2o RX, and strong bases, E2 > SN2 at 3oRX.

enolates are good nucleophiles, SN2 > E2 at Me, 1o and 2o RX, and strong bases, E2 > SN2 at 3oRX.

enolates are good nucleophiles, SN2 > E2 at Me, 1o and 2o RX, and strong bases, E2 > SN2 at 3oRX.

H

R CX

R

SPh2

sulfur salt = ylid

S

S

C

H

H

dithiane

n-butyl lithium Li n-Bu

Keq = Keq =

Ka(HCR2SPh2) Ka(H-C4H9)

10-33 = 10+17 10-50

n-butyl lithium Li n-Bu

Keq = Keq =

Ka(dithiane) Ka(H-C4H9)

10-33 = 10+17 10-50

R

C

R

SPh2

betaine

S

S

C

H

Li

dithiane carbanion

n-butyl lithium removes proton from sulfur salt and makes a good nucleophile at ketones and aldehydes, forming epoxides.

n-butyl lithium removes proton from dithiane and makes a good nucleophile at all of our electrophiles. It can react once or twice in SN2 reactions. Sulfur acetal forms carbonyl group after hydrolysis using Hg+2. Makes aldehydes and ketones.

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Typical First Year Organic Reactions

Beauchamp

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Arrow-Pushing schemes for the above reactions

O

C

H

R

O

carboxylic acids

Na OH sodium hydoxide

O

Na C

R

O

carboxylates

O

H

H

H2

C

H

R

S

thiols

H

N

diisopropylamine

Na OH

sodium hydoxide

H2 Na C

O

R

SH

H

thiolates

Li

H2

H2C

C C H2

CH3

n-butyl lithium

Li N

LDA lithium diisopropylamide

O

R

C

H

O

C

R2

esters

Na NR2 LDA

O Na

R

C

O

CR2

ester enolates

N

C

H

C R2

nitriles

Na NR2 LDA

N Na C CR2

nitrile enolate

H

R CX

R

PPh3

Wittig salt = ylid

Li

H2

H2C

C C H2

CH3

n-butyl lithium

R

C

R

PPh3

betaine

H2 C

R

O

alcohols

Na

H

H

sodium hydride

H2 Na C

R

O

alkoxides

H H

H C C R terminal alkynes

O

C

H

R

C

H2

ketones / aldehydes

O

H

C

H

O

C

R2

carboxylic acids

Na NR2

sodium amide

C

C

Na

R

terminal acetylides

O Na

NR2 LDA

2 eqs. Na NR2

LDA

C

R

CH2 Na

ketone enolates

O

Na

C

Na

O

CHR2

acid dianion

S

S

C

H

H

dithiane

H

R CX

R

SPh2

sulfur salt = ylid

Li

H2

H2C

C C H2

CH3

n-butyl lithium

S

S

CH

H

Li

dithiane carbanion

Li

H2

H2C

C C H2

CH3

n-butyl lithium

R

C

R

SPh2

betaine

Organometallics used in our course (Mg, Li and Cu)

Br

R

Li

Br R

R

bromohydrocarbons

Li

Br R

Mg

Br R

R

bromohydrocarbons

Mg

Br Li

Li discard

Br

Mg

Cu Br R Li

Cu R

R Li

R Cu

R

Li

dialkyl cuprates

R Li organolithium

reagents

+2 R Mg Br

R (MgBr) Grignard reagents (organomagnesium reagents)

reacts with RBr (SN2) reacts with acid chlorides reacts with ,-unsaturated C=O

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Typical First Year Organic Reactions

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SN2 versus E2 choices at 2oRX.

At secondary RX (X= OTs, I, Br, Cl) SN2 and E2 products are in close competition with each other. Anions whose conjugate acids have higher pKa's (stronger bases have weaker acids) generally produce more E2 relative to SN2. The examples that we will emphasize at 2oRX centers are carboxlyates (SN2 > E2) vs hydroxide and alkoxides (E2 > SN2), and cyanide (SN2 > E2) vs terminal acetylides (E2 > SN2), azide (SN2 > E2) vs dialkylamides (E2 > SN2) and metal hydrides (SN2 > E2) vs simple hydride (E2 > SN2). Higher basicity and steric hindrance in either RX or the electron pair donor also favors E2 > SN2.

The following examples show similar looking base/nucleophiles (used in our course) that react differently with 2oRX structures. (They all react by SN2 at methyl and 1oRX and they all react by E2 at 3oRX.) It is the reactions at 2o RX centers that are ambiguous.

Less basic, so SN2 > E2.

NC cyanide pKa of conjugate acid = 9

2o RX structures are the most ambiguous.

More basic, so E2 > SN2.

Less basic, so SN2 > E2. O

RCC

terminal acetylides pKa of conjugate acid = 25

C

R

O

carboxylates pKa of conjugate acid = 5

More basic, so E2 > SN2.

HO RO hydroxide and alkoxides pKa of conjugate acid = 16-19

Less basic, so SN2 > E2.

N

N

N

Na

azide pKa of conjugate acid = 5

More basic, so E2 > SN2.

Na

N

R

R

dialkyl amides pKa of conjugate acid = 37

Less basic, so SN2 > E2.

H Na

H Li

H B H H Al H

H

H

sodium borohydride lithium aluminum hydride

pKa of conjugate acid = ?

More basic, so E2 > SN2.

H Na

HK hydrides

pKa of conjugate acid = 37

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Typical First Year Organic Reactions

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1. Making RBr from alkane and alkene hydrocarbons and alcohols

a. RBr from alkanes - mechanism using Br2 / h for free radical substitution of alkane sp3 C-H bonds to form sp3

C-Br bonds at the weakest C-H bond.

overall reaction

H2 C

H3C

CH3

Br Br

Br

h

CH

H Br

H3C

CH3

1. initiation

Br Br

h

Br

Br

weakest bond ruptures first

H = 46 kcal/mole

2a propagation HH

C

Br

H3C

CH3

H

C

H3C

CH3

H Br

BE = +95 kcal/mole BE = -88 kcal/mole

H = +7 kcal/mole (overall)

H = -15

2b propagation H

C

H3C

CH3

Br Br

H Br

C

Br

H3C

CH3

BE = +46 kcal/mole BE = -68 kcal/mole

H = -22 kcal/mole (overall)

both steps

3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations

H

H Br

C

Br

H3C

CH3

C

H3C

CH3

H = -68 kcal/mole

H

H

C

C

H3C

CH3 H3C

CH3

CH3

H3C

CH

CH

CH3

H = -80 kcal/mole

CH3

very minor product

Example reactions

CH4

Br2 / h

H3C Br

achiral

Br2 / h Br2 / h

Br Br

achiral

enantiomers (R and S)

Br2 / h

Br

achiral

2 Br2 / h

Br Br

can do E2 twice, to make alkynes

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Typical First Year Organic Reactions

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Br2 / h

7

Br allylic substitution

b. RBr from alkenes (anti-Markovnikov addition of HBr using free radical chemistry): mechanism using HBr / ROOR / h for free radical addition to alkane pi bonds (anti-Markovnikov addition = Br adds to less substituted

position to form most stable free radical intermediate, and then H adds to more substituted position)

overall reaction

H C

H3C

CH2

HBr

R2O2 (cat.) h

H2

C

Br

H3C

C H2

1. initiation (two steps)

R

O

O

R

h

(cat.)

R O

H Br reagent

R O

R

H

O

O R

Br

H = 40 kcal/mole

BE = +88 kcal/mole BE = -111 kcal/mole H = -23 kcal/mole

2a propagation

H C

H3C

CH2

Br

H

C

Br

H3C

C H2

BE = +63 kcal/mole BE = -68 kcal/mole

H = -5 kcal/mole

2b propagation H

C

Br

H3C

C H2

H Br

H2

C

Br

H3C

C H2

BE = +88 kcal/mole H = -15 Br BE = -98 kcal/mole

both steps H = -10 kcal/mole (2a + 2b)

3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations

H

Br

C

Br

H3C

C H2

H

H

Br

C

C

Br

C H2

CH3 H3C

C H2

H Br

C

Br

H3C

C H2

CH3

H = -68 kcal/mole

H2

C

CH

Br

Br

CH

C

H2

H = -80 kcal/mole

CH3

very minor products

Example reactions

H-Br / h ROOR (cat.)

Br

achiral

Br2 / h ROOR (cat.)

Br achiral

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Typical First Year Organic Reactions

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Br2 / h ROOR (cat.)

Br2 / h ROOR (cat.)

Br R/S

enantiomers

Br cis and trans

c. RBr from alkenes (anti-Markovnikov addition of HBr using borane chemistry): mechanism using 1. BH3 2. Br2 / CH3O-- for anti-Markovnikov addition of H-Br to alkane pi bonds (concerted, syn addition of H-BH2 to alkene pi

bond, followed by complex with Br2 and migration of R group to Br)

overall reaction

H C

H3C

CH2

1. (BH3)2 2. Br2, CH3O

H2

C

Br

H3C

C H2

step 1

CH3

H

BR

C

H2C

CH

R

H2C

CH2

C H2

syn addition, with H at more substituted position and B at less substituted position.

R H3C H

C

BR

H2C

CH

H2C

CH2

C H2

step 2

R H3C H

BR C

H2C

CH

Br Br

H2C

CH2

C H2

R H3C H

BR

C

H2C

C

Br Br

H

H2C

CH2

C H2

R

H3C H

BR

C

Br

H2C

C

H

H2C

CH2 Br

C

H2

H3C O

H3C H

C

Br

H2C

C

H

H2C

CH2

C H2

R BR O CH3

R

H3C H

C

H2C

C

BR O CH3

Br

H

H2C

CH2

C H2

Example reactions

1. (BH3)2 2. Br2, CH3O

Br

achiral

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