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Chem 201/Beauchamp Reactions and Mechanisms Worksheet 1

Starting organic compounds Br

Br Br Br CH4 1o given 1o given o 1 given rearrangement example

R-X Compounds (synthesis and reactions = R-Br in our course)

1. Make other R-Br compounds (nine examples for us, 3 primary examples given above and six more made below)

a. R-Br from using free radical substitution (three part sequence: 1. Initiation 2. Propagation (2 steps) 3. termination

1. initiation - high energy photon ruptures the weakest bond (= = homolytic cleavage) atoms bond energy Br-Br 46 3 Br h sp H3C-H 105 Br Br Br sp3 1o C-H 98 sp3 2o C-H 95 sp3 3o C-H 92 2a. propagation (step 1) - bromine atom abstracts H from weakest C-H bond and makes an H-Br bond sp3 C-Br 68 H-Br 88 H2 CH2 C Br H Br H3C H3C H 2b. propagation (step 2) - free radical abstracts Br atom from bromine molecule and makes a C-Br bond

CH Br H2 2 C H3C Br H3C Br Br 3. termination - two reactive free radicals find one another and combine

H2 C CH CH2 H C 3 2 H C C H3C 3 CH3 H2

H2 C CH2 Br H C Br H3C 3 Other R-Br to make from our starting alkanes. Six possible RBr from our starting alkanes plus three primary RBr are given = 9 total.

CH3 Br CH3 H CH3 H C Br 2 3 C C H C H C CH 3 H3C Br CH 3 H3C Br H C Br C Br 3 H2 Br h Br2 h Br 2 Br2 h Br 2 h 2 h Br2 h CH4

shown above

There is no easy way to make a primary R-Br compound in our course yet (from our given starting structures). Three examples are provided above until we can do this. (Not in 201)

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In our course we will propose dibromoalkanes from ethane, propane and butane by using 2 equivalents of Br2/h. We will use these to make (ethyne, propyne and but-1-yne)

Br Br Br Br Br

CH C H3C C 1. 3 eqs. NaNR2 H C Br H C CH 1. 3 eqs. NaNR C CH3 3 2. workup 3 3 2 H 2. workup 2 1. 3 eqs. NaNR2 2 eqs. 2 eqs. 2. workup h h 2 eqs. Br2 Br h 2 Br2

b. Make R-Br from (reaction with HBr, SN2 at methyl and primary ROH, SN1 at secondary and tertiary ROH)

SN2 reactions with with methyl and primary alcohols and H-Br (steps = 1. protonaton 2. SN2 reaction with bromide, with water leaving group)

H2 Br H H2 C C H H Br H H H3C O H C O Br CH 3 2 O H C H 3

SN1 reactions with secondary and tertiary alcohols and H-Br (steps = 1. protonaton 2. water leaving group forms 3. bromide adds)

CH3 CH3 H H H C H H Br H Br C H H3C O Br H3C O C C H3C CH3 H H3C CH3

SN1 reactions with rearrangement to more stable carbocation H H H H O H H O H2 H Br H H C C H2 O C C H2 H3C C CH3 C C H2 H2 H3C C CH3 C C H3C C CH3 H3C H H3C C CH3 H3C H H3C H (2S,3R) achiral (2S,3R) rearrangement CH3 (2S) to more stable carbocation Br add (both sides) Later we will introduce a sequence to avoid H2 H2 C C rearrangements in situations like this. carbocation lose beta H+ + H3C C CH3 1. Ts-Cl / reactions (R ) (either side) 2. NaBr rearrange achiral H3C Br

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Examples of other R-Br to make from alcohols. There will be more possibilities as we progreas through organic chemistry. H 2 H2 H2 H2 H C C H H 3 C C H H3C C H 2 C O C H H3C C O CH O H2 H3C Br H2 H3C O CH3 SN2 S 2 SN2 SN2 N SN2 H H H 2 2 H2 H2 H2 C H H3C C H C C H H C C H H C O 3 3 H3C O C O H C C O CH O H 3 2 H2 shown above CH3

CH CH3 3 CH3 Br H3C CH H3C CH C H3C Br C Br H C Br H2 3 S 1 SN1 N SN1 SN1 CH CH3 3 CH3 O H3C H CH H H3C CH H C H C O H3C O H3C O H2 shown above c. Make R-Br from and H-Br (addition reactions – Markovnikov addition = form most stable carbocation) Addition reaction of H-Br to - 1. form the most stable carbocation 2. add bromide (possible rearrangements) H Br H3C CH2 C C H Br Br CH H3C CH3 H C CH Make the most stable carbocation 3 3 H (rearrangements are possible) Alkene addition reactions with rearrangement to more stable carbocation.

H H2 H H Br H2 H2 H2 C C C C H2 H2 C C C C H3C C CH2 H3C C CH3 H3C C CH3 H3C C CH3 H3C H CH Br H3C H 3 H3C Br (3R) rearrangement (3S) achiral achiral to more stable carbocation Other R-Br to make from alkenes Br CH CH3 3 CH3 H2 H C C 3 CH H3C CH C H3C Br C Br H3C Br H3C Br H2 HBr HBr HBr HBr HBr H H CH3 CH 2 C H3C C H2C C H3C CH2 C CH2 H2 shown above H3C CH2

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 4 d. Make RBr2 from alkanes + Br2/hυ (2x free radical substitution) or use Br2 + alkenes (addition reactions with Br2, forms bromonium bridge followed by anti attack of bromide at more + carbon).

Addition reaction of Br-Br to alkene - 1. forms a bridging bromonium cation 2. adds bromide anti to bridge

H Br H H CH2 C C Br Br Br C Br H CH2 H C anti attack at H H Br 2 bromonium bridge is more + carbon the most stable cation can be used to make alkynes Addition reaction of Br-Br to alkene - 1. forms a bridging bromonium cation 2. adds bromide anti to bridge

H Br H H3C CH2 C C Br Br Br C Br H3C CH2 H C C anti attack at 3 H H more + carbon Br 2 bromonium bridge is the most stable cation can be used to make alkynes

Addition reaction of Br-Br to alkene - 1. forms a bridging bromonium cation 2. adds bromide anti to bridge

H H H2 Br C CH2 H C C Br Br 3 H C C Br H3C C Br 3 C CH2 H C C 2 anti attack at H2 H2 H more + carbon Br bromonium bridge is the most stable cation can be used to make alkynes

Double E2 reaction to make alkynes: Use RBr2 + 3 equivalents NaNR2

Double elimination reaction (E2) forms alkynes using NaNR2 as the base. The acidity of sp C-H uses a third equivalent of the base and can form a terminal acetylide which is either protonated in a workup step or reacted further with an (2. methyl or primary RBr or 2. carbonyl compound or 2. )

R H Na NH Na Na NH2 2 C Br R C H C further H2N H C C H C C reactions Br C R possible H H Br Na R

H R = H, CH3 or CH3CH2 from our starting materials Na H H H H C O C Na H C C C H H C O C C H3C C R R H C 2. workup H C C H 3 H2

H2 C H2 C C Br C C CH3 H3C Br R C Na Na R 2. SN2

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H H H H O H O H C O O C O C C H C CH3 H H C CH R H C 3 Na 3 C C 2. carbonyl R 3. workup addition Na R Na

C H H H2 H C 2 O O C O C R C CH C CH O H2O Na C H H C 2. epoxide Na R CH R CH3 opening 3 3. workup Na

Zipper reaction – moves internal alkynes to a terminal position, forming terminal acetylide

The zipper reaction changes a linear internal into a terminal acetylide that can be made into a terminal alkyne (2. simple workup) or reacted with one of our three common (2. methyl or primary RBr) or (2. or 3. workup) or (2. epoxide 3. workup). The steps of the zipper reaction are similar to the steps of in base: 1. proton off, 2. resonance, 3. proton on. This continues until the terminal alkyne is formed. Loss of the sp C-H forms the most stable anion and the reaction stops there until one of the workup possiblities completes the reaction. H

H2 C CH C 2 CH2 C H N R C C C H3C H C C C C H3C H C R 3 H3C H N R H N R R

N R R

protonate H H R C o H C Me or 1 C C C H3C C RBr C C H3C H C C C aldehyde 3 H C C 3 C or ketone H2 H N R H2 H H epoxide R

2. Make other functional groups from R-Br

a. Make alcohols using SN2 reaction with NaOH at methyl and primary RBr. Use SN1 with H2O at secondary and tertiary RBr (rearrangement is possible). H From our starting compounds: O O H2 C Me and primary RBr = 5 possibilities H CH2 secondar and tertiary RBr = 4 possibilities H3C Br Br S 2 H3C N H CH3 H H H O H O H O H O C C O H H H H H3C Br H C CH C C SN1 3 3 H H rearrangements H3C CH3 H3C CH3 are possible

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Other alcohols from R-Br (nine possible in our course) H H2 C H H3C O H H H H3C O O O O

SN2 NaOH SN2 NaOH S 2 N NaOH SN2 NaOH SN2 NaOH H2 C H3C Br H3C Br Br Br Br shown above given given given

CH 3 O H CH H H H H3C O O O S 1 N H2O S 1 H O N H2O S 1 H O SN1 2 CH N 2 3 Br CH H3C Br Br Br shown above

b. Make using SN2 reaction with NaOR at methyl and primary RBr; SN1 with ROH at secondary and tertiary RBr

Make from and NaH (acid/base reaction) to use in SN2 reaction

Na O O H H R Na HH 10-16 R K = = 10+21 pK = 37 pKa = 16 eq 10-37 a

SN2 reactions with and methyl and primary RX compounds Except E2 > SN2 with: R O Na H C 3 O O H2 C C R CH2 K Na H3C Br Br H3C H3C SN2 CH3

SN1 reactions with alcohols and secondary and tertiary RX compounds H CH 3 H H O R O H O R O H O H R H R C C H R C C H3C Br H C CH H C CH H C CH SN1 3 3 3 3 3 3

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Other ethers from R-Br (9 ROH x 9 RBr = 81 possibilities in our course, some duplicates) R H2 C R H3C O R R R H3C O O O O

SN2 NaOR SN2 NaOR S 2 N NaOR SN2 NaOR SN2 NaOR H2 C H3C Br H3C Br Br Br Br shown above given given given

CH 3 O R CH R R R H3C O O O

SN1 ROH S 1 ROH N S 1 ROH SN1 ROH CH N 3 Br CH H3C Br Br Br shown above

c. Make using SN2 reaction with CH3CO2Na (example carboxylate, more possible later) at methyl, primary and secondary RBr; and SN1 with CH3CO2H (example acid, other acids are possible later) at tertiary RBr

o o Make carboxylate from and NaOH (acid/base reaction) to use in SN2 reactions with methyl, 1 , 2 RX compounds O O Na Na O H O H -5 O H H O 10 = 10+11 Keq = -16 10 pKa = 16 pKa = 5 SN2 reactions with carboxylates and methyl, primary and secondary RX compounds O O

H2 C O Br H3C Br O S 2 N SN1 reactions with carboxylic acid and tertiary RX compounds H CH3 CH3 O CH O H C O CH 3 3 3 H C C O B 3 C C H C Br H C 3 H C CH H C O SN1 3 3 O 3 H3C CH3 rearrangements B: = CH CO H are possible use the C=O 3 2 (use the C=O) resonance (not shown)

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Other esters from R-Br (only nine examples using ethanoic acid, later more when other carboxylic acids are possible)

O O O O H2 H3C C C C O CH3 H3C O CH3 O O S 2 N NaO2CCH3 SN2 NaO2CCH3 SN2 NaO CCH 2 3 SN2 NaO2CCH3 H2 C H3C Br H3C Br Br Br shown above

O O O O O

O O O O O

SN2 NaO CCH SN1 CH3CO2H SN2 NaO2CCH3 SN2 NaO2CCH3 2 3 S 2 NaO CCH N 2 3 Br CH3 H3C C Br Br Br H3C Br shown above

d. Make using SN2 reaction with NaCN at methyl, primary and secondary RBr

SN2 reactions with NaCN and methyl, primary and secondary RX compounds Na NC H2 N C C Br Na H C Br 3 SN2

Other nitriles from R-Br (eight possible from our starting RBr, tertiary RBr does not work) N N N N N C C C C C CH 3 S 2 S 2 N NaCN SN2 N NaCN S 2 NaCN N NaCN SN2 NaCN H2 C Br CH Br 3 Br CH3 Br Br shown above

N N N C C C

Not possible S 2 SN2 NaCN N NaCN SN2 NaCN at 3o RX. Br

Br Br

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 9 e. Make larger alkynes using SN2 reaction with NaCCR (R = H, CH3, CH2CH3) at methyl and primary RBr.

Make terminal acetylides from NaNR2 and HCCH (acid/base reaction) Na H Na H N H C C R N -25 C C R 10 +12 H H K = = 10 H eq -37 pKa = 25 10 pK = 37 a SN2 reactions with NaCCH and methyl and primary RX compounds (too basic to use at secondary RX = E2 > SN2) R C Na R CC H2 C C CH 3 Br Na H3C Br C SN2 H 2 Other alkynes from R-Br (five possible from our starting RBr, only works at methyl and primary RBr) R R R C R R C C C CH C C 3 C C C C C H CH3 2 S 2 SN2 NaCCR N NaCCR SN2 NaCCR SN2 NaCCR SN2 NaCCR H2 C H3C Br H C Br 3 Br Br Br shown above

f. Make , then primary using: Reaction 1: SN2 reaction with NaN3 at methyl, primary and secondary RBr Reaction 2: SN2 with LiAlH4 at the 3. Workup  RNH2

Reaction 1: SN2 reactions with NaN3 and methyl, primary and secondary RX compounds makes azides

a. N N H2 Na H2 N C N -2 C N N CH3 Br H3C Br Na SN2 Me, 1o, 2o RBr azidoalkane Reaction 2: a. reduce azide with lithium with SN2 reaction at nitrogen b. workup a. b. workup N H NN H2 H N H H2 C 2 H C N CH H Al H C 3 H O H N CH N CH3 3 SN2 H Li Li H H

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Other amines from R-Br (eight possible from our starting RBr, does not work at tertiary RBr) H H2 H CH3 C H H H N N H3C N N N H H H H H 1. NaN 1. NaN3 3 1. NaN3 1. NaN 1. NaN3 2. LiAlH 3 2. LiAlH4 4 2. LiAlH4 2. LiAlH 2. LiAlH4 3. workup 4 3. workup 3. workup 3. workup 3. workup H C Br H2 3 C Br H3C Br Br Br shown above

H H N N H Two synthetic steps: N H H 1. NaN3 1. NaN 1. NaN 1. LiAlH4 3 3 H 2. LiAlH4 2. LiAlH 2. LiAlH NaN3 2. workup 4 4 R-Br R-N R-NH 3. workup 3. workup 3. workup 3 2 Br Not possible at 3o RBr Br Br

g. Make using SN2 reaction with NaSH at methyl, primary and secondary RBr

SN2 reactions to make thiols with NaSH and methyl, primary and secondary RX compounds

Na S H2 H C S Br H C Br Na 3 SN2 H

Other thiols from R-Br (eight possible from our starting RBr, does not work at tertiary RBr)

S CH S 3 S S S H C H CH3 H H H H2 S 2 N NaSH SN2 S 2 SN2 NaSH SN2 NaSH N NaSH NaSH H2 H3C Br C Br Br Br Br CH3 shown above

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S S S H H H

NaSH NaSH Not possible SN2 S 2 o N SN2 NaSH at 3 RBr Br Br Br

h. Make sulfides using SN2 reaction with NaSR at methyl, primary and secondary RBr

Make thiolates with NaOH and thiols (acid / base reaction)

O S S O -8 H H R 10 = 10+8 R H H Keq = -16 Na pKa = 8 10 Na pKa = 16

SN2 reactions to make sulfides with NaSR and methyl, primary and secondary RX compounds

Na S H2 C R S Br Na H3C Br SN2 R

Other sulfides from R-Br (8 RSH x 8 RBr = 64 RSR in our course, does not work at tertiary RBr) S CH 3 S S S S R C R R H2 R R CH3 S 2 N NaSH SN2 SN2 SN2 NaSH SN2 NaSH NaSH NaSH H2 C Br Br Br Br CH3 Br CH3 shown above

S S S R R R

NaSH NaSH Not possible S 2 S 2 NaSH SN2 N N at 3o RBr Br Br Br

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 12 i. Make Grignard carbanions using 1. Mg with R-Br 2. react Grignard reagents with a. carbonyl ( and ), b. and c. electrophiles 3. Workup

Make Grignard carbanions and bromide anion with Mg metal and RX compounds (oxidation / reduction reaction), Mg+2 inserts itself between carbanion and bromide

H2 (MgBr) C we will H C Mg +2 2 H3C Br CH2 Mg Br write it this way CH3 H3C Simplified mechanism for our course carbanion

Other Grignard reagents (nine possible from our starting R-Br, tertiary does work on this reaction)

(BrMg) (BrMg) (BrMg) (BrMg) (BrMg)

H C H C CH3 2 2 H2C H2C CH3

Mg Mg Mg Mg

H2 Mg C H C Br Br CH 3 3 Br Br Br shown above

(BrMg) (BrMg) (BrMg) (MgBr) C C H3C CH3 H3C CH3 H CH3 Currently 9 possibilities Mg Mg Mg Mg from our starting structures, but there will be more Br possibilities later.

Br Br Br

1. React Grignard reagents with aldehydes and ketones 2. workup : makes alcohols (Various carbonyl compounds will become available when E2 reactions are discussed via oxidation reactions with CrO3. For now we will just list the carbonyl compounds that will be made later.)

(BrMg) O H H (BrMg) O O O H2C H H H CH3

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OH OH OH OH OH OH OH H O

new 1. (BrMg) H2C bond 9 x 8 possibilities (some duplicates) CH3 2. workup Carbonyl compounds (aldehydes and ketones) that will be made later from our starting RBr compounds (available to use until then). O O O O O O O O

H H H H H H shown

1. Grignard reagents with epoxides 2. workup : makes alcohols H H (BrMg) O (BrMg) O O O H H H2C CH3

Epoxide compounds that will be made later from carbonyl compounds (available to use anytime until then). new OH OH OH OH bond OH

1. (BrMg) H2C CH3 2. workup O O O O O

shown

H OH OH O

O 9 x 8 possibilities (some duplicates)

O O

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1. Grignard reagents with carbon dioxide 2. workup : makes carboxylic acids

(BrMg) O H H (BrMg) O O C O H2C H H CH 3 O O O

Carboxylic acids that can be made from our starting RBr compounds using the Grignard reagents with carbon dioxide.

O O O O O

OH OH OH OH OH shown O O O O

OH OH OH OH

1. Grignard reagents with nitriles 2. workup hydrolyzes the C=N and makes ketones (C=O) H OH 2 H (BrMg) H (BrMg) N N N H O H C H C C H C 3 H3C C 2 C CH CH3 3 C CH3 CH3 H2 2. workup H 2 H

O H H2OH H H H H H H H OH2 N N O H N O H 2 H2N O H H3C C resonance C CH3 H2

H H H 9 RMgBr x 8 RCN = 72 possibilities H (some duplicates) N H N H H H Ketones from nitriles and Grignard resonance O O reagents followed by . The hydrolysis or the C=N uses an addition reaction (H2O) followed by an elimination reaction (NH3) to form a C=O.

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Nine Grignard reagents can be made from our starting RBr compounds and reacted with eight possible nitriles from our RBr compounds make for 72 possible combinations, though some produce similar products. Each "R" below represents nine possibilities. O O O O O

R R shown with R R R "R" = ethyl O O O 9 possible N O 1. R2MgBr R C 2. workup R R R1 R1 R2 8 possible some duplicates j. Lithium aluminum hydride (LiAlH4) = nucleophilic hydride with methyl, primary and secondary R-Br compounds (reduces Br to H, we will use LiAlD4 to show where hydride reaction occurs, D = deuteride / deuterium). Also reacts at carbonyl and epoxide electrophiles, followed by a workup step (similar to Grignard reaction above, except using nucleophilic hydride or deuteride reagents = LiAlH4 or LiAlD4 (for us). For now we will consider lithium aluminium hydride (LiAlH4) as equivalent to sodium borohydride (NaBH4) and only use LAH or LAD (LiAlD4).

SN2 reactions to reduce Br to H (or D) with 1. LiAlH4 2.workup, at methyl, primary and secondary RX compounds (not tertiary) D Li 8 possible from our Li starting structures D Al D H2 D C SN2 Br not possible H3C Br D at 3o RBr

D D D D D D D D H3C

1. LiAlD4 S 2 N 2. workup Br Br Br Br Br Br Br Br H3C

o shown 1o given 1o given 1 given

1. Nucleophilic hydride addition reactions with aldehydes and ketones 2. workup : makes alcohols H D H O Li O Li O 8 possible from our D Al D O starting structures H H H H H D D D workup

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Carbonyl compounds (aldehydes and ketones) that will react with LiAlD4 / workup to form alcohols (carbonyl addition reactions). These carbonyl compounds will be made later from our starting RBr compounds. (RCN are a source of ketones too, see above.) D OH D OH D OH D OH D OH D OH D OH D OH

H H H H H H

1. LiAlD4 2. workup

O O O O O O O O

H H H H H H shown

1. Nucleophilic hydride addition reactions with epoxides at less hindered carbon 2. workup : makes alcohols H H Li O Li D O O O 8 possible from our D starting structures D Al D S H H D S S workup D Epoxide compounds will be made later from the above carbonyl compounds and trimethylsulfonium iodide / n-butyl lithium. The first step is SN2 attack by hydride or deuteride on the least hindered carbon atom, followed by workup to neutralize the alkoxide.

OH OH OH OH OH OH OH H O

D D D D D D D D 1. LiAlD4 2. workup O O O O O O O O

3. a. E2 elimination reactions can make alkenes from R-Br compounds (E2 reactions using bulky, basic t-butoxide in our course).

E2 reactions using potassium t-butoxide and primary, secondary or tertiary RBr (eight possible from our starting RBr compounds), requires anti C-H and C-Br to be able to start forming pi bond in transition state.

H2 H H C O CH K C Br 2 O H H2C K 2 E2 Br

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Other E2 reactions (eight possible from our starting R-Br, two are duplicates and one produces a mixture of alkene products)

H2C CH2

potassium potassium potassium potassium t-butoxide t-butoxide t-butoxide t-butoxide H2 C Br Br CH3 Br Br shown above

mixture of duplicate duplicate mono, cis and trans alkenes, not useful for us potassium t-butoxide potassium potassium t-butoxide t-butoxide potassium t-butoxide Br

Br Br Br

b. E1 elimination reactions can make alkenes from alcohols. ROH and concentrated sulfuric acid and heat forms alkenes and alkenes distill away from the mixture. Rearrangements are possible due to carbocation intermediates.

E1 reactions using concentrated H2SO4/ and ROH, rearrangements are possible

H H H H H H O H O O H

O SO3H C C H CH CH H C CH H C C 2 3 H3C CH3 E1 H3C CH3 3 H2 rearrangements are possible (but not here)

Other alcohol dehydrations to alkenes (eight ROH possible from our starting R-Br, methyl won't work because we need at least two , the two straight chain, 4C alcohols won't be useful because they will produce a mixture of mono, cis and trans , the other 4C skeleton produce duplicate alkenes, as do the two 3C skeletons, so only four different alkenes are produce in this E1 reaction.) CH H 3 CH 2 Mixture of mono, C H2C C cis and trans butenes. H2C CH3 H2C CH3 E1 H2SO4/ H SO / H SO / E1 2 4 E1 H2SO4/ E1 2 4 H2 H C H H H O H3C O O O

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duplicate duplicate CH 3 CH Mixture of mono, 3 C cis and trans butenes. C H2C H H2C CH3 H SO / E1 H2SO4/ E1 2 4 E1 H2SO4/ E1 H2SO4/ CH3 O H CH H H H H3C O O O shown above

c. A very important E2 elimination reaction involves methyl, primary and secondary alcohols and highly oxidized chromium +6 (we will write it as CrO3). There are many variations of this overall transformation but for now we will only present one simplified version, pyridinium chlorochromate (PCC = CrO3/pyridine). A preliminary step forms an inorganic and uses pyridine as a base to pick off protons. A second step is our familiar E2 reaction, though it occurs across C and O with a Cr leaving group taking electrons with it, instead of C and C and a bromide leaving group. The details of all the steps are written out for you below. This reaction allows us to make aldehydes and ketones from methyl, primary and secondary alcohols, a very valuable interconversion (FGI).

The oxidation sequence uses a methyl, primary or secondary alcohol to form a (aldehyde or ketone). In the first step an inorganic ester is formed and a proton is lost from the OH. In the second step an E2 elimination reaction occurs across the C-O bond.

N H O O H O H C C O Cr pyridine = base O 3 Cr O H3C C O H H O O O (step 1) acid/base Cr H H H H3C C O C = -1 PCC conditions O (base = pyridine) H Cr = +6 Cr = +6 N N H C = -1

E2 (oxidation) pyridine = base O methanal H3C O C Cr O 1o alcohol aldehyde N H H C = +1 o O 2 alcohol ketone The oxidation reaction stops Cr = +4 o here because there is no water 3 alcohol no reaction to hydrate the C=O bond.

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Carbonyl compounds prepared from alcohols and CrO3/pyridine (PCC). O O O O O O O O

C H H H H H H

CrO CrO CrO 3 3 CrO3 3 CrO3 CrO3 CrO pyridine pyridine pyridine 3 pyridine pyridine pyridine pyridine CrO3 (PCC) (PCC) (PCC) (PCC) (PCC) (PCC) (PCC) pyridine H (PCC) O OH OH OH OH OH OH OH C H H H

4. Carbonyl addition reactions at aldehydes and ketones with strong (negatively charged, for us).

a. Hydration of carbonyl groups with aqueous hydroxide to make carbonyl hydrates.

1. Nucleophilic hydroxide addition reactions with aldehydes and ketones forms carbonyl hydrates, reversible reaction reforms carbonyl H H O Li O O Na Na O C C C O H O H H CH3 H CH3 H CH3 H O workup O H H Other carbonyl compounds (aldehydes and ketones) that will react with hydroxide to form a carbonyl hydrate. HO OH HO OH HO OH HO OH HO OH HO OH HO OH HO OH

H H H H H H

NaOH (aq)

O O O O O O O O

H H H H H H shown

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 20 b. Carbonyl groups reacting with alcoholic alkoxides form hemi- and hemi-ketals. (Similar to hydration, above.)

1. Nucleophilic alkoxide addition reactions with aldehydes and ketones forms hemi-acetals and hemi-ketals, reversible reaction reforms carbonyl H H O Li O O Na Na O C C C O R O H R1 R2 R1 R2 R1 R2 H O workup O alkoxide R R (from alcohol + NaH) hemi- if R1 or R2 = H hemi-ketal if R and R = C 1 2 Other carbonyl compounds (aldehydes and ketones) that will react with hydroxide to form hemi-acetals (from aldehydes) and hemi-ketals (from ketones). HO OR HO OR HO OR HO OR HO OR HO OR HO OR HO OR

H H H H H H

NaOR (alkoxide) ROH O O O O O O O O

H H H H H H shown

c. Carbonyl groups reacting with (C=O addition reaction) to form .

Nucleophilic cyanide addition reactions with aldehydes and ketones forms cyanohydrins. H O O H O Na Na C C O C N C H H H3C H H3C H H3C H C C cyanide workup N N

Carbonyl compounds (aldehydes and ketones) that will react with NaCN / workup to form cyanohydrins (carbonyl addition reactions). N N N N N N N N OH C OH C C OH C OH C OH C OH C OH C OH

H H H H H 1. NaCN 2. workup O O O O O O O O

H H H H H shown H

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 21 d. Carbonyl groups reacting with terminal acetylides (C=O addition reaction) to form propargylic alcohols, after workup.

Make terminal acetylide nucleophiles from terminal alkynes and sodium , NaNR2, then add electrophile (methyl or primary RBr, a carbonyl compound or an epoxide).

Na Na R C C H NR R C C terminal acetylide terminal React with an electrophile (methyl or primary terminal R alkyne acetylide RBr, a carbonyl compound or an epoxide).

Nucleophilic acetylide addition reactions with aldehydes and ketones forms propargyl alcohols. H O O H O Na Na C C O C R C C H H H3C H H3C H H3C H C C terminal workup acetylide C C propargyl R = H, CH3 or CH2CH3 alcohol in our course, for now. R R

Carbonyl compounds (aldehydes and ketones) that will react with NaCCR / workup to form propargyl alcohols (carbonyl addition reactions). R R R R R R R R C C C C C C C C OH C OH C C OH C OH C OH C OH C OH C OH

H H H H H 1. NaCCR 2. workup O O O O O O O O

H H H H H shown H

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 22 d. Sulfur ylid additions to aldehydes and ketones – epoxide syntheses

Make sulfur ylid from sulfonium iodide salt and n-butyl lithium (acid/base reaction)

Li H C H 3 H2 H3C H C CH Li H 2 3 C CH3 S CH2 S CH H2C C 2 C C H I 2 H2 H2 H3C H C I buy 3 n-butyl lithium sulfur ylid nucleophile trimethylsulfonium iodide salt

Sulfur ylid reactions with carbonyl compounds makes epoxides

H O H O H H3C H3C S O C C S CH2 CH3 H2C CH3 H2C CH3 carbonyl dimethylsulfide H C H3C intramolecular epoxide 3 addition (good leaving group) H3C S SN2 reaction CH3

Other epoxides that can form from similar reactions. O

O O O O O O O

(CH ) SCH 3 2 2 (CH3)2SCH2 (CH ) SCH (CH ) SCH (CH ) SCH (CH ) SCH 3 2 2 3 2 2 3 2 2 (CH3)2SCH2 (CH3)2SCH2 3 2 2 O O O O O O O O

H H H H H H

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 23 e. Hydration of epoxide groups with aqueous hydroxide.

1. Nucleophilic hydroxide addition reactions with epoxides forms . H H O O Na O Na Na O H C R H C O H O H H3C R CH2 H3C R CH2 H workup O O R O reacts similarly. H H

Other epoxide examples also form diols.

OH OH OH OH OH OH OH H O

OH OH OH OH OH OH OH OH

NaOH O O O O O O O O

f. Alkoxide addition to epoxide groups.

1. Nucleophilic alkoxide addition reactions with epoxides forms alcohol-ethers. H H O O Na O Na Na O H C R H C O R O R H3C R CH2 H3C R CH2 R workup O O diol R R

Other epoxide examples also form diols.

OH OH OH OH OH OH OH H O

OR OR OR OR OR OR OR OR

NaOH O O O O O O O O

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5. Substitution reactions at carboxyl functional groups (examples: acid chlorides and esters)

a. Carboxylic acids reacted with (SOCl2)

Make acid chlorides from carboxylic acids and thionyl chloride (SOCl2)

O Cl Cl Cl O O Cl O S S S O S O O O Cl O Cl Cl C H C H C H C H C H3C O H C O H3C O H3C Cl 3 H3C O Cl Cl H Cl

Nine acid chlorides made from carboxylic acids and thionyl chloride. O O O O O C H C Cl 3 Cl Cl Cl Cl

O O O O

Cl Cl Cl Cl

SOCl2 Nine carboxylic acids made from our starting RBr compounds using the Grignard reagents with carbon dioxide.

O O O O O

OH OH OH OH shown OH O O O O

OH OH OH OH

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6. b. Anhydrides from acid chlorides (nine possible above) reacted with carboxylates (nine possible from above)

Make carboxylate from carboxylic acid and NaH (acid/base reaction) to use in reactions with acid chlorides. O O Na Na C H C H H H -5 O CH O CH 10 = 10+32 3 3 Keq = -37 10 pK = 37 pKa = 5 a

O Na O O Cl Na O acyl O O substitution Na H C C H C C C 3 C H3C C C 3 C Cl C O CH3 C O CH3 H O CH3 H 2 H2 Cl 2 ethanoate ethanoic propanoic anhydride propanoyl chloride (acetate) T.I. = tetrahedral intermediate

Nine acid chlorides x nine carboxylic acids = 81 possible anhydrides (with some duplicates). Only a few examples shown.

O O O O O O O O

O O O O 1. NaH 1. NaH 2. 1. NaH 1. NaH O 2. O 2. O 2. O Cl Cl Cl Cl O O O O

OH OH OH OH

c. Nine acid chlorides reacted with nine alkoxides makes a lot of esters. This is a second way from the SN2 approach. Using the SN2 approach the carboxylate was the nucleophile reacting with the electrophilic RBr compound and in this approach the acid chloride is the electrophile reacting with the nucleophilic alkoxide.

Make alkoxide from alcohol and NaH (acid/base reaction) to use in acyl substitution reactions with acid chlorides.

Na Na H2 H2 C H C H H H -16 O CH O CH 10 = 10+21 3 3 Keq = -37 10 pK = 37 pKa = 16 a

O O Na acyl Na O Cl substitution H2 H2 Na H C C H2 H C C C 3 C H3C C C 3 C Cl C O CH3 C O CH3 H O CH3 H 2 H2 Cl 2 ethoxide propanoyl chloride ethyl propanoate T.I. = tetrahedral intermediate

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Nine acid chlorides x nine alcohols = 81 possible esters. Only a few examples shown.

O O O O

O O O O 1. NaH 1. NaH 1. NaH 2. O 2. 1. NaH O 2. O 2. O Cl Cl Cl Cl

OH OH OH OH

d. Nine acid chlorides reacted with eight amines makes a lot of . In this reaction the is both a nucleophile and a base.

Make amides from amines and acid chlorides using acyl substitution reactions.

O acyl O O substitution H H H H 2 H2 H C C 2 H C C C 3 H C 3 H3C C C C Cl C N CH 3 C N CH3 H2 N CH3 H 2 Cl H2 H2 Cl ethylamine C propanoyl chloride H H ethanamine H2N CH3 o 1 amine T.I. = tetrahedral (nucleophile) intermediate 1o amine O (base) H2 H3C C C C N CH3 Cl H2 2o amide H N-ethylpropanamide

Nine acid chlorides x eight amines = 72 possible esters. Only a few examples shown. O O O O

N N N N H H H H O O O O Cl Cl Cl Cl

NH2 NH NH2 NH2 2

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 27 e. Esters reacted with Grignard reagents, followed by workup.

1. React 2 equivalents of Grignard reagent with esters. This occurs in 2 steps. The Grignard reagent adds to the ester carbonyl forming a tetrahedral intermediate (TI), which collapses back to a carbonyl group with the extrusion of the alkoxide anion. The newly formed ketone is more reactive than an ester so it immediately reacts with another equivalent of Grignard reagent forming a tertiary alkoxide. 2. The final workup step protonates the alkoxide forming a tertiary alcohol with 2 identical groups at the alcohol carbon atom. CH O 3 (BrMg) O (BrMg) (BrMg) O O C CH3 C CH3 H2C H3C O C CH3 H3C O CH3 CH2 H3C C Ketones are more H2 reactive than esters. H3C Grignard ester reagent TI

H2C CH3 H H O O 3o alcohol O C CH3 H H C CH3 H3C C H C C H2 3 H2C CH H2 2. workup 2 CH3 H3C

OH OH OH OH OH

H

1. 2eqs. 1. 2eqs. 1. 2eqs. 1. 2eqs. 1. 2eqs. CH3CH2MgBr CH CH MgBr CH3CH2MgBr CH3CH2MgBr 3 2 CH3CH2MgBr 2. workup 2. workup 2. workup 2. workup 2. workup O O O O O R R R R R O O H O O O Carbonyl compounds (aldehydes and ketones) that will be made later from our starting RBr compounds (available to use until then).

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 28 f. Reactions of esters reacted with lithium aluminum hydride (deuteride), followed by workup.

1. React 2 equivalents of hydride (deuteride) from LAH (LAD) with esters. This occurs in 2 steps. The hydride (deuteride) reagent adds to the ester carbonyl forming a tetrahedral intermediate (TI), which collapses back to a carbonyl group with the extrusion of the alkoxide anion. The newly formed aldehyde is more reactive than an ester so it immediately reacts with another equivalent of Grignard reagent forming a primary alkoxide. 2. The final workup step protonates the alkoxide oxygen forming a with 2 identical groups at the alcohol carbon atom. CH O 3 Li O Li Li O O C CH D C CH 3 3 H C O C H C O 3 Aldehydes are more 3 D H C D D Al D 3 reactive than esters. T.I. = tetrahedral ester intermediate D D D Al D H H D O O 1o alcohol C O H H C H3C D H3C D D D 2. workup T.I. = tetrahedral intermediate

H H H H H O O O O O

D H D D D D D D D D D 1. LiAlD 1. LiAlD 1. LiAlD 1. LiAlD 1. LiAlD 4 4 4 4 4 2. workup 2. workup 2. workup 2. workup 2. workup O O O O O R R R R R O O H O O O Carbonyl compounds (aldehydes and ketones) that will be made later from our starting RBr compounds (available to use until then).

y:\files\classes\201\201 Organic Reactions Worksheets.doc Chem 201/Beauchamp Reactions and Mechanisms Worksheet 29 g. Nitriles reacted with aqueous sodium hydroxide, followed by workup.

1. Aqueous base with nitriles can form primary amides (or continue to carboxylic acids).

O H Na Na H N N N C H O H O H C H C O CH H CH3 3 O CH3 2. workup

H O H H H H Under forcing N H conditions can NaOH N N continue on to  resonance C carboxylic acids C C (after workup) O CH3 O CH O CH3 3 1o amide

Other nitriles to consider. O O O O

C H H H H N H3C N N N

H H H H NaOH NaOH NaOH NaOH N N N N C C C C CH3

O O O O

H H H H N N N N H NaOH H H H NaOH NaOH N NaOH N N N C C C C

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7. Hydrolysis of nitriles and terminal alkynes in aqueous sulfuric acid.

a. Synthesis of ketones from aqueous of alkynes.

H H H enol H H C C H C C H O H 3 H C C C H C H 3 C C H H3C H3C O H O H O terminal H H H alkyne H O H H

H O H

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

b. Synthesis of primary amides from aqueous acid hydrolysis of nitriles. Notice the similarities to the reaction, just above. H H N H H O H H C N H3C N N C H3C C resonance C H O H H3C nitrile H3C O H O H H H

H O H H H H H H3C N H C N C H 3 H C N H C N resonance C H 3 3 C H C resonance O O H O O H H H H H O H H O H H Several resonance structures not in H C N the above example because of the 3 nitrogen and oxygen lone pairs, but C H otherwise very similar.

O primary amide

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Basic RX patterns to know, with isoptope substitutions to show mechanism details (horizontal and vertical perspectives, templates for studying SN and E mechanisms) Example 1 - two possible perspectives (deuterium and tritium are isotopes of hydrogen that can be distinguished) T D methyl RX example T H reaction C Br reaction  conditions C conditions H ? ? D Br S-bromoderteriotritiomethane Bold = actual structure S-bromoderteriotritiomethane R-bromoderteriotritiomethane others = possible structures R-bromoderteriotritiomethane

Example 2 - two possible perspectives (deuterium is an isotope of hydrogen that can be distinguished)

CH3 primary RX example H D H C reaction D  conditions C H reaction ?  conditions C Br H3C C ?  D H D Br (1S,2S)- 1,2-dideuterio-1-bromopropane (1S,2R)- 1,2-dideuterio-1-bromopropane (1R,2R)- 1,2-dideuterio-1-bromopropane Bold = actual structure (1S,2S)- 1,2-dideuterio-1-bromopropane (1R,2S)- 1,2-dideuterio-1-bromopropane others = possible structures (1R,2R)- 1,2-dideuterio-1-bromopropane (1S,2R)- 1,2-dideuterio-1-bromopropane (1R,2S)- 1,2-dideuterio-1-bromopropane

Example 4 - two possible perspectives (deuterium is an isotope of hydrogen that can be distinguished) D CH3 secondary RX example D H H C reaction conditions H reaction C Br ? C C    conditions ? H H3C C CH2CH3 CH2CH3 H H C H3C Br CH3 (2S,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4S)-2-deuterio-4-methyl-3-bromohexane (2S,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4R)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2S,3R,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3R,4R)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4S)-2-deuterio-4-methyl-3-bromohexane

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Example 3 - two possible perspectives (deuterium is an isotope of hydrogen that can be distinguished)

D secondary RX example CH3 H H H C reaction H reaction conditions C C C Br ?   conditions H H3C C CH3 ? H D H H C Br CH3 (2S,3R)-3-deuterio-2-bromobutane (2R,3R)-3-deuterio-2-bromobutane (2R,3S)-3-deuterio-2-bromobutane Bold = actual structure (2S,3S)-3-deuterio-2-bromobutane (2S,3S)-3-deuterio-2-bromobutane others = possible structures (2S,3R)-3-deuterio-2-bromobutane (2R,3R)-3-deuterio-2-bromobutane (2R,3S)-3-deuterio-2-bromobutane

Example 5 - two possible perspectives (deuterium is an isotope of hydrogen that can be distinguished) D CH tertiary RX example 3 H H C D H reaction reaction conditions CH C Br 2 conditions ? C C H C   ? H C C CH CH H2 CH CH 3  2 3 H C 2 3 H  H3C Br CH3 (2S,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4S)-2-deuterio-4-methyl-3-bromohexane (2S,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4R)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3S,4R)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3R,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4S)-2-deuterio-4-methyl-3-bromohexane (2R,3S,4S)-2-deuterio-4-methyl-3-bromohexane (2S,3R,4R)-2-deuterio-4-methyl-3-bromohexane (2S,3R,4R)-2-deuterio-4-methyl-3-bromohexane

Blank Templates primary RX examples secondary RX examples tertiary RX examples

C reaction C C reaction C Br conditions  conditions reaction  ? conditions C ? C Br ? C Br H C C

reaction reaction H reaction C C conditions conditions C C C conditions C ? C ? C ? C

Br Br Br

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