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Home , Robinson annulation

Lecture 23

April 12, 2016 Chemistry 328N

 Michael reaction: conjugate addition of an enolate anion to an ,Arthur-unsaturated Michael carbonyl compound!!  Following are two examples – in the first, the nucleophile is the anion of malonic ester – in the second, it is the enolate anion of acetoacetic ester  An excellent route to 1,5 dicarbonyl compounds

Chemistry 328N Michael Reaction

O

EtOC O - + Et O Na CH 2 + CH 2 =CHCCH 3 EtOH EtOC 3-Buten-2-one O (Methyl vinyl ) Diethyl propanedioate O (Diethyl malonate) EtOC O CH CH 2 CH 2 CCH 3 EtOC O

Chemistry 328N Michael Reaction

O O CH 3 C - + EtO Na CH 2 + EtOC EtOH O O 2-Cyclohex- enone O Ethyl 3-oxobutanoate (Ethyl acetoacetate) CH 3 C CH EtOC O

Chemistry 328N Retro-synthesis of 2,6-Heptadione from acetoacetic formed in a ester Michael reaction O O O O

CH 3 CCH 2 CH 2 CH 2 CCH 3 CH 3 CCH-CH 2 CH 2 CCH 3 lost by CO 2 H decarboxylation O O

CH 3 CCH 2 + CH 2 =CHCCH 3

CO 2 Et Ethyl Methyl vinyl acetoacetate ketone

Always gives a 1,5-dicarbonyl product

Chemistry 328N Michael Addition

 The Michael reaction is a useful method for forming carbon-carbon bonds….1,5 dicarbonyls

O O

2 1 3 5 4

Chemistry 328N Michael Addition

 It is also useful in that the product of the reaction can undergo an intramolecular to form a six- membered ring. One such application is called the Robinson annulation.

 This reaction enabled the first synthesis of

Chemistry 328N The Robinson Annelation: 1. Michael addition O O CH3

+ H2C CHCCH3 O KOH, methanol

O CH3 O

CH2CH2CCH3 O Chemistry 328N Robinson annelation: 2. aldol condensation O O CH3 CH3 O NaOH heat CH2CH2CCH3 O O OH

not isolated; dehydrates under reaction conditions

Chemistry 328N Robinson annelation: 3. elimination O O NaOH CH CH O 3 3 heat

CH2CH2CCH3 O O OH

O CH3

Robert Robinson O Nobel 1947 Chemistry 328N Testosterone Cortisone

Chemistry 328N The Signature Page

Claisen Condensation: -ketoesters Dieckmann: Cyclic -ketoesters Aldol: , -unsaturated and Acetoacetic ester synthesis: decorated acetones Malonic ester synthesis: decorated acetic acids Michael Reaction: 1-5 dicarbonyl compounds Grignard Reaction: Alcohols Wittig Reaction: Alkenes. …, etc

Chemistry 328N The Diels-Alder Reaction

Otto Paul Hermann Diels Kurt Alder 1876-1954 1902-1958

Chemistry 328N Diels-Alder Reaction:

• The Diels-Alder reaction is an addition reaction between a 1,3-diene and an alkene (called a dienophile), that forms a new six-membered ring.

Chemistry 328N Predict the products

Chemistry 328N All Diels-Alder reactions:

1. are initiated by heat; that is, the Diels-Alder reaction is a thermal reaction. 2. form new six-membered rings. 3. involve breaking three  bonds and making two new  bonds and one new  bond. 4. are concerted; that is, all bonds are broken and new bonds formed in a single step.

Chemistry 328N 4 Rules that govern the Diels-Alder reaction

1. The diene can react only from the s-cis conformation.

Chemistry 328N 2. Electron-withdrawing substituents in the dienophile increase the reaction rate.

• The conjugated diene acts as a nucleophile and the dienophile acts as an electrophile. • Electron-withdrawing groups make the dienophile more reactive • If Z is an electron-withdrawing group, then the reactivity of the dienophile increases as follows:

18 Chemistry 328N Common dienophiles

The carbonyl group is electron-withdrawing and activates dienophiles

Chemistry 328N Example

O

+ H2C CHCH CH2 H2C CH CH

benzene 100°C via: O O

CH CH

(100%) Chemistry 328N 3. The stereochemistry of the dienophile is retained.

Chemistry 328N Chemistry 328N Example O

C6H5 COH + H2C CHCH CH2 C C H H

H

C6H5

COH only product H O

Chemistry 328N Example O H COH + H2C CHCH CH2 C C

C6H5 H

C6H5 H

COH only product H O

Chemistry 328N O

H COCH3 + C C H CH3OC

O H O

COCH3

H

COCH3

O

Chemistry 328N H O O COCH COCH 3 is the 3 H H same as H COCH COCH3 3

O O

Chemistry 328N 4. When endo and exo products are possible, the endo product is preferred.

endo and exo indicate the orientation of Z.

endo = on the side of the big bridge

exo = on the side of the small bridge

Chemistry 328N The endo product is preferred!

Chemistry 328N Some nomenclature

Chemistry 328N Nomenclature of Bicyclic Systems

Bicyclo [#.#.#]alkane Where # is the number of carbons on the bridges (in decreasing order) and the alkane name includes all the carbons in the compound.

Chemistry 328N Nomenclature of Bicyclic Systems

Numbering begins at a bridgehead, goes around the largest ring first, to give the lowest number to any functionality on the ring.

5 6 4 7

8 O 3 1 2

7-Methyl-bicyclo[4.2.0]octan-3-one

Chemistry 328N Some nomenclature

 If substituents are present, number the bridge ring system beginning at on bridge-head, proceeding first along the longest bridge to the other bridge-head. The shortest bridge is named last

Chemistry 328N Chemistry 328N Amines

 Organic derivatives of ammonia.

 Many are biologically active.

=>

Chemistry 328N Biologically active amines

Methamphetamine

Morphine Quinine

Strychnine

Chemistry 328N AMINES

 Tend to have foul odors (two of the amines produced in decaying flesh have suggestive names - cadaverine and putresine)

 Essential to life as constituents of amino acids Skatol  Occur in many drugs and vitamins  Essential starting materials for many synthetic processes Chemistry 328N Nomenclature of Amines

 IUPAC name – Remove final “e” of longest alkane group and replace by “”. The name is one word.

CH3CH2CH2CH2NH2 CH3CHCH2NH2

1-butanamine CH3 2-methylpropanamine

Chemistry 328N IUPAC Nomenclature of secondary and tertiary Amines • Find the longest chain bonded to the nitrogen • Final “e” is replaced with “amine” • Number the carbon to which nitrogen is bonded • Number any substituents on the alkyl chain • Use italicized N- for each additional substituent(s) on the nitrogen

N,N-dimethylethanamine

Chemistry 328N IUPAC Names

 Name is based on longest carbon chain.

 -e of alkane is replaced with -amine.

 Substituents on nitrogen have N- prefix.

N(CH3)2

CH3CH2CHCH2CH2CH3

N,N-dimethyl-3-hexanamine

Chemistry 328N Amine as Substituent

 On a molecule with a higher priority functional group, the amine is named as a substituent. The substituent name is amino.

NH2CH2CH2CH2COOH OH

NHCH3 -aminobutyric acid or 4-aminobutanoic acid

2-methylaminophenol

Chemistry 328N Basicity of Amines

1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity.

Chemistry 328N Basicity of Amines in Aqueous Solution

Amine Conj. Acid pKa + NH3 NH4 9.3 + CH3CH2NH2 CH3CH2NH3 10.8 + (CH3CH2)2NH (CH3CH2)2NH2 11.1 + (CH3CH2)3N (CH3CH2)3NH 10.8

Notice that the difference separating a primary, secondary, and tertiary amine is only 0.3 pK units.

Chemistry 328N Effect of Structure on Basicity

1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity. 3. Arylamines are much weaker bases than ammonia.

Chemistry 328N Decreased basicity of arylamines

H + •• N H + H2N H Stronger Stronger pKa = 4.6 acid base

•• + + NH2 H3N Weaker Weaker pK =10.6 base a acid Chemistry 328N Decreased basicity of arylamines

 Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.

pKa of conjugate acid

C6H5NH2 (C6H5)2NH (C6H5)3N 4.6 0.8 ~-5

Chemistry 328N p-Nitroaniline

•• – •• • • • O • • O • + •• + + N NH2 N NH2

• • • • • O • • O • – •• – ••

 Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. Delocalization lost on protonation.

Chemistry 328N Effect is Cumulative

 Aniline is 3800 times more basic than p-nitroaniline.

 Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.

Chemistry 328N Synthesis of Amines

Chemistry 328N Alkylation of Ammonia

This method doesn't work well in practice. Usually gives a mixture of primary, secondary, and tertiary amines, plus the quaternary salt.

RX RX NH3 RNH2 R2NH

RX + – RX R4N X R3N

Chemistry 328N Example

NH3 CH3(CH2)6CH2Br CH3(CH2)6CH2NH2 (45%) +

CH3(CH2)6CH2NHCH2(CH2)6CH3 (43%)

 As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine. Chemistry 328N