Second meet and third meet (19 September 2013, 26 September 2013)

ALDEHID DAN KETON ENOLAT ION

Reaksi Adisi Nukleofilik pada Aldehida dan Keton

I. Merupakan reaksi yang terpenting untuk aldehida dan keton.

Nukleofil
HO H (ion hidroksida) (ion hidrida) (karbanion) (ion alkoksida) (ion sianida)

Nukleofil bermuatan negatif

Nu

R3C RO N C

HOH

(air) (alkohol) (amonia) (amina)

3

Nukleofil netral
Nu H

ROH H 3N RNH2

Dua variasi adisi nukleofilik pada aldehida dan keton

(1) Intermediat tetrahedral diprotonasi oleh air atau asam menghasilkan alkohol
O Nu R R' R R' Nu O HA R R' Nu OH

(2) Atom oksigen karbonil dikeluarkan sebagai HO- atau H2O menghasilkan ikatan rangkap karbon-nukleofil
O NuH2 R R' R R' NuH2 R R' O Nu + H2O

Kereaktifan relatif: aldehida > keton

(1) Alasan sterik: perbedaan halangan ruang
Nu Nu

(2) Alasan elektronik: perbedaan kestabilan muatan positif parsial

O R H

O R 5 R'

Adisi Nukleofolik H2O: Hidrasi

O H2O R R' OH R OH R' suatu geminal diol

O H2O H3C CH3 Aseton (99,9%) O H2O H H Formaldehida (0,1%)

OH H3C OH H3C Aseton hidrat (0,1%) OH H OH H Formaldehida hidrat (99,9%)

Mekanisme hidrasi
(1) Katalis basa
O OH O OH H OH OH OH OH

(2) Katalis asam

O H OH2 OH H2O O H OH H H2O OH OH H3O+

Chapter 18 Lecture 1 Enols

I. Enolate Ions
A.
O C CH a

Carbonyl Reactivity 1) Nucleophilic carbonyl oxygen 2) Electrophilic carbonyl carbon 3) a-carbon containing acidic a-protons (the subject of this chapter) Acidity of Aldehydes and Ketones 1) pKa of protons alpha to an aldehyde or ketone carbonyl = 19-21 a) Ethene pKa = 44 b) Ethyne pKa = 25 c) Alcohol pKa = 15-18

B.

2)
O C

Strong bases can remove a-hydrogens to produce an Enolate Ion

B
-

O C C

O C C

Enolate Ion

3)

Why are carbonyl a-protons acidic? a) The conjugate base is stabilized by the enolate ion resonance structures b) The + carbon of the carbonyl destabilizes the a CH bond

C.

Formation of Enolate Ions 1) LDA (lithium diisopropyl amide) or other strong bases are used 2) Aprotic solvents are used to prevent solvent deprotonation

O H H H H + H3C CH H3C 2 NLi THF H H

O H + H3C CH H3C NH 2

3)
O C C -

Enolate Resonance Hybrid a) The a-carbon and the oxygen of an enolate ion are both nucleophilic b) Ambident = two-fanged = a species that can react at 2 different sites to give 2 different products

O CH3 CH3I, THF alkylation

O H , H2O protonation
+

OH

O H tautomerization

a) b)

The carbon atom is the normal site of reaction by SN2. This type of reaction is called alkylation or C1-alkylation of the enolate ion. The oxygen atom is the normal site of protonation, forming an enol, which will tautomerize to the original ketone.

II.

Keto-Enol Equilibria
A. KetoneEnol Tautomerization 1) This reaction is reversible, and the extent of reaction depends on conditions 2) Base-catalyzed Enol-Keto Equilibration a) Base removes proton from the enol b) The mechanism is the reverse of the original enolate formation
O H B C C enolate ion O C C O BH C C O H keto

enol

2)

Acid Catalyzed Enol-Keto Equilibration a) Protonation occurs at the double bond b) Resonance stabilized C is next to O c) Protonated carbonyl deprotonates to give the keto form
H
+

O H C C

H C C

H O H H C C O -H+ C C

O H keto

enol

3) 4) 5) B.

Both reaction are fast if the catalyst (B- or H+) are present Keto form is usually dominant Keto to enol tautomerization mechanisms are the reverse of those above

Effects of Substituents on Keto-Enol Equilibria 1) Ketone donating substituents stabilize keto form 2) Aldehyde lack of donating substituents pushes equilibria toward enol form
O OH H
-7 o

O H CH2 C CH3
-9 o

OH H2C C CH3 G = +11.3 kcal/mol

H CH2 C K = 6 x 10

H2C

C H

G = +8.5 kcal/mol

K = 5 x 10

C.

Deuteration of Carbonyl a-Carbons 1) Dissolving an aldehyde or ketone in D2O, DO- (or D+) replaces all of the aHydrogens with Deuteriums O O D2O CH3 CD2 C CD3 CH3 CH2 C CH3 OD 2) Even though the keto form dominates, a small % is always tautomerizing to the enol. Over time, reprotonation at C gives the fully deuterated product. Reaction can be followed by 1H NMR as a-H signal disappears

3) D.

Interconversion of a-C stereochemistry 1) Keto-Enol tautomerization proceeds through an achiral intermediate

O CH2CH3 KOH O CH2CH3 CH3 planar enol O CH2CH3 CH3 trans, less crowded

CH3 cis, crowded

2)
O H H3C C C

Loss of optical activity occurs under basic or acidic conditions

B CH3 H3C C O C CH3 H3C O C C H R,S-racemic mixture CH3

S-enantiomer

III. Halogenation of Aldehydes and Ketones

A. Acid-Catalyzed a-Halogenation of Ketones and Aldehydes 1) In acidic conditions, only one halogen is able to add

O CH3 C
2)

O CH3 Br2, HOAC H2O, 70 C

o

BrCH2 C

CH3

+ HBr

The reaction rate is independent of X2 concentration, suggesting that the rate determining step depends only on the carbonyl compound

3)

Mechanism of acid catalyzed a monohalogenation

OH BrCH2 C CH3 Br Br -H
+

O CH3 C CH3 keto

OH CH2 C CH3 enol

O BrCH2 C CH3

OH BrCH2 C CH3

4)

Why does the reaction stop after only one halogenation? a) Mechanism requires enolization b) Electron withdrawing Br prevents protonation needed in first step
H H
+

O C C H keto

H C C

H C C

-H+ C C enol

O Br CH2 C CH3

O is no longer basic enough To attack proton. Enolization Cant happen.

B.

Base Mediated Halogenation of a-Carbon Goes to Completion 1) Mechanism

O C C B enolate ion C C O C C Br Br Br O

O C C H keto

2)

Electron Withdrawing Br increases a-Hydrogen acidity, favoring complete bromination of all a-Carbons
O Br CH2 C CH3

3)

The Iodoform test for Methyl Ketones is base catalyzed halogenation

O R C CH3

I2, HO

O R C CI3 OH
-

O R C OH + HCI3 Iodoform Yellow solid

IV. Alkylation of Aldehydes and Ketones

A. Alkylation of Ketones Using NaH 1) Ketones with only one a-Hydrogen are alkylated in high yield a) Example:
O C CH(CH3)2 O 1. NaH, benzene, 2. CH3CH2Br C C(CH3)2 CH2CH3 88% yield

b)
O C C(CH3)2 H

NaH is a strong base yielding enolate ion when reacted with carbonyls
O Na H
+ -

O C(CH3)2 CH3CH2Br SN2 C C(CH3)2 CH2CH3

C enolate

2)

Polyalkylation occurs if multiple a-Hs are present

O H 1. NaH 2. CH3I 27% H O + CH3 38% CH3 CH3 O

3) O

Unsymmetric Ketones give multiple products

O CH3 1. NaH 2. CH3I H H H CH3 CH3 36% + H3C H

O CH3 H 53%

H H

B.

Enamine Route to Ketone/Aldehyde Alkylation 1) Enamine formation makes C=C bonds electron rich by resonance 2) The nucleophilic a-Carbon can then attack electrophiles
H N CH3CH2 OH C N CH2CH3 azacyclopentane Enamine -H2O N

O CH3CH2CCH2CH3 +

CH3CH

CH2CH3

CH3CH

CH3CH

CH3I

CH3 CH3CH C N CH2CH3

CH2CH3

CH2CH3

3)
I C

The amine is removed from the alkylated product by acid to give the alkylated ketone or aldehyde
-

CH3 CH3CH

H+, H2O N

CH3 CH3CH C

O CH2CH3

HN

CH2CH3 Iminium Salt

4)

The Enamine Alkylation Route is Preferred

a)
b)

No multiple alkylations
Works on Aldehydes and Ketones
O (CH3)2CHCH 1. azacyclopentane 2. CH3CH2Br 3. H , H2O
+

O (CH3)2CCH CH2CH3

Mekanisme Pembentukan Imina

O aldehida/keton NH2R

O NH2R

transfer proton

OH NHR karbinolamina

H3O

OH2 NHR

H2O

R N

H OH2

ion iminium

R H3O
+

19

imina

Mekanisme Pembentukan Enamina

O H

NHR2 OH H R2N OH2 H R2N R N H R

H+

OH2 R H3O+ N R

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Adisi Nukleofolik HCN: Sianohidrin

O HCN R R' OH R CN R' suatu sianohidrin

Dengan HCN murni reaksi sangat lambat Dengan penambahan sedikit basa atau ion sianida reaksi cepat

O C H N

CN HCN H

HO

CN H C N

Benzaldehida

Mandelonitril (88%) (suatu sianohidrin)

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Pentingnya pembentukan sianohidrin

I. Merupakan metode transformasi aldehida dan keton ke berbagai gugus fungsi sambil memperpanjang rantai karbon dgn 1 atom C.
OH 1. LiAlH4, THF O HCN H OH Benzaldehida Mandelonitril H3O ,
+

CHCH2NH2

OH CHCN

2. H2O 2-Amino-1-feniletanol

CHCOOH

Asam mandelat (90%)

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Adisi Nukleofilik Pereaksi Grignard: Pembentukan Alkohol

I. Pereaksi Grignard adalah nukleofil karena ikatan karbon-magnesium sangat terpolarkan dengan kerapatan elektron yang tinggi pada karbon
+

MgX

O R

MgX

H3O+

OH HOMgX R Alkohol

Karbonil

Intermediat tetrahedral

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Adisi Nukleofilik Hidrida: Reduksi

I. Pereaksi pereduksi (misalnya LiAlH4 atau NaBH4) berfungsi sebagai ekivalen ion hidrida (H-).
O R R' " H" (dari NaBH4) R R' O H H3O+ R R' OH H2O H

Karbonil

Intermediat tetrahedral

Alkohol

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Adisi Nukleofilik Amina: Pembentukan Imina dan Enamina

I. Adisi amina primer menghasilkan imina; adisi amina sekunder menghasilkan enamina.
O C C RNH2 R N H2O C C Imina H Keton / Aldehida R2NH R N C C Enamina H H2O R H

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Oksim
O Sikloheksanon NH2OH hidroksilamina N OH H2O Sikloheksanon oksim (tl. 90C)

Semikarbazon
O C H O H2NNHCNH2 Semikarbazida Benzaldehida N C

H N C O H NH2

Benzaldehida semikarbazon (tl. 222oC)

2,4-Dinitrofenilhidrazon
H O C H3C CH3 NO2 2,4-Dinitrofenilhidrazina H3C Aseton H2N N N C CH3 NO2 Aseton 2,4-dinitrofenilhidrazon (tl. 126 oC) NO2 H N NO2

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Adisi Nukleofilik Hidrazina: Reaksi Wolff-Kishner

I. Merupakan metode sintesis yang penting untuk mengkonversi keton/aldehida alkana.
O C CH2CH3 H2NNH2 KOH Propiofenon O C H H2NNH2 KOH Siklopropanakarbaldehida CH3 N2 Metilsiklopropana (72%) H2O Propilbenzena (82%) H C CH2CH3 N2 H2O H

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Mekanisme Reaksi Wolff-Kishner

O C R R' H2NNH2 NH2 R N N C OH R' H2O H R R' N C H R C H R' H2O R' H OH
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H OH N H

H2O N N

N C R

R' N C R

R C H R'

Reduksi Clemmensen
I. Mengkonversi keton/aldehida ke alkana. II. Mekanisme rumit dan belum sepenuhnya dipahami. III. Digunakan bila substrat tidak tahan kondisi basa.

O C CH2CH3 Zn(Hg) H3O Propiofenon

+

H C

H CH2CH3

Propilbenzena (86%)

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Adisi Nukleofilik Alkohol: Pembentukan Asetal

I. Alkohol merupakan nukleofil lemah yang mengadisi keton/aldehida secara lambat pada suasana netral. II. Adisi berlangsung cepat pada suasana asam.
O C Keton/aldehida 2 R'OH asam OR' Asetal katalis OR' H2O

(H3C)C

HOCH2CH2OH katalis asam

O (H3C)C O 4-ters-Butilsikloheksanol etilena asetal (suatu asetal siklik) H2O

4-ters-Butilsikloheksanol

(88%)

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Mekanisme Reaksi Pembentukan Asetal

O H Cl OH ROH O R OH H H2O OR Hemiasetal OH H3O+

Cl

OR OR Asetal + H3O+

H2O

OR H O R ROH

OR

OH2 OR

+ H2O

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Manfaat Penting Asetal

I. Asetal merupakan gugus pelindung yang penting untuk aldehida/keton.

O HOCH2CH2OH katalis H+

H2C O C H3C

CH2 O O

CH3CCH2CH2COCH2CH3 Etil 4-oksopentanoat tak dapat dilakukan secara langsung O CH3CCH2CH2COH 5-Hidroksi-2-pentanon

CH2CH2CHOCH2CH3 1. LiAlH4 2. H3O+ H2C CH2 O C CH2CH2CH2OH

+ HOCH2CH2OH

H3O+

O H3C

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Adisi Nukleofilik Thiol: Pembentukan Thioasetal

I. Serupa dengan pembentukan asetal. II. Tioasetal penting karena dapat diubah menjadi alkana dengan desulfurisasi menggunakan Raney nikel.
HSCH2CH2SH H3C O HCl H3C S Suatu tioasetal (96%) S + H2O

4-Metilsikloheksanon

S H3C S

Raney Ni H3C

H + H Suatu alkana NiS

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Adisi Nukleofilik Fosfonium Ilida : Reaksi Wittig

R C O + (C6H5)3P C R' fosfonium ilida R alkena R aldehida/ keton R' R C C R' R' + (C6H5)3P O

trifenilfosfina oksida

I. Reaksi Wittig digunakan untuk membuat alkena mono-, di- dan trisubstitusi. II. Ilida: molekul dengan muatan + dan berdampingan. III. Betaina: molekul dengan muatan + dan tidak berdampingan.
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Mekanisme Reaksi Wittig

O C keton/ aldehida + R2C P(C6H5)3 ilida THF O C P(C6H5)3 C R betaina R

R + R alkena trifenilfosfina oksida (C6H5)3P O

O C

P(C6H5)3 C R R

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Pembuatan Ilida

H3C

Br

SN2 P CH3 Br

BuLi P THF CH2

Bromometana

Trifenilfosfina

Metiltrifenilfosfonium bromida

Metiltrifenilfosforana

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Keunggulan Reaksi Wittig

CH3 1. CH2MgBr 2. POCl3 O 1-Metilsikloheksena Metilenasikloheksana CH2

CH2 Sikloheksanon (C6H5)3P THF CH2 + Metilenasikloheksana (84%) (C6H5)3P O

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Reaksi Wittig dalam Produksi b-Karotena di Hoffmann-LaRoche (Swiss)

CHO + Retinal Reaksi Wittig Retinilidenatrifenilfosforana CHP(Ph)3

b-Karotena

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Reaksi Cannizzaro
I. Hanya berlaku untuk aldehida yang tidak memiliki atom H pada atom C di sebelah gugus CHO (formaldehida dan turunan-turunan benzaldehida). II. Keton tidak bereaksi.
CHO 1. OH, H2O 2. H3O+ Benzaldehida Asam benzoat Benzil alkohol
-

CO2H +

CH2OH

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Mekanisme Reaksi Cannizzaro

O O O C H OH O C OH H C H 1. 2. H3O+ Intermediat tetrahedral (teroksidasi) + H C OH H C OH

(tereduksi)

Substitusi asil nukleofilik pada turunan asam karboksilat (KO II):

O C R Y + Nu O R C Nu Y R O C Nu + Y

40

Adisi Konjugat pada Gugus Karbonil a,b-Takjenuh

O C a C C b O C C pusat elektrofilik C O C C C

Adisi langsung (adisi 1,2):

O C 1 2 Nu O C Nu H3O OH C Nu

Adisi konjugat (adisi 1,4):

4 O 3C C C 1 2 Nu O C C C Nu O C C C Nu H3O
+

O C C H C Nu

intermediat ion enolat

41

Adisi Konjugat Amina

Bila digunakan satu ekivalen amina hanya terbentuk produk adisi 1,4.
O CH3CCH 3-Buten-2-on CH2 + HN(CH2CH3)2 Dietilamina Etanol O CH3CCH2CH2N(CH2CH3)2 4-N,N-Dietilamino-2-butanon (92%) O Etanol NHCH3 2-Sikloheksenon Metilamina 3-(N-Metilamino)sikloheksanon

CH3NH2

42

Adisi Konjugat HCN

O C C Aldehida/keton C HCN O C C H C CN

Metode Nagata (1966) rendemen lebih baik.

O C H3C C H CH3 C 1. (C2H5)2Al CH3 2. H3O+ CN , toluena H3C O H3C C C CH3 CN

4-Metil-3-penten-2-on CN , toluena

H H 2,2-Dimetil-4-oksopentananitril (88%) 1. (C2H5)2Al

O H

2. H3O+

O H CN H

43

Adisi Konjugat Gugus Alkil: Pereaksi Organotembaga

O C C C 1. " R " 2. H3O+ O C C H C R

Sebagai :R- pereaksi Gilman (litium diorganotembaga).

RX 2 Li Pentana CuI 2 RLi Eter RLi + Li+XLi+(RCuR) + Li+ILitium diorganotembaga
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Contoh Adisi Konjugat Gugus Alkil

O CH3CCH 3-Buten-2-on O 1. Li(C6H5)2Cu, eter 2. H3O+ 2-Sikloheksenon 3-Fenilsikloheksanon (70%) O 1. Li(CH3)2Cu, eter 2. H2O O O O Rudyanto (2002) O O CH2 1. Li(CH3)2Cu, eter 2. H3O+ O CH3CCH2CH2CH3 2-Pentanon (97%) O

(89%)

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Adisi Nukleofilik dalam Makhluk Hidup

I. Bacillus subtilis: sintesis alanina
O CH3CCOOH Asam piruvat + NH3 NH enzim CH3CCOOH suatu imina pereduksi CH3CHCOOH Alanina NH2

Pertahanan diri Apheloria corrugata (kelabang)

NC OH H Enzim O H + HCN

Mandelonitril

RACUN

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