oc 2 (fs 2013) lecture 5 prof. boden.ethz.ch/~nielssi/download/4. semester/oc...

OC 2 (FS 2013) Lecture 5 Prof. Bode

1

Advanced Functional Group Transformations and Reactions

1 Overview of Important Concepts 1.1 Arrow Pushing Arrow pushing is a technique used to describe the progression of a mechanism. Arrows represent the movement of electrons when bonds form and break. A full arrow represents a pair of electrons (heterolytic cleavage). A half arrow represents one unpaired electron (homolytic cleavage). Full arrows start at a lone electron pair or a bonding electron pair and point to another atom or to the middle of another bond. Arrows show where electrons are going, so the place electrons are going to gets more negatively charged, while the place electrons are coming from gets more positively charged but in all cases: the total formal charge of the system does not change and the octet rule must not be violated. 1.2 Kinetics vs. Thermodynamics When a step can lead to different products via competing pathways, the composition of the product mixture is controlled by thermodynamics and kinetic factors. The product which forms faster is called the kinetic product. It has the lowest activation energy. The more stable product is called the thermodynamic product. Reaction parameters (temperature, solvent, pressure…) control the reaction pathway and thus ratios between the different products. When the products and the reactants are in equilibrium, the step is called reversible. If it is not the case, the step is irreversible. An irreversible step is thus under kinetic control. A reversible step can be under thermodynamic control. 1.3 Bond Energies Bond energy describes the amount of energy required to cleave a chemical bond. It is important to have a rough idea of these energies in order to know which bonds are more likely to be cleaved and formed when you draw a mechanism. 2 Elucidating Mechanisms In order to predict or to propose the outcome of certain reaction it is necessary to know the mechanism of the reaction. To elucidate this mechanism different techniques were developed. 2.1 Isotopic Labeling An atom in the reactant is selectively replaced by one of its isotopes. The reaction is carried out as usual, and the location of the isotopic label in the product is determined. The suggested mechanism can be supported or dismissed. In the mechanistic study of α-ketoacid-hydroxylamine ligations, many plausible pathways were excluded by a series of isotopic labeling experiments.

Bond Bond strength (in kcals/mol) Bond Bond strength

(in kcals/mol) C-H 98 N-N 38 C-N 73 N-O 48 C-O 85 C=C 147 C-F 116 C=O 178 C-Cl 81 C=N 147 C-Br 67 P=O 110 C-I 58 S=O 94

types of arrows

electron pair transfer

single electron transfer

equilibrium

resonance

reaction coordinate

thermo P

kinetic PΔΔG

ΔGT

ΔGK

E

starting material

activation energyTS

TS


2

A plausible pathway

Labeling experiment

2.2 Kinetic isotope effects (KIEs) Isotopic substitution can affect reaction rate, which gives us useful insights into the reaction mechanisms such as rate-determining step. The zero-point-energy for a C-D is lower than that of C-H. The C-D bond energy is higher than the C-H because the energy is the same at the dissociation limit. Primary KIE arises when the bond to the isotopic substitution is broken in the rate-determining step. For example, primary KIE was observed in NHC-catalyzed intramolecular Stetter reaction.

Secondary KIE is defined as the isotope effect observed when the bond to the isotopically substituted atom does not cleave during the course of the reaction, and classified into α or β depending on the length between the isotopic substitution and the reaction center.

α-secondary KIE β−secondary KIE

2.3 Isolation of key intermediates If an intermediate is stable enough to be isolated, standard characterization techniques can be used to identify it. It is important to show that the isolated intermediate is not a side product and provides the same product under the reaction conditions. If a speculated intermediate is synthesized from a different route, the synthesized compound can also be examined under the same reaction condition. In the mechanistic study of α-ketoacid-hydroxylamine ligations, the speculated intermediate was synthesized and shown to provide the product after protonation.

O

OHR1

N+R2O*

R1

O

OHNHO*

R2O*H

R1CNR2

–H2O*, –CO2R1

HN R2

O*/O*R1

O

OHO*

NH

R2H*O+

hemiaminal (I)

+H2O

-nitrone (II)

predicted product

intermediate

Ph NHOH

+

O

O

HO Ph25 °C, 3 h

d6-DMSO

Ph

N+O-

O

HO 18O-H2OPh

HN

OPh

40 °C

Ph

0% atom transfer

the plausible pathway can be ruled out

O

H/D CO2Et

O

O CO2EtN N

NPh

Bn

PhMe20 mol%

O

HO RN

RN N

H/D

O

OH/DRN

RHN N

rate-limitingrate = k[ald]1[cat]1

KIE = kH/kD = 2.62O

MeO

H(D)

O

+ HCN

MeO

H(D)

NC OH

kH/kD = 0.73

MeO

Cl

H(D)H(D)aq. CF3CH2OH

MeO

O

H(D)H(D) H2C CF3 kH/kD = 1.30

OTsCH(D)3 kH/kD = 1.89(for solvolysis)


3

Proposed mechanism

Preparation of the speculated intermediate

2.4 Kinetics The rate of a reaction depends on the energy barrier to be surmounted. This dependence is represented by a proportionality constant between concentration of reactants ([R]) and the rate constant (k). This means that the rate of reaction is time dependent, and the rate at each moment can be described as a derivative.

Reaction Reaction order Rate law Integrated rate law

A → P Zero-order 𝑑[𝑃]𝑑𝑡

= 𝑘 𝐴 = 𝑘𝑡 + [𝐴 0 ]

A → P First-order 𝑑[𝑃]𝑑𝑡

= 𝑘[𝐴] ln 𝐴𝐴(0) = −𝑘𝑡

2 A → P Second-order 𝑑[𝑃]𝑑𝑡

= 𝑘[𝐴]! 1[𝐴] = 𝑘𝑡 + 1 [𝐴 0 ]

A + B → P Second-order (two species)

𝑑[𝑃]𝑑𝑡

= 𝑘 𝐴 [𝐵] 1/( 𝐵 0 − [𝐴 0 )] ln(A 0 BB 0 A

) = 𝑘𝑡

In SN2 reactions, both nucleophiles and electrophiles are first order. In SN1 reactions, on the other hand, only electrophiles are first order. These results suggest that both reactants involve in the rate-determining step in the former reaction and only the electrophile in the latter reaction.

𝑑[𝑃]

𝑑𝑡 = 𝑘! (𝐶𝐻!)!𝑁!𝑅! [𝑂𝐻!]

𝑑[𝑃]𝑑𝑡 = 𝑘! (𝐶𝐻!)!𝑁!𝑅!

3 Reactive Intermediates Whether a reaction occurs or not, depends on the activation energy ΔG‡. The pathway to a product can have only one transition state (TS) or several. The local minimum between two TS’s is called an intermediate. The unreactive functional groups are converted during the reaction in reactive intermediates, which react further to a product. In the following, several examples are presented where relatively unreactive starting materials are activated first to reactive intermediates, which can then react further towards desired product.

N O

O

OHPh

N OH

O

O Ph

N OH+

O

O-Ph

nitrone a-lactoneoxaziridinyl acetate

amide

–CO2

Ph Ph

PhHN

OPh

Ph

Ph NHOH

+O

O

HO Ph

Me

Me Me MeMe

1.0 equiv TFA

d6-DMSO, 30 °C>95 % conversion

NH

O MeN

O

O– K+

Me

PhON

O

OMe

Me

Ph

(H3C)3N C8H19

OH

H2O +CH3OH

[First order]

[First order] (H3C)2N C8H19

(H3C)3N Ph

Ph

OH

H2O + N(CH3)3HO Ph

Ph[First order]

[Zero order]


4

3.1 Dehydration reactions In the following some examples for activation of carboxylic acids towards nucleophiles are discussed:

3.1.1 DCC amide couplings Carboxylic acids are relatively unreactive with nucleophiles due high lying LUMO and bad leaving group (OH). A solution is the use of reagents which selectively activate a carboxyl group towards nucleophilic substitution. Carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC) are frequently used for amide and ester bond formation. As a driving force for the reaction serves the formation of urea (DCU).

However, in the case of peptide synthesis the activation can leads to racemization of stereocenter at α-C position during the reaction.

E

reaction coordinate

ΔGstarting material

TS

product

E

reaction coordinate

starting material

TS 1

product

TS 2

intermediate

a) b)

ΔG

ΔG

ΔG

R

O

OH R

O

LG R

O

NuNu

NH

O

O

O

OH

O

OtBu NHO

O

O

HN

O

NH2DCC (1.1 eq.)

Mechanism

R

O

O OR

O

R' NH

R'NR

O

NCN N

NOR

O

NH

N

R'' O NH

N

RO

NR' R''H

O NH

N

RO

NR' R''

H

R''

HN

HN

O

DCC

DCU

R' NR''

HH

R' NR''

HH

CH2Cl2

activated intermediate

BuO

OO

NHN


HN

R1

R

OON

R1 O

R

-H+ON

R1 O

R

R' NHR''

ON

R1 O

Renantiomeric pure racemate

R'NO

R''R1

HN

O

R


5

Therefore reagents as HOBt, HBTU etc. were introduced as co-coupling agents. They react faster with the activated intermediate than the racemization at α-C position occurs.

Other coupling agents frequently used:

3.1.2 Acid chloride using DMF/oxalyl chloride The standard way to activate a carboxyl group is to convert it in to an acid chloride. The oxygen of the carboxyl group is a very weak nucleophile and therefore does not react with oxalyl chloride. Readily after addition of catalytic amount of DMF a reactive intermediate formed which is electrophilic enough to react with the carboxyl group.

3.1.3 Mukaiyama coupling (2-chloromethylpyridinium iodide)

OR

O

NH

N

1st activated intermediate

NN

N

OH

+

R O

ON N

N-DCU

2nd activated intermediate

R' NHR''

R'NR

O

R''HOBt

1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) hydrochloride

N C NMe

NMe

MeH

Cl

water soluble by-producteasier purification in solution phase synthesis

DIC

N C NMe

Me

Me

Meby-product soluble in organic solvents

easily removed in solid phase synthesis

NN

N

OP

N

N

N

PF6

PyBOP

NN

N

ON

N

Me Me

MeMe PF6

HBTU

R Cl

O

R

O

OH

H

O

NCH3

CH3

Cl

O

O

Cl

cat.

H

O

NMe

Me Cl

O

O

ClH

O

NMe

Me

H

O

N

OCl

O Me

Me

Cl

H Cl

N MeMe

- CO2, COCl

R

O

HO

H Cl

N MeMe

R

O

O H O

N MeMe

ClR

O

R Cl

O

H

O

NMe

Me+


regenerated catalyst

N

Me OH

O

H2N

I

NClMe

I

Et3NCH2Cl275%

N

MeHN

O

I


6

The amide bond formation follows a similar mechanistic pathway. 3.2 Macrolactonization The cyclization reactions are highly dependent on two types of energy: enthalpy and entropy. Ease of ring formation is dependent on the size of the cycle to be formed. For small and medium size rings (4, 5 and 6-membered) cyclization is favored due to the higher enthalpy over entropy. For the 8 to 13 membered rings the entropy is higher than ethalpy and therefore they are the hardest to form.

3.2.1 Yamaguchi Factorization The Yamaguchi macrolactonization is a powerful method to form macrolactones. Its exceptionally high reaction rate allow the reaction to be conducted at very high dilution, avoiding intermolecular couplings and by-products. 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent) forms a mixed anhydride with a carboxylate, activates more the electrophilic carbon of the carboxyl group for a nucleophilic attack. One of the carbonyl groups is shielded by two chlorine atoms at positions 2 and 6. Therefore the attack of the nucleophile occurs exclusively at the less hindered position.

Mechanism

R

O

OH NClMe I

NClMe

ONEt3

-NEt3.HCl

SNAr

I

R

OH NMe

O

I

R

O

R' OH

NMe

OO

ROR' H

I

R'OR

O

H

NMe

O

IR'OR

O NMe

HO

I


COOH

O OMeMe Me

O

OMe

Me

Me

OH

Cl

ClCl

O

Cl

NEt3

(1.5 eq.)

(13 eq.)

1)

THF, rt

2)

(DMAP, 6 eq.)

N

N MeMe

toluene, 0.001M, rt

OOMeMe

Me

O

OMeMe

Me

OO

OH

O

O

O

OH -H2O

lactone


7

As a first nucleophile serves N,N-dimethyl pyridine (DMAP, Steglich base), which activates the carbonyl group for the intramolecular attack of hydroxyl group.

4 Mitsunobu Reactions Activation of alcohols towards nucleophiles:

The Mitsunobu reaction is a modern SN2 reaction on alcohols involving in-situ activation using phosphorus chemistry.

Mechanism

OH

O

On

O

Cl

Cl

Cl Cl

OH

O

OO

ClCl

Cl

Cl

OH O

O

+ NEt3

- NEt3.HCl

NNMe

Me

O

Cl

Cl

Cln n

N NMe

MeOH

O

O

OCl

Cl

Cl

n

-

O O

Cl Cl

Cl

OH

O

N

NMe

Me

n

O

N

Hn

ONMe

Me

- DMAP

- H+OO

n


tetrahedral intermediate mixed anhydride

OH

O

O

O

Cl

Cl

Cln

N NMe

Me

R OH R LG R NuNu

Me

Me

Me

OH

O2N

O

OH

EtOOCN N

COOEt

(DEAD, 4 eq.)

(4 eq.)

PPh3 (4 eq.)

THF Me

Me

Me

O

O

O2N

Mechanism

EtOOCN N

COOEt

PPh3

EtOOCN N

COOEt

PPh3

H NuEtOOC

N NCOOEt

PPh3

HNu

R

OH

R'

EtOOCN N

COOEt

H

H

R

O PPh3

R'Nu

SN2R

Nu

R' PPh3HO

betaine


8

The pKa value of the NuH plays very important role, which is deprotonated by the betaine. If the proton of NuH is not acidic enough, the reaction does not occur. The pKa values are preferably below 11, which cover a broad spectrum of different types of nucleophiles, e.g. carboxylic acids, indoles, heterocycles and thiols. The driving force of the reaction is the formation of triphenylphosphine oxide (P=O bond 110 kcal/mol). The alcohol undergoes a complete inversion of configuration. When a carboxylic acid is used as nucleophile, the resulting ester can be hydrolyzed yielding the starting material with inversion of configuration.

Other possible nucleophiles:

DPPA serves as an azide group (N3

-) transfer reagent. Phthalimide is a masked primary amine which is used in Gabriel synthesis of primary amines.

A related reaction is the Appel reaction, in which an alcohol is substituted by a halogen. The driving force of the Appel reaction is the formation of P-O double bond (P=O 110 kcals/mol).

5 Phosphorous Ylide Chemistry Transformation of aldehydes to olefins:

5.1 Wittig Reaction The Wittig reaction is a powerful method for the formation of alkenes, involving a phosphorous ylide (formed by deprotonation of a phosphonium salt with a base) and an aldehyde or a ketone.

R

OH

R'

1) DEAD, PPh3, AcOH

2) K2CO3, MeOH R

OH

R'

azides imides

HN3

O PO

ON3

(DPPA)

NH

O

O

dicarbonyls thiols, alcohols

R

O

R'

O ROH

RSH

synthon N3- RNH2

Mechanism

PPh3

Br PPh3 Br PPh3

RO PPh3

PPh3O

BrBr

BrBr Br

Br

Br R O H CBr3R O

BrR Br

Me OH

CBr4 (1.1 eq.)PPh3 (1.1 eq.)

CH2Cl2Me Br

R H

O

R H

R'Hor

R H

HR'

E Z


9

The four-membered intermediate, an oxaphosphetane, which is formed via [2+2] or stepwise mechanism from phosphorous ylide and an aldehyde , undergoes retro-[2+2] ringopening, forming corresponding akene and phosphorous oxide as a by-product. There are 3 different types of ylides, depending on the nature of the R’ and R’’ substituents:

In the case of stabilized ylides, oxaphosphetane formation is reversible and equilibrates to the most stable structure (anti), affording mainly the E olefin (reaction under thermodynamic control). In the case of non-stabilized ylides, the oxaphosphetane formation is irreversible, the syn oxaphosphetane is formed preferentially, affording mainly the Z olefin (reaction under kinetic control). See section 1.2 5.2 Horner-Wadsworth-Emmons reaction (HWE) The HWE reaction is a modification of the Wittig reaction affording α,β-unsaturated carbonyls with mainly E selectivity.

Mechanism

PR RR

HR''R' X B PHR RR

R''R'

-BHX

R'''

O

H PR RR

R''R' O

R'''

PRRR

R''R'

O

R'''R'

PR RR

O R''

R'''H

PR RR

R'' R'

phosphorous ylide

phosphorane

betaine oxaphosphetane

PR3

HR'

R'''

O

H

H PR3

R'H O

R'''

PR3R'

OR''' - R3PO

H

HR'

R'''

HR3P

R'R'''O

H

R3P R'

O R'''- R3PO

H

R' H

R'''

(E)-Alkene (Z)-Alkene

PPh3Br H

O

THF

Ph

65%

anti syn

Selectivity

Kinetic product(lowest activation energy)

thermodynamic product(most stable)

phosphonium salt

PPh3

phosphorous ylide

n-BuLi

PR RR

R'' R'phosphorane

R'''

O

H

PRRR

R''R'

O

R'''R'

PR RR

O R''

R'''H

oxaphosphetane

+

+

+

Stabilized ylides Semi-stabilized ylides non-stabilized ylides

R' or R'' = EWG (CO2R, SO2R...) R' or R'' = Aryl, alkenyl... R' and R'' = alkyl

mainly E olefins mainly Z olefinspoor stereoselectivity


10

If R’=H, betaines and oxaphosphetanes intermediates equilibrate to the most stable anti oxaphosphetane, yielding mainly E alkenes (see the Wittig reaction mechanism). Still and Gennari have introduced a modification of this reaction using phosphonate with EWG under strongly dissociating conditions affording nearly exclusively Z alkenes.

EWG on the phosphonate accelerates elimination relatively to isomerization. 5.3 Examples

6 Sulfur Ylide Chemistry Transformation of ketones and aldehydes into 3-membered rings:

Two of the most widely used reagents are dimethylsulfonium methylide (1) and dimethylsulfoxonium methylide (2). 2 is more stable than 1. Addition of 2 to carbonyls is reversible.

6.1 Corey-Chaykovsky Epoxidation The reactions of sulfur ylides with carbonyl electrophiles give epoxides unlike the reaction of phosphorus ylide, due to the lower affinity of sulfur for oxygen.

TBDMSO

OTBDMS

O

Me

HH

HMeO P

O

OMe

O

O

NMe

NaH

THF, rt

TBDMSO

TBDMSO

MeH

H

H

ON

O

MeMechanism

PRO

ROR'

EWG

B

-BH

R''

O

H PRORO

GWER'

O

R''

PRO

GWER'

O

R''R'

PO OROR

O EWG

R''H

OH P

RORO

R'

EWG

O O ORO

O

H

PO

OMeF3CH2COO

F3CH2CO

KHMDS, 18-Crown-6THF, -78˚C

O OMe

95% yield50:1 Z:E

Me

MePPh3

3n-C13H27CHO

MeMe

3

Me

11 91% Yield, all Z

EtO PPh3

O

OHC

OO

Me MeO

O

Me Me

EtO2C96% Yield, all E

(EtO)2PO O

OEt

NaOEt, EtOH

RCHOR

O

OEtO

OEt

R

E Z

AldehydeRatio(E:Z)

PhCHO

n-PrCHO

i-PrCHO

98 : 2

95 : 5

84 : 16

R

O

R R R

O

R R

Oor

H3CSCH3

CH2 H3CSO

CH2CH31 2


11

6.2 Corey-Chaykovsky Cyclopropanation The reactions of sulfur ylide (dimethylsulfoniummethylide) with α,β-unsaturated carboxyl compounds give epoxides, but the reactions of dimethyloxosulfoniummethylide with α,β-unsaturated carboxyl compounds give cyclopropanes.

Phosphorus forms very strong double bond to oxygen. This leads to another mechanism via oxaphosphetane as intermediate and formation of an olefine. Sulfer ylides react with ketones to epoxides with formation of dimethyl sulfide as a by-product.

6.3 Epoxide to Allylic Alcohol

Sulfur ylides also react with epoxides to provide homologated allylic alcohols.

7 Proline-Catalyzed Reactions The equilibrium between ketone and enol form usually lies on the side of ketone. In enamine-iminium ion case the equilibrium is shifted to the side of enamine, which is formed from ketone and a secondary amine.

Enamine is more nucleophilic at α-C carbon as ketone, iminium ion is more electrophilic as a ketone.

Otert-Bu tert-Bu

H3CSCH3

CH2

Otert-Bu tert-Bu

H3C SO

CH2H3C

O

O

R

O

RH3CSHCH3

CH2 R R

O(H3C)2S

R R

O + Me2S

Ph

O

Ph Ph

O

PhPh Ph

O H3CSCH3

CH2H3C

SO

CH2H3C

(H3C)2 SO

CH2 Ph

O

PhPh

O

Ph

SH(H3C)2

O

Ph

O

Ph

H3CO

CH3S CH2H3C

(2 equiv.) H3COH

O

R2R1

CH2S CH3H2C

R2R1

O

H

SH3C CH3

CH3S CH3H2C

R2R1

OH

ketone Enol form %

acetone 0.00025 butan-2,3-dione 0.0056 cyclohexanone 0.02

Me

O

Me NH Me

N

Me

N

Meiminium ion enamine

+

Me Me

O

Me

OH

ketone enol


12

7.1 Proline Proline is reported to catalyze many transformations. This amino acid has a secondary amine moiety and reacts with a carbonyl compound to form an enamine intermediate, which works as a nucleophile.

L-Proline is used in catalytic amount (30 mol%) and the iminium ion intermediate is hydrolyzed back to ketone and L-Proline.

7.2 Cascade Reactions A cascade sequence sometimes occurs with a substrate that has multiple functional groups. In the following example, proline catalyzes both an intermolecular Michael addition and an intramolecular aldol reaction to provide the Wieland-Miescher ketone, which is a versatile synthon in natural product syntheses.

H3C CH3

OL-Proline(30 mol%)

CH3

OOH

O2NO2N

H

O

+

NH

CO2H

N CO2H

CH3CH3HR

ON

O

OH

R

N CO2HOH

H3C CH3

O

H2O

R H

O

H2O

R CH3

OH O

Mechanism proposed by List et al.enamine

N CO2H

CH3iminium ion

H3C

O+ H3C

O

O

CH3O

O

L-Proline

Wieland–Miescher ketone

NH

OOH

H3CO

O

H3C

O

N OH2N

H3C

O

NH3C

O

H3C

O

N

O

H3CO

H3C

H OH

OH

N

O

H3CO

H3C

OH

O

H3CO

H3C

O

Intermediate

NH

CO2H

O

H3CN

H2C

OCH3O

OHNdesymmetrization

CH3O

OHOH

CO2H CO2H CO2H

CO2H

CO2HHO2C

CO2H

iminium ion enamine

NH

COOH

L-Proline

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