Wittig reaction
The Wittig reaction is an organic chemical reaction that serves the formation of C = C bonds and is named after its discoverer Georg Wittig. It can be used carbonyl compounds (aldehydes or ketones) olefinieren with phosphorus ylides with substitution of the carbonyl oxygen to alkenes:
As Olefinbildungsreaktion it has great importance in laboratory and industry. The Wittig reaction is a widely applicable method for the synthesis of olefins and tolerates a variety of functional groups. As disturbing for the Wittig reaction normally only prove quite acidic functional groups such as carboxylic acids or 1,3- dicarbonyl compounds.
- 4.1 Wittig reaction generally
- 4.2 Wittig reaction, stereochemical aspects 4.2.1 possibilities of varying the reactivity of the oxaphosphetane
- 4.2.2 Multi-stage (less reactive components)
- 4.2.3 Concerted ( reactive components)
- 7.1 In other carbonyl compounds and heterocarbonyl
- 7.2 arsenic ylides
General
In the Wittig reaction, both inter-and intramolecular variants are known. The reaction is regioselective, that is, the newly formed carbon-carbon double bond can be found at the site of previous carbon-oxygen double bonds again. As a carbonyl component are aldehydes and ketones in question, which aldehydes are more reactive and less sterically hindered ketones can be selectively olefinated towards sterically hindered ketones. Carboxylic acid esters are virtually inert in a Wittig reaction.
A disadvantage is the principle little pronounced (E, Z)- selectivity, but which can be controlled by appropriate reaction conditions. Due to its high tolerance to functional groups, the Wittig reaction may also bring the Wittig reagent, a plurality of functional groups themselves.
Use is the Wittig reaction in the synthesis of natural substances such as olefinic vitamins A and D, carotenoids ( β -carotene, see below), squalene, unsaturated pheromones, insect hormones, fragrances and prostaglandins.
History
Discovery
Wittig has received a zwitterion in his experiments to quaternization of the main group elements, which had remarkable properties.
In the presence of carbonyl compounds, they reacted smoothly with the carbonyl carbon to form a carbon - carbon double bond and triphenylphosphine oxide.
Wittig published this in 1947 at the University of Tübingen discovered novel reaction under the heading About triphenylphosphine - methylene as olefin-forming reagents and called this reaction henceforth carbonyl olefination. However, the name Wittig reaction became common later. Today, in general, the Triphenylalkylphosphoniumsalz is used as a Wittig salt in this reaction, and is obtained as a by- product triphenylphosphine oxide.
The Wittig reaction quickly proved to be very versatile and universally applicable. Georg Wittig in 1979 awarded the Nobel Prize for Chemistry.
First industrial applications
With enthusiasm, BASF took note of the new method. You allowed it to an existing element of synthesis ( derivative of ( 2E, 4E )-3 -methyl- 5-( 2,6,6- trimethylcyclohex -1 - en-1- yl ) pentane ) with the easily accessible (2E, 4E, 6E ) -2,7 - dimethylocta -2 ,4,6- trienedial link to β -carotene. Only three years after the publication of a Wittig patent was filed. (BASF)
Production of the ylides
Trisubstituted Phosphoralkyle / aryls can be quarternisieren in an SN2 reaction. Triphenylphosphine (1) reacted with, for example, ethyl bromide (2) with the formation of the phosphonium salt through ethyltriphenylphosphonium bromide ( 3) to a 4 and a ylide ylene:
Triphenylphosphine (1) and ethyl bromide (2 ) are heated in the autoclave in benzene for 20 hours at 130 ° C. For cooling, the crystalline phosphonium salt falls off ( yield 90 %).
Phosphines are good nucleophiles but poor bases. For this reason, the SN2 reaction competing E2 elimination is almost completely suppressed. Thus, for most primary and secondary alkyl halides converted in good yields into their phosphonium salts.
In contrast to the mostly isolated phosphonium ylides produced therefrom by the deprotonation at the α - C atom are usually further reacted directly.
Under inert gas in the DMSO Ethyltriphenylphosponiumbromid ( 3) is deprotonated with sodium hydride.
It is a neutral phosphorus compound to the outside is formed which is called 4 ylide or phosphorane. This Betaine can, however, also express ylene. Are other common Deprotonierungsreagenzien phenyllithium or n-butyllithium.
A modern and simple method for the deprotonation of the phosphonium ion from lithium -free conditions, the use of potassium tert- butoxide in THF or sterically hindered carbonyl group in toluene. Here, the Wittig salt can be dry mixed in equimolar ratios with the base and are mixed with the solvent, which is a simple -to-use alternative to the instant ylide. Phosphorus ylides can also be obtained by carbene addition to phosphines.
Mechanisms of the Wittig reaction
The mechanism of the Wittig reaction can be considered in general or from a stereochemical point of view.
Wittig reaction generally
The following mechanism explains the general Wittig reaction with phosphorus ylides to react with the carbonyl compounds to olefins.
The negatively charged carbon atom of the phosphorus ylide 5 attacks the carbonyl of the starting material and there is a phosphorus - betaine 6 further oxaphosphetane to 7, a four-membered ring, reacts. Finally, this is divided into the 8 alkene and triphenylphosphine oxide 9, due to the strong phosphorus-oxygen double bond.
Wittig reaction, stereochemical aspects
Overall, the exact mechanism is not yet clearly understood, and it runs depending on the substituents different from. For the most part, the reaction proceeds in several stages; individual intermediate compounds can be isolated. In reactive ylides / carbonyl compounds of the attack of the carbanion and the formation of the Oxaphosphetans done in concert according to the Woodward -Hoffmann rules. There is also evidence that in the presence of very large substituents (high steric hindrance ), the reaction proceeds via free radical levels (SET single electron transfer ) passes.
Already in the formation of the betaine is determined whether the alkene (E ) - or ( Z) - configured. The first step, however, is partially reversible.
- In reversible addition the thermodynamically more stable adduct is formed (thermodynamic reaction control) in these cases.
- In irreversible addition, the product is formed, the faster forms ( lower activation energy, kinetic reaction control).
Shortly after the discovery it was realized that the Wittig reaction usually is fairly diastereoselective. Depending on the reactivity of the ylide / carbonyl components used, the diastereoselectivity the yield ratio of the isomers can be selectively changed ( both the ylide and the carbonyl compound ), and the reaction conditions, by selection of the substituents. Since the reactivity of the carbonyl is added to the rule, one tries to influence the diastereoselectivity of the adjustment of the reactivity of the ylide. General:
Possibilities of varying the reactivity of the oxaphosphetane
The destabilization can be done at the phosphorus with π / σ - donors by replacement of the substituents. Are then formed generally in high yield, the (Z)- olefins.
The stabilization can be carried out at phosphorus with π / σ - acceptors by replacement of the substituents. Are then formed generally in high yield, the (E)- olefins.
Multi-stage (less reactive components)
Is initiated the reaction by the attack of the carbanion to the positively polarized carbonyl carbon atom and the formation of the betaine. The carbonyl compound is prochiral in most cases, that is, in the betaine formation is a chiral newly formed, depending on the application side ( pro-R or pro-S ) (R) - or (S) - is configured.
The carbanion of the ylide is also prochiral. It is therefore an intermediate to form a compound containing two adjacent chiral carbon atoms. Depending on the arrangement of the substituents leads to two different forms, which can be attributed to the carbohydrates Threose and erythrose. To name one assigns the substituents on the size. If there is a conformation in which the large, medium and small substituents ( by rotation about the CC axis ) in each case against, one speaks of the erythro form, alternatively of the threo form. Going through the betaine intermediate could be detected by isolation of stable representative.
The betaine across the responding conformers that allows thermal [2 2] to the cyclic Cyloaddition oxaphosphetane. The existence of the four-membered ring intermediate could be detected by 31P NMR spectroscopy. The oxaphosphetane formed at -80 ° C and is stable at these temperatures. On warming to 0 ° C it decomposes.
With a retro -[2 2 ] cycloaddition leading to the formation of triphenylphosphine oxide and the (E)- alkene.
Concerted ( reactive components)
For non- stabilized ylides, the reaction proceeds rapidly. By Coulomb attraction particles are approaching orthogonal ( respectively the positively polarized atoms attach to each negatively charged at ). At the same time the "big" methyl groups for steric reasons be positioned as far away from one another. The bond is formed by torsion of the transition complex and concerted [2s 2 a] cycloaddition ( disrotatory ring closure ). The betaine intermediate is effectively bypassed.
About a " twisted " four-membered ring (twisted ) eventually forming the Z- oxaphosphetane.
Side reactions
Non- stabilized ylides are unstable to oxygen and water. Produced by hydrolysis of an ylide and a phosphine oxide, a hydrocarbon.
By partial reaction with oxygen ( or by adding oxidizing agents ) can be re-oxidize a portion of the ylide to the carbonyl compound. This carbonyl compound reacts with another ylide to give an alkene.
Typically, these side reactions are undesirable and ausbeutevermindernd therefore is carried out under inert gas and with exclusion of moisture. Some of these reactions are also used preparatively.
Enantioselective Wittig reactions
By using chiral phosphorus ligands achieved consolation and Curran in an intramolecular Wittig reaction an enantiomeric excess (ee) of 30-40%. See there.
Wittig -like reactions
In other carbonyl compounds and heterocarbonyl
Phosphorus ylides to react in a similar manner with other carbonyl compounds as aldehydes or ketones, for example, ketenes, isocyanates, anhydrides, and various imines.
Arsenic ylides
The homologues of phosphorus forms like this Arsonium quaternary salts, which can also be deprotonated with bases in the α -position. These arsenic ylides behave in the carbonyl olefination as nitrogen ylides.
Examples
The versatility of the Wittig reaction is shown in the following figure with a few examples:
Boundaries of the Wittig reaction
A disadvantage of the Wittig reaction is its restriction to aldehydes and ketones ( see exceptions above). Carboxylic acid derivatives are virtually inert to ylides. The Wittig reaction still requires basic conditions, can initiate side reactions such as elimination or racemization. Olefination alternative example, in the titanocene compounds ( see Tebbe reaction).
Alternative to the Wittig reaction
Peterson olefination, the Julia olefination and the Tebbe reaction. Moreover, the metathesis.