Wrintig Reaction of Semi-Stabilised Ylides with Benzaldehydes Studies on the Effect of ortho Position

Introduction

            In organic chemistry, Wittig reaction has attracted both immense interest and controversies among synthetic chemists. It continues to generate contentious issues especially where lithium salt-free reactions are involved. Much of these controversies arise from the original Wittig proposal that the reaction progresses via oxaphosphetane, an idea that was vehemently opposed almost immediately [1]. The topic has received several excellent reviews concerning reaction mechanisms [2, 3].  Mutual consensus among researchers is that all Wittig reactions share a common experimental effect for all phosphonium-based ylide reactions. Similarly, selectivity is consistent for cis-oxaphosphetane together with its derivative products such aserythro-β-hydroxyphosphonium and Z-alkene salt in reactions where aldehydes bearing a heteroatom on the β-position as a substituent are involved. This effect usually operates for both aliphatic aldehydes and benzaldehydes, while in the absence of a substituent heteroatom they do not operate [4].

 

            Following the discovery of shared common effect for ylide type reactions, strong arguments have emerged on whether there is also a common operational mechanism for all Wittig reactions involved in Lithium-salt free reactions. Different researchers [5, 6] have come to a conclusion that the reaction mechanism involves the [2+2] cycloaddition based on the strength of confirmatory experimental evidence supporting this argument.  For instance, the most notable effect is ‘cooperation’ for ortho-substituted ylides particularly involving semi-stabilized cases. Therefore the cycloaddition mechanism is re-affirmed as the reason for the cooperative effect in semi-stabilized ylide Witting reaction. This effect has also been demonstrated in reactions involving ylide derivatives of triphenylphosphine under aqueous conditions [7]. This finding suggests existence of a kinetic control during the reaction operation in both cases.

Background

            Synthetic chemists continue to face a permanent challenge regarding carbon-carbon bonding.  The 1953 Wittig reaction (illustrated in Eq.1) succeeded in forming C=C by exploiting efficiency, reliability, and stereoselectivity.

………………… (Eq.1)

 

  

The reaction in Eq.1 above was a revelation as it set the platform for synthesis of Vitamin A by the BASF Company soon afterwards.  This co-joined academia and industry in a remarkable cooperation display.

            Wittig reaction comprises two basic steps: Step 1 is the generation of a ‘phosphorous ylide’ using a base and phosphorium salt. Step 2 is a follow-up reaction of the generated phosphorus ylide reacts with a carbonyl group producing phosphane oxide and olefin.  The produced alkene (olefin) is thus the product of ylide (generated from phosphonium salt) reaction with ketone or aldehyde [9]. The resultant alkene geometry is largely dependent on the ylide reactivity as will be demonstrated in subsequent sections bellow. Equation 2 gives a summary of the two steps:

……………………………Eq.2

 

            As aforementioned, the reactivity of the generated ylide depends mainly on the nature of the group that is attached to ylidic carbon atom. For example, substituent’s that exhibit strong conjugation such as CN, C(O)R stabilizes the phosphorous ylide thus making it easy to isolate due to less reactivity. Recent literature describes the stabilizing nature of ylides with growing consensus that the P=N and P=O bonding possessing polar σ-bonds that covalently combine with electrostatic interactions.  However, new evidence suggests that the negative hyperconjugation witnessed in ylides may be due to the existence of lone pair on the ylides’ alpha-carbon within the σ* orbitals.  The lone pair is believed to be responsible for the bonding with phosphorous and its substituent’s despite P-C bond being heavily polarized towards C [10, 11, 12]  Because of this unique characteristics, ylides are categorized as “stabilized” ylides,   “semi-stabilized” ylides (featuring substituent’s showing mild conjugation such as allyl, Ph), and “non-stabilized” ylides which lacks all the functional features named above.  Both non-stabilized and semi-stabilized ylides are very unstable to isolate hence produced in situ following immediate reactions with ketone or aldehyde [13].

The three ylide classes

The present report focused more on the trends of Z/E variability of semi-stabilized ylides shown bellow.

            The fact that Z alkene that is thermodynamically unstable is capable of producing unstabilizedylides has generated investigative interests. At present, Wittig reaction and the derivative products are widely researched for academia and industry. Among major focus by industry is development of aroma and fragrance compounds, carotenoids, hormones, steroids, fatty acid derivatives, pheromones, prostaglandins, terpenes, and many other synthetic and natural olefinic compounds of interest to chemists. However, Wittig reaction’s stereoselectivity control remains a major concern to chemists. The present study delves in the discussion of the importance of Wittig reaction withspecific focus onsteroselectivity and reaction mechanismpatterms [14].


 

Wittig Reaction Mechanism

            As stated earlier, stereoselectivity plays a critical role in ylide Wittig reactions.  The ylide substituent’s determines the selectivity: stabilized ylides favor E-alkenes; non-stabilibed favor Z-alkenes; while semi-stablized generates both mixtures of E- and Z- alkenes [15]. This makes semi-stabilized ylides of greater importance in the present discussion. The E/Z ratio is mainly affected by carbonyl substituents, reaction conditions, pressure, temperature, and solvent (Eq. 3)

………………………….…….. Eq. 3

 

            Historically, the reaction mechanism was believed to follow reversible nucleophilic addition of ylide carbanion on to carbonyl group species, in the process generating betaine intermediates [14]. The intermediate betaine is then cyclised to respective oxaphosphetane (OPA), as the phosphine oxide is dissociated leaving the desired alkene/olefin (Eqs. 4, 5, 6).

……Eq. 4

 

Formation of strongly stable phosphine oxide drives the forward reaction as follows:

…………………………….. Eq. 5

 



Formation of the z-alkene occurs rapidly depending on the ylides reactivity causing the ring open as illustrated in Eq. 6

…………………….. Eq. 6

 

            However, modern thinking proposes a different version, suggesting that oxaphosphetanes could be the intermediates with betaine serving as a transition state model. This argument arises because betaine existence is yet to be fully established despite playing intermediary zwitterionic role in Wittig reaction involving bases such as NaOme, NaH, and NEt3 [15]. Likewise, OPAs have only been detected in reactions involving aldehydes with alkyl substituent’s but none in benzaldehydes which are reacting partners [16]. Based on the similar theme, Wittig reaction has provided a wide scope of alternate reactions. One example is the Schlosser-Wittig reaction [17] where the olefin stereochemistry is anticipated to be reversed in the presence of organolithium base and lithium salt.

The ortho position cooperative effect

            The increase in Z-selectivity in semi-stabilized ylides is attributed to the ortho-halo species co-operative effect. These effects are experimentally significant enough to be interpreted using Wittig mechanism model [18].  Experiments have demonstrated that Wittig reaction involving benzylidenetriphenylphosphrone and benzaladehyde results to none or partial z-selectivity [19], however, when both the aldehyde and ylide have ortho-substituents, their selectivity shifts in either direction of the E/Z ratio (Eq. 7). Therefore, substitution at ortho-position for semi-stabilised ylides with benzaldehydes affects the phosphorus reactions in an inexplicable manner. For example, one study demonstrated in reactions involving meta- and para-substituted benzaldehydes, substitution of ortho-methoxy substituent’s on the aryl ring attached to phosphorus  results to higher E-selectivity [20]

……………………… Eq. 7

 

            On the contrary, Wittig reaction involving benzylidenetriphenylphosphorane with halo and methoxy substituent’s on benzaldehydes results to Z-stilbenes are the predominant derivatives.  These findings could be explained as due to the chelating effects when filled p-orbitals interact with phosphorus’ carbonyl oxygen atom forming σ-complex of ylide and aldehyde [21]. The ortho-position thus exerts its effects based on similar explanations.

            Experimental analysis of Wittig reaction products show that keto-stabilized ylides with benzaldehydes substituted at ortho- position yield a relatively higher content of Z-alkene (50%) compared to similar ylide analogous reactions with benzaldehyde itself [22]. The unusual Z-alkene content is further witnessed through a cooperative effect if the augmented ylide has higher steric bulk at alpha-position.  The experimental results show consistence with prior observations for all ylide reactions with β-heteroatom bearing aldehydes. This cooperative effect was previously seen in semi-stabilized ylides, however, it has been extended to other ylide form including the stabilized ylides and non-stabilized N-sufonyl amines [22, 23].  The cooperative effect coupled to the observed anomalous Z-alkene content increase can be rationalized through Wittig reactions involving [2+2] cycloaddition mechanism as shown Scheme 1.1 below:

Scheme 1.1 cooperative effect resulting to anomalous Z-selectivity

            Available literature show that the Z/E mixture for semi-stabilized ylides depends on reaction conditions [25, 26]. Thus changes could occur that shifts the Z/E ratio due to fragility of E-isomers particularly in the presence of acids such as benzoic acid (Eq. 8)

……………. Eq. 8

 

Where, the X, Y, and Z groups in the Wittig reactions (Eq.8) are alkyl, alkoxy or aryl. R2 may be vinyl, aryl, alkyl or any electron withdrawing group.Hence the stilbenes Z/E ratio produced frombenzylidenemethyldiphenylphosphoranes reaction, a derivative of phosphonium salt with ortho-substituent at X with ortho-substituent Y benzaldehydes.


 

Modern mechanistic interpretation

            The Z/E ratio in reactions involving semi-stabilized ylides with Benzaldehydes have been investigated with intend of establishing the kinetic OPA selectivity during the formation step in Wittig reactions [24]. As seen from Eq. 6 above, the Z/E ratio must be reflective of the cis/trans ratio during OPA kinetic control.      

            The general consensus is that the cis/trans ratio in OPA formation step in Wittig reaction is reflective of the alkene Z/E ratio. Decomposition of OPA is usually irreversible and streospecific, with cis-OPAs having relatively higher energy compared to trans-OPAs. The kinetic control mechanism operates in Wittig reactions involving semi-stabilized ylide derivative of methyldipheyl-phosphine (see Scheme 1.2). The decomposition has been demonstrated to be stereospecific for OPAs and betaines that are transiently formed in experimental β-HPS deprotonation [8, 9, 10].

Scheme 1.2 The kinetic control mechanism involving semi-stabilized ylide derivative of methyldipheyl-phosphine

From the Wittig reaction scheme above, the different ylides and corresponding adehydes react under specified conditions resulting to varying Z/E ratio as shown in Table 1 bellow.

Table 1 Z/E selectivity for different Witting reactions and varying conditions

(The ratioc e.g 11c, 12c, 22c, and 27c denotes Ylides generated at 20oC from the parent phosphorium salts by dry THF while under NaHMDs treatment, the rest were at treated at -78oC)

Comparing reactions from Eq. 8 and table 1 Z/E rations, the following deductions were made:

  1. If both benzaldehyde and benzylidenemethyldiphenylphosphorane  are unsubstituted, the ratio of stilbene produced is  85: 15 respectively.
  2. If benzaladhyde with ortho-heteroatom substituent reacts with benzylidenemethyl-diphenylphosphorane there is a higher selectivity of Z-isomer where benzaldehyde reactivity is higher at carbonyl while 2-methoxybenzaldehyde has less reactivity, while iodobenzaldehyde displays similar reactivity as benzaldehyde.
  3. Reaction of ylides bearing ortho-heteroatom substituent with benzaladehyde demonstrates a relatively low E-selectivity 
  4. On the other hand, reactions of ortho-substituent bearing ylides on the benzylide with benzaldehyde display a relatively moderate to higher E-selectivity. The observed increase in E-selectivity is almost parallel to increase in ortho-subsituent activating ability. This means ylides that are more reactive gives higher E-selectivity.
  5. For ortho-substituted benzylides, reaction with benzaladhydes bearing ortho-heteroatom substituent displays even higher Z-selectivity compared to (b) above. This can be explained based on the electron withdrawal bearing aldehydes hence higher reactive compared to benzaldehyde which is electron donor hence less reactive.

            The general deduction from the cooperative effect of ortho-positioned substituent as seen in (a) to (d) is that unsubstituted benzylides show greater z-selectivity attributed to the steric effect. This is because whether the ortho-subsituted ylide is a lone-pair or not, the ylide still operates. On the other hand, the same ortho-subsituted bensylide can react with benzaldehyde at moderate to greater E-selectivity because of the latter’s TSs geometry which is different compared to ortho-heteroatom substituent benzaldehydes [25]. 

The TS geometry diagram showing Wittig reaction coordinates during cis-OPA formation

            As seen from the activation energy diagram above, the cycloreversion barrier for cis-OPA formation when ylide reacts with aldehyde must be surmountable.  This is because, aldehydes bearing β-heteroatom substituents must gain sufficient free energy similar to the OPA intermediates in the analogous reaction species where the aldehyde lacks the substituted group. The assumption is that the cis-OPA is disfavoured thermodynamically compared to its trans-isomer is such reactions hence activation energy for cis-selective TS is lower during OPA formation hence the E-selectivity [26].

            On the other hand, presence of ortho-heteroatom on benzaladehyde acts as inducer for higher Z-selectivity due to electronic effect but not steric [27]. Similarly, the electronic effect acts via space, not through electron donation or withdrawl in the benzaladehyde aromatic ring [28].  Hence, we conclude that, presence of ortho-substituent alone on benzaladehyde partner may be necessary but has no capacity of inducing Wittig reactions Z-selectivity.  The following scheme 1.2 summarizes these observations.

Scheme 1.2 Reactions of aldehydes with a ortho-substituent

Where: (a) and (b) show varying perspectives for cis-selectivity due to the phosphorus and hetero-atom bonding. In this case, the ortho-substituent is oriented in ways that minimizes steric interactions at 2-3 by avoiding R3 phosphorus substituents. (c) Shows a trans-selective Wittig reaction where bonding between heteroatom and phosphorus greatly suffers from the 2-3 steric effects [29].


 

Conclusion

            Georg Wittig reported the first Wittig reaction in 1953, setting forth the continuing controversy and interest in reactions leading to olefin generation to date. Wittig reaction plays a central role in alkene preparation from reaction of ketone or aldehyde with ylide generated from phosphonium salt. The resultant alkene geometry is highly dependent on the ylide reactivity.  For stabilized ylides, the R is Ph thus less reactive due to the alkyl group giving E-alkenes. On the other hand, non-stabilized ylides gives Z-alkenes, while semi-stabilized ylides gives a mixture of Z/E whose ratio is dependent on various factors including reaction conditions and Z- / E- stereo-selectivity. Lithium salts have been known to exert stereochemistry effect on Wittig reactions. However, NMR experiments give alternative views on the reaction mechanism particularly regarding the ortho-position on lithiated phenyl group. This report, reached a general deduction that the cooperative effect of ortho-positioned substituent is responsible for Z or E-selectivity.   

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