Wadsworth-Emmons Cyclopropanation Response | Analysis


This project aims to look at the development of the Wadsworth-Emmons cyclopropanation effect and compare it to substitute ways of cyclopropanation to be able to comprehend why it may be used preferentially. Current applications of the WE cyclopropanation effect are explored to start to see the efficacy and yield that effect.

Key of Abbreviations

Seen below is a assortment of all abbreviations used within this task and their subsequent meaning.

 3: Tertiary

Bn: Benzyl group

CCR: Corey-Chaykovsky Reagent

d. e

DME: Dimethoxyethane

e. e

Et: Ethyl group

EWG: Electron Withdrawing Group

HWE: Horner-Wadsworth-Emmons

iPr: isopropyl

Me: Methyl


Ph: Phenyl group

THF: Tetrahydrofuran

WE: Wadsworth-Emmons

1: Introduction

Cyclopropane was used as an anaesthetic until it was discovered to be highly reactive and dangerous when coupled with air. The reactivity of cyclopropane is mainly due to the high amount of band pressure and the bond strength between your carbons being weaker than normal carbon bonds, allowing the diamond ring to open easily. Cyclopropane structures tend to be found within chemical substances in nature (physique 1. ) that are observed to have medicinal and commercial applications, e. g. degradable insecticides such as the pyrethroid family that are less dangerous to other pets or animals in the environment, . Cyclopropanation can also produce a volume of hallucinogens and opoid drugs that are most widely used recreationally for there results on individuals mental and visual belief, exploiting their psychedelic properties. This sort of use has historically been seen within Native North american tribes and ancient civilisations. Just lately more research demonstrates they may potentially be useful in restorative doses in the treating pain, depressive disorder, alcoholism and other behavioural problems. An example of this is Codorphone, an analgesic that may be both an agonist and antagonist at ј-opioid receptors in the body and shows a higher potency than codeine.

As an outcome, efficient artificial routes that produce high yields have been developed to be able to produce artificial analogues of these natural materials, with special attention being paid to the cyclopropanation step. Over the years there were many methods of cyclopropanation, from using zinc carbenoids (Simmons-Smith reaction ) to stabilised ylides (Corey-Chaykovsky Response ), all producing different ratios of isomers of the product. Often, one enantiomer is a lot more biologically energetic molecule, therefore stereoselective reactions must obtain high produces of the desired product. The Wadsworth-Emmons cyclopropanation effect is an exemplory case of a reaction that is selective for the technology of the trans-isomer and has advantages over other stereoselective reactions.

1. 1: Chemistry of the Cyclopropane Ring

Cyclopropane is the smallest of the cycloalkanes that can be formed and contains three sp3 hybridised carbon atoms bonded to one another to form a triangular ring. Although it is the smallest cycloalkane additionally it is the most reactive because of the bond position within the ring.

The ideal connection position for sp3 hybridised carbons is 109. 5 as it at this perspective that orbitals can overlap properly and form the highest durability carbon-carbon bonds possible. As the propane engagement ring is planar and made up of only three carbon atoms, a relationship perspective of 109. 5 is not possible which is reduced to a bond viewpoint of ~60. In order to achieve bond angles of 60 the sp3 orbitals need to form 'bent' bonds where their p-characteristics are increased, causing the carbon-hydrogen relationship size to shorten (body. 2). It really is this significant difference between the ideal bond position and the real bond viewpoint exhibited that triggers a high amount of ring pressure. Also, the connection position and the changed overlap of orbitals brings about carbon-carbon bonds that are weaker than normal.

In shape. 3, as the wedding ring size rises from cyclopropane to cyclohexane, the engagement ring strain decreases because the perfect bond angle is come to (when in a planar conformation) and much larger rings can suppose a non-planar conformation. Compared to cyclopropane, the most strained and planar wedding ring, cyclohexane has ideal relationship angles and can form both 'seat' and 'sail boat' folded conformations to become minimal strained band possible.

Further tension in the cyclopropane band is because of the planar conformation of the molecule, where in fact the two hydrogens present on each carbon atom are in an 'eclipsed' position (body. 4)2. The carbon-hydrogen bonds are locked into this high energy conformation, as the carbon-carbon bonds of the wedding ring cannot rotate to create a more staggered conformation and reduce torsion tension.

The total strain believed by the molecule leads to the ring composition being highly unstable and is finally responsible for the high reactivity of cyclopropane. Due to instability, the cyclopropane engagement ring can break open quickly and produces a whole lot of energy along the way. This ring strain causes cyclopropane release a more energy on combustion than a standard strain-free propane chain.

2: Precursors of the Wadsworth Emmons Cyclopropanation Reaction

As with most reactions the Wadsworth-Emmons cyclopropanation response is simply a new application of a mature effect, the Horner-Wadsworth-Emmons effect, which has the purpose of forming E- alkenes selectively. Therefore is a derivation of the initial Wittig effect first learned in 1954 by Georg Wittig in which phosphonium ylides are being used in order to form alkenes products from aldehyde or ketone reactants.

2. 1: Wittig Reaction

The Wittig reaction is very useful in that it will form a carbon-carbon dual bond in one site specifically on the desired molecule but the stereoselectivity of the response is manipulated by the kind of phosphonium ylide used. An ylide is a varieties that posesses positive and a negative fee on adjacent atoms of the molecule, and in this situation this can be a phosphorus atom that holds the positive fee. As seen in structure 12, the negatively recharged carbon atom of the ylide serves as a nucleophile towards the carbonyl of the ketone (electrophile) and sorts a betaine kinds. The betaine cyclises into an oxaphosphetane wedding ring which quickly collapses to form an extremely strong phosphorus-oxygen dual bond and ends in the production of your alkene and a triphenyl phosphine oxide.

When an unstablised ylide is present in the response, the kinetic isomer (Z-alkene) is produced preferentially (shape. 5)2 as the intermediate oxaphosphetane wedding ring forms irreversibly. As the stereochemistry of the substituents are 'locked' into a syn-conformation (shape. 7), when elimination of the triphenyl phosphine oxide occurs the alkene developed has it's substituents on the same aspect of the plane.

When the negatively recharged carbon is adjacent to an electron withdrawing group (EWG), in number 6 this is represented by the ester substituent, the ylide group becomes more stable as the charge can be dispersed. This causes the forming of the enolate resonance form and is referred to as a stabilised ylide. Unlike the unstabilised ylide, the oxaphosphetane diamond ring that is produced is now a reversible effect allowing interconversion between Z-orientation to E-orientation of organizations in the engagement ring before an removal step occurs. Beneath the right conditions, the interconversion step may become faster than the removal of phosphine oxide step (collapse of the ring) allowing the reaction to proceed via the thermodynamic product way. The E- isomer is the thermodynamic product as the anti- conformation (Physique. 7) of the oxaphosphetane diamond ring has the substituents on complete opposite sides of the molecule, minimizing steric effects and producing a conformation lower in energy. The eradication of the Z-isomer is slower than that of the E-isomer, allowing the oxaphosphetane diamond ring to open and rotation about the carbon-carbon relationship to occur to form more of the E-isomer.

Although the Wittig reaction works successfully with simple carbonyl reactants, a lot more sterically hindered a ketone reactant is, the slower the reaction can become. This will not necessarily have a poor effect on the produce of product but will impact the suitability of the response in time delicate application, e. g. the commercial industry wishes a high produce of product with a reasonably fast synthetic path in order to keep costs low.

2. 2: Horner-Wadsworth-Emmons reaction

The Horner-Wadsworth-Emmons response (scheme 2. ) is the most well-liked method to select for the E-alkenes product and instead of using phosphonium ylides (amount 6. ) uses a lot more nucleophilic phosphonate-stabilized carbanions with an EWG attached, usually by means of phosphonate esters. Firstly, the phosphonate ester is deprotonated using sodium hydride resulting in the generation of enolate species. This enolate/stabilised carbanion is then reacted with the chosen aldehyde or ketone to give product. Following its more nucleophilic aspect, similar or better produces are produced and faster rates of reactions for aldehydes and ketones that will be more sterically hindered are found. The stereoselectivity of the response for E-alkene can be further increased by modifying the effect conditions and the substituent groups of the phosphonate ester (number 8. ). The larger the alkyl categories attached to the phosphate and ester functional groups the greater the proportion of E-isomer obtained. Making use of the same idea, the bigger the substituent group mounted on the aldehyde/ketone reagent a more improved E-selectivity is seen, for example a phenyl wedding ring. Increasing the heat of the reaction to room temps (23C) and changing the solvent from THF to DME will also encourage E-selectivity.

Figure 9 shows that the pka of the HWE reagent is lower than that of the Wittig reagent which is because of the ester EWG on the adjacent carbon to the acidic hydrogen. The EWG really helps to stabilise the carbanion that'll be formed by the increased loss of hydrogen making the phosphonate ester a more powerful acid than the phosphonium sodium, whose conjugate base will be less stabilised.

As observed in Scheme 2, with the E-alkene, there's a normal water soluble phosphate molecule within solution. Because of its solubility, the recovery of the clean product from the perfect solution is can be done with a simple build up and this is one of the benefits of the HWE response over the utilization of stabilised ylides where a  3 phosphine oxide is shaped. Through Wadsworth and Emmons' investigations into the creation of alkenes such as stilbene in 19619, it was reported that the utilization of phosphonate carbanions was a more cost effective process that led to faster rates of reactions. In addition, it produced very good yields in more slight conditions in comparison to stabilised phosphonium ylides. Phosphonate carbanions have a larger scope in number of different ketone and aldehyde reagents they can successfully behave with.

Comparing both methods, when working with stabilised ylides the resulting solution will contain a mixture of the isomers and for that reason a suitable method is needed in order to separate them.

Scheme 2.

2. 3: Wadsworth-Emmons Cyclopropanation

Similarly to the HWE effect and remember the steric ramifications of large substituents, the reaction uses phosphonate-stabilised carbanions like the phosphonoacetate anion with epoxide and lactone reagents in order to form trans-cyclopropane rings within substances. As observed in program 3, the phosphonate carbanion serves as a nucleophile on the electrophilic carbon of the epoxide resulting in the beginning of the strained wedding ring. Because of the negative demand present on the oxygen atom the phosphoryl group undergoes 1, 4 migration to the oxygen, creating another carbanion. The carbanion may then cyclise resulting in the -reduction of the phosphono- -oxyalkanoate and the closure of the cyclopropane diamond ring. These stabilised phosphonates give a similar produce of trans-cyclopropane to reactions using phosphonium ylides but with faster response times and improved upon diastereoselectivity.

3: Other Ways of Cyclopropanation

In order to understand how effective the WE cyclopropanation response is and its advantages, other methods with somewhat different methods to the same problem can be considered.

3. 1: Simmons-Smith Reaction

First developed in 1958, the Simmons-Smith response uses the chemistry of carbenes groups, producing cyclopropyl wedding rings from the conversation between alkenes and a carbene derivative, zinc carbenoid. A standard carbene 'is a natural species filled with a carbon atom with only six valence electrons'2 and can be put into Ж-bonds and/or -bonds of other reagents. Examples of these carbenes are :CH2 and :CCl2, where in fact the entire carbene reagent is incorporated into the last product framework. In situations using reagents like :CCl2, further steps must remove the halide atoms if a standard cycloproyl diamond ring is desired. Compared, the zinc carbenoid is a species capable of developing carbenes but does not react in a similar way as them. The zinc carbenoid is shaped by the insertion of a zinc atom into a molecule diiodomethane utilizing a copper catalyst, as seen below, and its system of action is in comparison to that of a singlet carbene where in fact the effect is concerted. The carbon framework (-CH2) within the zinc carbenoid is included in to the cyclopropyl band whilst the causing steel halide is released into solution. This is done via an intermediate complicated formed between the alkene, carbene and metallic halide so that the carbene is not released on its own. One of the advantages of this technique of cyclopropanation is the simplicity with that your stereochemistry of the merchandise can be handled. As the reaction is stereospecific, in order to secure a product with a trans-cyclopropane diamond ring, an alkene with E- stereochemistry can be utilized as the initial stereochemistry will be retained. The speed of result of this can be dramatically increased by the presence of allylic alcohols with the same stereochemistry as the alkene, as the zinc atom can organize with the oxygen in a changeover state to include the carbene to the same face of the molecule. The example below (body. 10) demonstrates this reaction is incredibly effective at producing high yields of trans-cyclopropane product.

Scheme 4.

This reaction exhibits easy control over stereoselectivity and undergoes a comparatively simple mechanism, making it easy to comprehend why this is one of the most popular ways of cyclopropanation. A disadvantage that the WE cyclopropanation response does not share is the fact that there will have to be further steps taken in order to remove the merchandise from the solution containing the zinc halide (insoluble) whilst stopping impurities being obtained. Although in some instances the Simmons-Smith response has increased stereoselectivity than the WE cyclopropanation response with comparable produces.

3. 2: Corey-Chaykovsky Effect

This response uses sulphonium ylides, instead of the phosphonium ylides of the Wittig response, reacting with enones to be able to create cyclopropyl buildings in the molecule. Firstly you have the generation in situ of the dimethyloxosulfonium methylide, categorised as the Corey-Chaykovsky Reagent (CCR), from dimethyl sulfoxide and methyl iodide reacting to provide a trimethyl sulfoxonium iodide sodium. This sodium is then deprotonated by using a strong bottom like sodium hydride leading to the CCR.

In the system of cyclopropanation, the CCR acts as a methylene transfer agent, with the carbanion acting as a nucleophile on the alkene carbon-carbon dual relationship of the enone. This one 1, 4 addition is followed by cyclisation within the molecule using the new carbon dual connection reacting as a nucleophile toward the now electrophilic ylide carbon to create the cyclopropyl composition and a sulfonium cation (Structure 5).

In an attempt to help make the response stereoselective more substituted sulfonium ylides with specific chirality can be used to encourage the formation of a particular enantiomer as they transfer other substituents to the enone as well as methylene (physique. ).

Scheme 5.

4: Uses of the Wadsworth-Emmons Cyclopropanation Reaction

Though there are only a few specific types of WE cyclcopropanation doing his thing, a good idea of its efficiency can be acquired.

4. 1: Synthesis of Belactosin A

(+)-Belactosin A is a by natural means happening antitumor antibacterial compound that functions as an alkylating agent in chemotherapy treatment. As an alkylating agent it contributes alkyl groupings to electronegative groups such as phosphates or the amines entirely on guanine nucleotide bases, which are present in all skin cells of your body, although it is utilized to target mutating cancer cells. Belactosin A specifically prevents the cell cycle of cancer skin cells at the G2/M period, where normal DNA will have been replicated and the cell undergoes mitosis. In mutated DNA, the areas on the nucleotide bases influenced by alkylation form mix bridges with other atoms on the complementary base of the contrary strand of DNA. These 'bridges' prevent the DNA strands from separating at these specific points, halting steps such as transcription. As a result this prevents the mutated DNA from being copied, cells from dividing into more cancers cells and halts proliferation of these cells through out your body. It affects mutated DNA skin cells more easily as they undergo cell pattern at a faster and uncontrolled rate and their repair mechanisms are less effective.

Armstrong and Scutt reported a good produce of 63% of the cyclopropane intermediate with higher than 95%e. e. By using H1 NMR and NOE they motivated that the product obtained was the trans-isomer.

4. 2: Synthesis of (R, R)- 2-Methylcyclopropanecarboxylic Acid

In agriculture and veterinary methods, insecticides like Cyromazine and Pyrethrum Remove4 are formed using the WE cyclopropanation effect in the formation of (+) - and (-)-chrysanthemum dicarboxylic acids from anhydro sugar. The pyrethroids are energetic molecules that prevent normal transmitting and excitation over the nerve skin cells in pests by acting on sodium/potassium programs. This ends in immediate fatality to agricultural pests such as locusts and parasitic insects such as ticks and fleas on home pets. Due to the quantity of nerve cells and the quickness of transmission these insecticides are up to 100 times more effective on pests than humans. As a result, Pyrethrum draw out can be used pharmaceutically without harmful effects in the treating worms and scabies.

Using the WE cyclopropanation solution to obtain the biologically productive enantiomer, Brione and company obtained excellent product produces of ~85-90% with exceptional trans-selectivity (>98%). These results were obtained under the conditions of 150C with HexLi/MeTHF solvent.

5: Conclusion

Whilst the WE cyclopropanation reaction proves itself to be always a useful part of the system of development of a few interesting biologically productive compounds, the actual fact remains that it's an underused method. That is shown in the tiny volume of books that can be obtained designed for this reaction. As with most reactions the right balance of factors and reaction conditions are had a need to get the most efficiency, and excellent produces have demonstrated that the WE cyclopropanation reaction is with the capacity of this in the cases of (R, R)- 2-Methylcyclopropanecarboxylic Acid and Belactosin A. Perhaps one of the reason why it is overlooked as a fabricated course is the existence of better known reactions like the Simmons-Smith response, as you may still find some small areas that aren't fully known e. g the degree of specificity of the effect. The field of chemistry is one predicated on the advancement of ideas and extended search for improved upon produces and rates of reaction, especially in a growing area such as the synthesis of man-made analogues of natural substances. In the same way that the WE cyclopropanation effect was derived from the Wittig response, it might provide as a good basis for future better methods of cyclopropanation that come up from the adjustment of its reagents.

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