Wadsworth-Emmons Cyclopropanation Reaction | Analysis

Wadsworth-Emmons Cyclopropanation chemical chemical reaction Analysis generalizationThis childbed aims to look at the development of the Wadsworth-Emmons cyclopropanation reaction and comp ar it to pick methods of cyclopropanation in inn to beneathstand why it may be employ preferentially. Current internal cove coteries of the WE cyclopropanation reaction atomic number 18 explored to see the efficacy and yield that result. find of AbbreviationsSeen below is a collection of all abbreviations put ond in spite of appearance this project and their subsequent meaning.3 TertiaryBn Benzyl congregationCCR Corey-Chaykovsky Reagentd.eDME Dimethoxyethanee.eEt Ethyl concourseEWG Electron Withdrawing GroupHWE Horner-Wadsworth-EmmonsiPr isopropylMe MethylNOEPh Phenyl radicalTHF TetrahydrofuranWE Wadsworth-Emmons1 openingCyclopropane1was utilize as an anaesthetic until it was disc e very(prenominal)placeed to be high uply oxidizable and dangerous when combined with oxygen. Th e reactivity of cyclopropane is mainly due to the high make sense of doughnut strain and the hold fast strength between the carbon papers creation weaker than commonplace carbon trammels, allowing the elude to open easily. Cyclopropane social structures are often found indoors compounds in nature (figure 1.)2that are observed to have medicinal and commercialized applications, e.g. degradable insecticides such as the pyrethroid family that are less toxic to other animals in the environment3,4. Cyclopropanation do-nothing withal nonplus a number of hallucinogens and opoid drugs that are virtually widely used recreationally for there effects on human beings mental and visual perception, exploiting their psychedelic properties. This type of use has historically been seen within Native Ameri cannister tribes and ancient civilisations. Recently to a greater extent research shows that they may potentially be useful in therapeutic doses in the handling of pain, depression, al coholism and other behavioural problems. An example of this is Codorphone, an analgesic that can be both an agonist and antagonist at -opioid receptors in the body and shows a higher potency than codeine.As a result, efficient semisynthetic lanes that produce high yields have been substantial in evidence to produce synthetic analogues of these natural compounds, with special attention being paid to the cyclopropanation tincture. Over the historic period there have been many methods of cyclopropanation, from victimisation atomic number 30 carbenoids (Simmons-Smith reaction5) to fortify ylides (Corey-Chaykovsky Reaction6), all producing varying ratios of isomers of the ingathering. Often, one enantiomorph is the more(prenominal) than biologically active subatomic particle, therefore stereoselective reactions are required to contain high yields of the in demand(p) production. The Wadsworth-Emmons cyclopropanation reaction is an example of a reaction that is selective for the coevals of the trans-isomer and has advantages over other stereoselective reactions.1.1 Chemistry of the Cyclopropane RingCyclopropane is the beautifulest of the cycloalkanes that can be conformityed and consists of triad sp3 hybridised carbon atoms cohereed to each other to form a triangular rebound. Although it is the smallest cycloalkane it is also the nigh reactive due to the bond tilt within the ring.The exalted bond locomote for sp3 hybridised carbons is 109.5 as it at this angle that orbitals can convergency correctly and form the highest strength carbon-carbon bonds possible. As the propane ring is planar and make up of precisely three carbon atoms, a bond angle of 109.5 is not possible and is reduced to a bond angle of 60. In order to achieve bond angles of 60 the sp3 orbitals need to form bent bonds8where their p-characteristics are change magnitude, causing the carbon-hydrogen bond length to shorten (figure.2). It is this meaningful difference between the compositionl bond angle and the actual bond angle exhibited that causes a high amount of ring strain. Also, the bond angle and the modified overlap of orbitals results in carbon-carbon bonds which are weaker than normal.In figure.3, as the ring size increases from cyclopropane to cyclohexane, the ring strain decreases because the ideal bond angle is reached (when in a planar con constitution) and large rings can assume a non-planar conformation. In comparison to cyclopropane, the most strained and planar ring, cyclohexane has ideal bond angles and can form both chair and boat folded conformations in order to be the least strained ring possible.Further strain in the cyclopropane ring is due to the planar conformation of the molecule, where the two hydrogens present on each carbon atom are in an eclipsed position (figure.4)2. The carbon-hydrogen bonds are locked into this high energy conformation, as the carbon-carbon bonds of the ring are unable to turn off to form a more stag gered conformation and reduce torsion strain.The gibe strain felt by the molecule leads to the ring structure being highly unstable and is ultimately responsible for the high reactivity of cyclopropane. collectable to instability, the cyclopropane ring is able to break open very easily and releases a lot of energy in the process. This ring strain causes cyclopropane to release more energy on combustion than a standard strain-free propane chain.2 Precursors of the Wadsworth Emmons Cyclopropanation ReactionAs with most reactions the Wadsworth-Emmons cyclopropanation reaction is simply a diametric application of an older reaction, the Horner-Wadsworth-Emmons reaction, which has the purpose of forming E- alkenes selectively. This in turn is a derivation of the accepted Wittig reaction first discovered in 1954 by Georg Wittig in which phosphonium ylides are used in order to form alkenes products from aldehyde or ketone reactants.2.1 Wittig ReactionThe Wittig reaction is very useful i n that it give form a carbon-carbon triple bond in one site specifically on the desired molecule notwithstanding the stereoselectivity of the reaction is controlled by the type of phosphonium ylide used. An ylide is a species that carries a positive and a negative charge on coterminous atoms of the molecule, and in this instance it is a phosphorus atom that carries the positive charge. As seen in scheme 12, the negatively charged carbon atom of the ylide acts as a nucleophile towards the carbonyl of the ketone (electrophile) and forms a betaine species. The betaine cyclises into an oxaphosphetane ring which quickly collapses to form a very strong phosphorus-oxygen double bond and results in the production of an alkene and a triphenyl phosphine oxide.When an unstablised ylide is present in the reaction, the kinetic isomer (Z-alkene) is produced preferentially (figure. 5)2 as the fair oxaphosphetane ring forms irreversibly. As the stereochemistry of the substituents are locked i nto a syn-conformation (figure. 7), when elimination of the triphenyl phosphine oxide occurs the alkene formed has its substituents on the same side of the plane.When the negatively charged carbon is adjacent to an electron withdrawing group (EWG), in figure 6 this is represented by the ester substituent, the ylide group becomes more stable as the charge can be dispersed. This leads to the formation of the enolate resonance form and is referred to as a stabilised ylide. Unlike the unstabilised ylide, the oxaphosphetane ring that is formed is now a reversible reaction allowing interconversion between Z-orientation to E-orientation of groups in the ring before an elimination step occurs. Under the right conditions, the interconversion step can become fast than the elimination of phosphine oxide step (collapse of the ring) allowing the reaction to give give away via the thermodynamic product channel. The E- isomer is the thermodynamic product as the anti- conformation (Figure.7) of the oxaphosphetane ring has the substituents on opposite sides of the molecule, reducing steric effects and producing a conformation glower in energy. The elimination of the Z-isomer is slower than that of the E-isomer, allowing the oxaphosphetane ring to open and rotation closely the carbon-carbon bond to occur to form more of the E-isomer.Although the Wittig reaction works efficiently with simple carbonyl reactants, the more sterically hindered a ketone reactant is, the slower the reaction can become. This does not necessarily have a negative effect on the yield of product but will affect the suitability of the reaction in time sensitive application, e.g. the commercial industry wants a high yield of product with a moderately fast synthetic route in order to keep costs low.2.2 Horner-Wadsworth-Emmons reactionThe Horner-Wadsworth-Emmons reaction9(scheme 2.) is the prefer method to select for the E-alkenes product and instead of using phosphonium ylides (figure 6.) uses much mo re nucleophilic phosphonate-stabilized carbanions with an EWG tie, usually in the form of phosphonate esters. Firstly, the phosphonate ester is deprotonated using sodium hydride leading to the generation of an enolate species. This enolate/stabilised carbanion is then reacted with the chosen aldehyde or ketone to give product. As a result of its more nucleophilic nature, similar or better yields are produced and rapid rates of reactions for aldehydes and ketones that are more sterically hindered are observed. The stereoselectivity of the reaction for E-alkene can be further increased by modifying the reaction conditions and the substituent groups of the phosphonate ester (figure 8.)10. The larger the alkyl groups attached to the phosphate and ester functional groups the greater the proportion of E-isomer obtained. Using the same idea, the larger the substituent group attached to the aldehyde/ketone reagent a more improved E-selectivity is seen, for example a phenyl ring. Increasin g the temperature of the reaction to room temperature (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 and this is due to the ester EWG on the adjacent carbon to the acidic hydrogen. The EWG helps to stabilise the carbanion that will be formed by the loss of hydrogen making the phosphonate ester a stronger acid than the phosphonium salt, whose conjugate baseborn will be less stabilised.As seen in Scheme 2, on side the E-alkene, there is a water soluble phosphate molecule present in plosive speech sound. receivable to its solubility, the recovery of the pure product from the solution can be done via a simple work up and this is one of the advantages of the HWE reaction over the use of stabilised ylides where a 3 phosphine oxide is formed. Through Wadsworth and Emmons investigations into the formation of alkenes such as stilbene in 19619, it was reported that th e use of phosphonate carbanions was a more cost effective process that led to faster rates of reactions. It also produced very good yields in more moderate conditions in comparison to stabilised phosphonium ylides. Phosphonate carbanions have a greater oscilloscope in number of different ketone and aldehyde reagents that they can successfully react with. compare both methods, when using stabilised ylides the resulting solution will contain a mixture of the isomers and therefore a suitable method is needed in order to separate them.Scheme 2.2.3 Wadsworth-Emmons CyclopropanationSimilarly to the HWE reaction and keeping in mind the steric effects 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 molecules. As seen in scheme 312, the phosphonate carbanion acts as a nucleophile towards the electrophilic carbon of the epoxide resulting in the openin g of the strained ring. Due to the negative charge present on the oxygen atom the phosphoryl group undergoes 1, 4 migration on to the oxygen, forming another carbanion. The carbanion can then cyclise leading to the -elimination of the phosphono- -oxyalkanoate and the closure of the cyclopropane ring. These stabilised phosphonates give a similar yield of trans-cyclopropane to reactions using phosphonium ylides but with faster reaction times and improved diastereoselectivity13.3 Other Methods of CyclopropanationIn order to understand how effective the WE cyclopropanation reaction is and its advantages, other methods with slightly different approaches to the same problem can be looked at.3.1 Simmons-Smith ReactionFirst developed in 1958, the Simmons-Smith reaction uses the chemistry of carbenes groups, producing cyclopropyl rings from the interaction between alkenes and a carbene derivative, coat carbenoid. A standard carbene is a neutral species containing a carbon atom with only six valence electrons2 and can be inserted into -bonds and/or -bonds of other reagents. Examples of these carbenes are CH2 and CCl2, where the whole carbene reagent is incorporated into the final product structure. In cases using reagents like CCl2, further steps are required to sequestrate the halide atoms if a standard cycloproyl ring is desired. In comparison, the zinc carbenoid is a species sufficient of forming carbenes but does not react in exactly the same focussing as them. The zinc carbenoid is formed by the insertion of a zinc atom into a molecule diiodomethane using a copper catalyst, as seen below, and its mechanism of action is compared to that of a singlet carbene where the reaction is concerted. The carbon structure (-CH2) within the zinc carbenoid is incorporated into the cyclopropyl ring whilst the resulting metal halide is released into solution. This is done via an middling complex formed between the alkene, carbene and metal halide so that the carbene is not rel eased on its own. One of the advantages of this method of cyclopropanation is the ease with which the stereochemistry of the product can be controlled. As the reaction is stereospecific, in order to obtain a product with a trans-cyclopropane ring, an alkene with E- stereochemistry can be used as the original stereochemistry will be retained. The rate of reaction of this can be dramatically increased by the presence of allylic alcohols with the same stereochemistry as the alkene, as the zinc atom can coordinate with the oxygen in a novelty state to add the carbene to the same face of the molecule. The example below (figure. 10)14shows that this reaction is extremely effective at producing high yields of trans-cyclopropane product.Scheme 4.This reaction exhibits easily control over stereoselectivity and undergoes a relatively simple mechanism, making it abstemious to understand why this is one of the most popular methods of cyclopropanation. A hurt that the WE cyclopropanation rea ction does not share is that there will have to be further steps taken in order to remove the product from the solution containing the zinc halide (insoluble) whilst preventing impurities being obtained. Although in some instances the Simmons-Smith reaction has greater stereoselectivity than the WE cyclopropanation reaction with comparable yields.3.2 Corey-Chaykovsky Reaction15This reaction uses sulphonium ylides, as opposed to the phosphonium ylides of the Wittig reaction, reacting with enones in order to form cyclopropyl structures in the molecule. Firstly there is the generation in situ of the dimethyloxosulfonium methylide, often called the Corey-Chaykovsky Reagent (CCR), from dimethyl sulfoxide and methyl iodide reacting to give a trimethyl sulfoxonium iodide salt. This salt is then deprotonated using a strong base like sodium hydride resulting in the CCR.In the mechanism of cyclopropanation, the CCR acts as a methylene transfer agent, with the carbanion acting as a nucleophil e towards the alkene carbon-carbon double bond of the enone. This 1, 4 addition is followed by cyclisation within the molecule using the new carbon double bond reacting as a nucleophile toward the now electrophilic ylide carbon to form the cyclopropyl structure and a sulfonium cation (Scheme 5).In an attempt to make the reaction stereoselective more substituted sulfonium ylides with specific chirality can be used to encourage the formation of a specific enantiomer as they transfer other substituents to the enone as well as methylene (figure.)16.Scheme 5.4 Uses of the Wadsworth-Emmons Cyclopropanation ReactionThough there are only a hardly a(prenominal) specific examples of WE cyclcopropanation in action, a good idea of its efficacy can be obtained.4.1 Synthesis of Belactosin A17(+)-Belactosin A is a naturally occurring antitumor antibacterial compound that acts as an alkylating agent in chemotherapy treatment. As an alkylating agent18it adds alkyl groups to electronegative groups s uch as phosphates or the amines found on guanine nucleotide bases, which are present in all cells of the body, although it is used to target mutating cancer cells. Belactosin A specifically lolly the cell cps of cancer cells at the G2/M phase, where normal desoxyribonucleic acid will have been replicated and the cell undergoes mitosis. In mutated DNA, the areas on the nucleotide bases impact by alkylation form cross bridges with other atoms on the antonymous base of the opposite strand of DNA. These bridges prevent the DNA strands from separating at these specific points, stopping steps such as transcription. As a result this prevents the mutated DNA from being copied, cells from dividing into more cancer cells and halts proliferation of these cells through out the body. It affects mutated DNA cells more readily as they undergo cell cycle at a faster and uncontrolled rate and their repair mechanisms are less effective.Armstrong and Scutt reported a good yield of 63% of the cyclo propane intermediate with greater than 95%e.e. By using H1 NMR and NOE they determined that the product obtained was the trans-isomer.4.2 Synthesis of (R,R)- 2-Methylcyclopropanecarboxylic pane of glass19In agriculture and veterinary practices, insecticides like Cyromazine and painted daisy Extract4 are formed using the WE cyclopropanation reaction in the synthesis of (+) and (-)-chrysanthemum dicarboxylic acids from anhydro sugars20. The pyrethroids are active molecules that prevent normal transmission and excitation on the philia cells in insects by acting on sodium/ kibibyte channels. This results in immediate death to agricultural pests such as locusts and parasitical insects such as ticks and fleas on household pets. Due to the number of nerve cells and the speed of transmission these insecticides are up to 100 times more effective on insects than humans. Consequently, Pyrethrum extract can be used pharmaceutically without detrimental effects in the treatment of worms and scabies.Using the WE cyclopropanation method to obtain the biologically active enantiomer, Brione and company obtained excellent product yields of 85-90% with exceptional trans-selectivity (98%). These results were obtained under the conditions of 150C with HexLi/MeTHF solvent.5 ConclusionWhilst the WE cyclopropanation reaction proves itself to be a useful step in the mechanism of formation of a few interesting biologically active compounds, the fact remains that it is an underused method. This is shown in the small volume of literature that can be obtained specifically for this reaction. As with most reactions the right balance of factors and reaction conditions are needed to get the most efficiency, and excellent yields have proved that the WE cyclopropanation reaction is capable of this in the cases of (R, R)- 2-Methylcyclopropanecarboxylic Acid and Belactosin A. Perhaps one of the reasons it is overlooked as a synthetic route is the presence of better know reactions like the Si mmons-Smith reaction, as there are still some small areas that are not fully known e.g the degree of specificity of the reaction. The field of chemistry is one based on the ontogenesis of ideas and continued search for improved yields and rates of reaction, especially in a growing area such as the synthesis of synthetic analogues of natural compounds. In the same way that the WE cyclopropanation reaction was derived from the Wittig reaction, it could provide as a good basis for future improved methods of cyclopropanation that arise from the modification of its reagents.