Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes
September 8th, 2013
Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.
The overall goal of this video is to show how to synthesize hyper valent odium al Kindal tri fate, and then use them in subsequent reactions with azides to form cyan or carbs, control of product selectivity. Storage, handling and safety is also discussed. The acronym of Hiat will be used for hyper developent Odium al Kindal tri fate.
For the remainder of the video, the synthesis of many Hyatts have been previously published. Several methods of hi synthesis include the use of zephyros reagent and ER's reagent. However, this video will be using the more reactive Sano Phenyl odium tri fate Sano Phenyl Odium.
Tri fate can be synthesized from the literature preparation displayed the reagent reacts with the Triky 10 modified alkins to form the desired product. After the hi is synthesized, it can be reacted with azide to form a reactive sano carbine intermediate. The Sano carbine is trapped with solvent, and two examples of this process are demonstrated in this video.
Our proposed mechanism of substitution involves the addition of an azi source to the beta carbon of the alkin, thereby forming the I Oto iid, which decomposes to I oto benzene, and the vanilla Dine Carine. The vanilla de Carine can then undergo a one two rearrangement via migration of either the R group or the azide to afford the Al Kindal azide. The Al Kindal azide then extrudes dinitrogen to form the ano carbine, which can react with a substrate.
It should be noted that there can be a formation of a valent odium aquino trilight species depending on conditions. The byproduct is favored at low temperatures in product solvents, where the protonation of the I oto ILI is faster than the rearrangement to the kinal azide. Another possible product that occurs during oh insertion reaction is a vinyl ether where vanilla de carine is trapped before the rearrangement to the Al Kindal zyme can occur.
The propensity to form this vinyl ether is determined by the R group. Examples of how Sano carbine react include O insertion, where the oxygen nucleo ally attacks the carine, and then proton transfer occurs. Dimethyl sulfoxide complexation where the Carine reacts with the sulfur atom and cyclo propagation where the carbine reacts with an aine.
In this procedure, you will learn how to synthesize and isolate two different valent, odium Kinal trit. Several safety precautions should be considered before proceeding with these experiments. Some hyper valent odium al canal trites are unstable and will decompose sometimes violently when exposed to air and light.
The compound synthesized in this video are moderately stable and no explosive decomposition has ever been witnessed to form cyto carbs. The procedures require the use of azi sources. Azis are explosive and highly toxic.
Proper personal protection equipment should be worn while handling these materials and all manipulation of the reagent should be taken place in properly ventilated hoods. In this video, two valent odium al Kindal triplate will be synthesized to show the difference in isolation, technique and stability. Once synthesized, it can be used to generate a sano carbine.
The Sano carbine is a powerful, unstable, reactive intermediate. Initially perform all sano carbine reactions on small scales so that nitrogen gas evolution is controllable. The product mixture can be varied by changing the temperature concentration and the R group of the alkin.
The Sano carbine is a powerful hon, which can be used to generate chemical complexity for a targeted molecule. A dry 100 milliliter round bottom flask equipped with a magnetic stir was prepared under argon gas clamped to a stand and placed in a cryogen bath of acetyl nitrile and solid carbon dioxide pellets. The cryogen should be approximately minus 45 degrees Celsius.
10 milliliters of dry di chloral methane was then added to the cold flask, and the solvent was allowed to equilibrate to the temperature of the cryogen. 0.35 grams of Sano Phenyl Odium trilight was weighed out and quickly transferred to the cold flask. The solution should be fairly insoluble at this temperature.
An empty syringe was weighed out and teared tributyltin fennel acetylene was then pulled into the syringe and weighed to a mass of 0.37 grams. The tributyltin phenyl acetylene was then injected into the cold solution, and over time the solids dissolved. The dissolution was an indication that the Hyatt had been formed.
Di chloral methane was then removed under reduced pressure using a rotary evaporator or rotovap. Hexane was then added to the reaction to forced precipitation of the product. If a precipitate does not form evaporate the solvent then add dathyl ether and hexane to force precipitation of the hi.
A vacuum flask equipped with a buchner funnel was assembled and the solution was poured into the funnel. For filtration, the solid can be washed with Dathyl ether. The collected solid is light sensitive and should be stored in an OPA container.
For comparison, fennel, Hyatt was left in direct sunlight and it is clearly visible that the side most exposed to light has now changed color. The sample was placed in the refrigerator for future use. This procedure will show the synthesis of pintle Hyatt.
The main difference from the Nel Hyatt synthesis is that the filtration must be performed cold and under inert atmosphere. A dry 250 milliliter three neck round bottom flask equipped with a magnetic stir was prepared under argon gas clamped to a ring stand and placed in a cryogen bath of acetyl nitrile and solid carbon dioxide pellets. The cryogen should be approximately minus 45 degrees Celsius.
The flask was then fitted with a slink filtration apparatus so that the filtration can be performed quickly and at cold temperatures. Each joint was greased and clamped To make it secure, the filtration system can be constructed by several means, but it is important that the system has the capability to push with the inert gas and pull with a vacuum through a glass filter. 10 milliliters of dry di chloral methane was then added to the cold flask, and the solvent was allowed to equilibrate to the temperature of the cryogen.
The excess head space in the flask is important for adding hexane later to force precipitation. 0.35 grams of Sano phenyl odium trilight was weighed out and quickly transferred to the cold flask. The solution should be fairly insoluble at this temperature.
The tributyltin peptide was then injected into the cold solution, and over time, the solids in the solution became dissolved. The dissolution was an indication that the Hyatt had been formed to the extra Headspace. 75 milliliters of hexane is injected and a precipitate is formed.
The collection flask was then placed under vacuum. It is advised to wear a leather or cryogen glove while performing the filtration. The entire apparatus was then UNC clamped and carefully tilted to pour the solution onto the glass filter.
The collection flask vacuum was then open to pull the liquid through. Do not allow the vacuum to pull air into the vessel. Once the filtration is complete, the apparatus is dismantled and the solid was scraped off the filter.
The collected solid is light sensitive and should be stored in an OPA container. The sample was placed in the refrigerator for future use. The following procedure demonstrates how Hyatts can be used to generate ano carbine products.
A dry 50 milliliter round bottom flask equipped with a magnetic stir and a stopper was clamped on a stir plate and placed under argon gas. 20 milliliters of dry methanol was added to the flask, followed by 0.3 grams of previously synthesized phenyl hiat to this solution. 47 milligrams of sodium azide was quickly added and the septum was placed back on the flask.
After approximately two minutes, nitrogen gas evolution can be seen. The reaction was allowed to continue for as long as bubble formation occurred. After the bubbles had stopped, the solution was exposed to air and evaporated under a reduced pressure with a rotovap di chloral.
Methane was then added to the residual liquid and aqueous extraction was performed to remove the sodium tri fate. The organic phases of di chloral methane were collected and dried with and anhydrous sodium sulfate. The solution was decanted and evaporated.
Again, at this step, it is possible to perform column chromatography for purification. A silica slurry is prepared with hexane and poured into the column. The excess solvent is drained.
Sand is poured onto the silica gel and the product mixture is added. The procedure for dimethyl sulfoxide complexation is very similar to the oh insertion procedure and thus is not described. It should also be noted that sodium azide is only used when the chosen solvent can solubilize it.
Tetra butyl ammonium azide is used in instances where sodium azide is insoluble, as will be shown in the cyclo propagation Sano carbine reaction. The procedure for the cyclo propp nation Sano carbine reaction differs from the other sano carbine reactions, mainly in the use of tetra butyl ammonium azide, which is necessitated by the non-polar conditions due to the high gross complicity of tetra butyl ammonium azide. These reactions are typically done inside a glove box.
To show the hydroscopic properties of tetra butyl ammonium azide, the compound was poured from a vial containing a nitrogen atmosphere onto a watch glass. The compound quickly absorbs water from the air and sticks to the glass to begin the reaction. 0.125 grams of tetra butyl ammonium azide was weighed in a glove box and placed in a dry 10 milliliter round bottom flask equipped with a magnetic stir.
The 10 milliliter round bottom flask containing the tetra butyl ammonium azide was capped, removed from the glove box and placed under argon gas with a shank line. One milliliter of styrene was then added to the flask and allowed to stir The azid does not need to dissolve to this slurry. 0.2 grams of fiddle Hyatt was quickly added and the septum was placed back on the flask.
Immediately the solution began to darken and nitrogen gas was generated by the Sano carbine formation. The reaction was allowed to continue for as long as bubble formation occurred. After the bubbles have stopped, the solution can be exposed to air and column chromatography can be performed to purify the product.
After watching this video, you should be with the synthesis of hyper odium alkin, tri lates, and how they can be reacted with a azis. To generate Sano carbine. Please take the specified precautions when performing these experiments.
In summary, the alkin is converted to the hyper odium al Kindal triplate, which is then used to generate the Sano carbine. The Sano carbine is then used in oh, insertion reactions and cyclo propp nations.
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Overview
This article describes the synthesis and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures involve air-sensitive techniques and discuss the handling and safety of the synthesized compounds.
Key Study Components
Area of Science
- Organic Chemistry
- Synthetic Methods
- Chemical Safety
Background
- Hypervalent iodonium compounds are important in organic synthesis.
- Previous methods of synthesis have been published.
- Reactivity and selectivity in reactions with azides are crucial.
- Handling air-sensitive compounds requires specific techniques.
Purpose of Study
- To demonstrate the synthesis of HIATs.
- To explore their reactions with azides.
- To discuss safety and handling of these compounds.
Methods Used
- Cold filtration under an inert atmosphere.
- Use of Sano Phenyl iodonium triflate for reactivity.
- Techniques for handling air-sensitive materials.
- Discussion of safety protocols during synthesis.
Main Results
- Successful synthesis of HIATs was achieved.
- Reactions with azides produced cyanocarbenes.
- Product selectivity was controlled during the reactions.
- Safety measures were effectively implemented.
Conclusions
- The study provides a reliable method for synthesizing HIATs.
- Reactivity with azides is demonstrated effectively.
- Handling and safety considerations are crucial for successful synthesis.
Frequently Asked Questions
Executive Industry Relevance
The synthesis and controlled reactivity of hypervalent iodonium alkynyl triflates (HIATs) enable the generation of cyanocarbene intermediates, expanding the chemical space for complex molecule construction in early discovery. Mastery of these reactive intermediates supports mechanistic de-risking and enhances predictive confidence in synthetic route development. This capability is strategically relevant for portfolio teams seeking to accelerate lead identification and optimize synthetic tractability.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Facilitates access to reactive cyanocarbene intermediates for probing novel chemical transformations.
- Enables mechanistic studies that clarify reaction pathways and intermediate stability.
- Supports predictive confidence in synthetic feasibility for complex scaffolds.
Screening & Assay Development
- Provides validated intermediates for downstream reactivity screens and substrate scope evaluation.
- Enables reproducible generation of reactive species for assay standardization.
- Supports platform development for evaluating new chemical modalities.
Translational & Preclinical Research
- Offers mechanistic insight into intermediate reactivity relevant for translational chemistry workflows.
- Supports continuity from synthetic discovery to preclinical candidate synthesis when new scaffolds are required.
- Enables risk-adjusted advancement of synthetic routes with improved safety and handling protocols.
Pipeline & Workflow Integration
HIAT synthesis and cyanocarbene generation fit within the early discovery to lead identification continuum, providing a foundation for innovative synthetic strategies and mechanistic de-risking.
- Discovery Biology: Supports hypothesis testing of new chemical transformations and intermediate stability.
- Screening: Enables reproducible and scalable generation of reactive intermediates for compound evaluation.
- Analytics: Provides quantitative outputs such as gas evolution and product characterization for condition comparison.
- Translational Research: Aligns with preclinical chemistry needs for novel scaffold synthesis when supported by mechanistic data.
- Enterprise Reuse: Establishes a reusable workflow for generating and handling sensitive intermediates across projects.
Operational & Enterprise Impact
- Scientific Value: Increases predictive confidence and reduces mechanistic ambiguity in synthetic route design.
- Operational Value: Standardizes protocols for handling, isolation, and storage of sensitive intermediates.
- Strategic Value: Enables better go/no-go decisions for synthetic feasibility and safety in early-stage programs.
- Portfolio Impact: Supports risk-adjusted prioritization of synthetic strategies and resource allocation.
Implementation Considerations
- Requires expertise in air- and moisture-sensitive synthetic techniques.
- Demands specialized instrumentation for low-temperature and inert atmosphere operations.
- Necessitates cross-team standardization of safety and handling protocols.
- Adaptation may be needed for different substrate classes or scale-up scenarios.
- Practical limitations include compound instability and the need for rigorous safety precautions.
