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Temperature Effect on PhotoRedOx Chemistry


Temperature control of photoredox experiments is not easily accomplished. Most experiments are described using a fan to maintain the reaction near room temperature and no fan to let the reaction warm up. Moreover there are very few setups described allowing reaction to be performed below room temperature. In this context it is very challenging to study temperature effect on photocatalysis in a convenient way.

 

PhotoRedOx TCHepatoChem developed a device PhotoRedOx TC that makes this type of experiments easy to perform using a simple chiller/heater recirculator.


The PhotoRedOx TC (for Temperature controlled) fits many light sources like for example the LEDs EvoluChem 18W. It also has a photochemistry chamber to evenly distribute light. Regarding the format vials, this apparatus is very flexible (from 0.3ml to 20ml) thanks to the availibility of many racks. Flow reactor can also be used with this device. PhotoRedOx TC required to use a magnetic stirring plate to provide agitation and an external fluid circulator to heat or cool the reaction vessel. (light sources, racks, flow reactor, stirring plate and fluid circulator are supplied independently)

In the following examples, HepatoChem shows how CH alkylation using a BF3K reagent can benefit from lowering temperature of the reaction and how increasing the temperature can improve conversion of a C-O cross-coupling.

 

PhotoRedOx TC (Temperature Controlled)

  • Fits many light sources (EvoluChem 18W)
  • Photochemistry chamber to evenly distribute light
  • Flexible format vials (from 0.3mL to 20mL)
  • Flow reactor available
  • Stirring on magnetic stirring plate
  • External recirculatorneeded to heat or chill reaction vessel

 

BF3K Cyclopropyl and hydroquinine reaction

Reaction_Cyclopropyl BF3K & Hydroquinine

Reaction Conversion at 19°C, 28°C and 50°C

Reaction Conversion at 19°C, 28°C and 50°C

Experimental Details: Reaction performed in Evoluchem Photoredox Temperature control bath with circulating polyethylene glycol/water bath and an EvoluChem 18W 6200K white light for 2 hr. Reaction contains 50 µmol substrate, 1.5 equiv. RBF3K, 2 equiv. K2S2O8, 5 equiv. TFA and 2 mol% Ir(dF-CF3-ppy)2(dtbpy) in 0.5 ml DMSO.

 

C-O Coupling with Cyclohexanol

Reaction Conversion at 33°C and 50°C

Reaction Conversion at 33°C and 50°C

C-O Coupling with Cyclohexanol

Experimental Details: Reaction performed in Evoluchem Photoredox TC box with EC 450 nm LED. Reaction 2 mol% Ir(dF-CF3-ppy)2(dtbpy), 5 mol% NiCl2-dme/dtbpy and 3 equiv. base with 10 mol% quinuclidine. Conversion determined by LC-UV.

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Solutions for low temperature synthesis


Some chemical syntheses must be done at low temperatures over long periods of time.

To have the possibilities to do that, several solutions can be considered, like the use of:

A mixture of ice – salt:

Minimum temperatures of a ice-salt mixtures:

  • T ~ 0°C: ice bath.
  • T ~ -10°C: ice bath (70 %) + calcium chloride (30 %).
  • T ~ – 15 °C: ice bath (80 %) + amonnium chloride (20 %).
  • T ~ – 20°C: ice bath (75 %) + sodium chloride (25 %).

Percentages are given in mass.

 

An organic solvent mixture – dry ice:

Mixtures can be obtained bya  mixing of dry ice and organic solvents.

  • T ~ – 23°C: carbon tetrachloride / dry ice.
  • T ~ – 60°C: chloroform / dry ice.
  • T ~ – 78°C: acetone/ dry ice.
  • T ~ – 95°C: toluene/ dry ice.
  • T ~ – 100°C : ether/ dry ice.

 

The air or a liquid nitrogen or an organic solvent / liquid nitrogen:

  • T ~ – 170 – 180°C

 

Precautions to be taken and constraints encountered:

For each solution, some cautions should also be considered to maintain low temperatures, such as:

  • Add a thermal insulation of the synthesis system by covering it with an insulating material.
  • Use of a glass Dewar or Cool-It.

Despite these solutions and cautions, the stability of the temperature of the reaction medium will not be guaranteed and becomes very annoying for the synthesis of boronic acids.

Boronic acids can be done creating a magnesium or a lithian and then add it on a boric acid ester (Scheme 1) and then hydrolyze the arylboronic ester obtained and then recover the boronic acid.

 

Addition arylmetallique sur trialkylborateBoronic acids done from the organolithians have the advantage of preparing the aryllithians by ortholithization, freeing themselves from the halogenated precursor. It has also been shown that in some cases the unstable organolithien can be trapped in situ by adding the lithic base to a mixture of arene and borate (Scheme 2).

Borylation by ortholithiation & entrapment in situ

Limitations for the ortholithiation is that this synthesis must be done at very low temperatures (from -78°C to -40°C) with often, limited existing synthesis tools with which the need for monitoring the temperature due to frequent recharge of carboglace/solvent or liquid nitrogen/solvent, by the users, can quickly become cumbersome and time-consuming.

 

Push the limits with efficients solutions:

In order to push these limitations Interchim can support you offering effective and appropriate systems for specific applications.

For example, for applications where the stability of the temperature and an efficient stirring are required over long period time Interchim recommands:

For synthesis done in 10ml up to 2L round bottom flasks:

• The use of the Cool-It bowl from Radleys and the immersion cooler TC100E from Huber.

Reservoir incassable Cool-itThe unbreakable HDPE Cool-it
insulated bowls fit onto standard
stirring hotplate for round bottom flasks.
Cryoplongeur TC100EThe immersion cooler TC100E
allows a quick and a controlled cooling
of the liquid inside the Cool-It bowl
and to garantee a constant temperature
(T°C max: -100°C) with an accuracy of +/- 0.5k.
The combination of these two systems ensures the stability
of temperature of the reaction medium and an effective stirring
over an unlimited reaction time.

 

For synthesis done with parallel reactions stations:

• The use of the Cooled Carousel Reservoirs from Radleys and the immersion cooler TC100E from Huber.

Reservoir incassable Cool CarouselThe unbreakable HDPE Cooled
Carousel Reservoirs fit onto standard
stirring hotplate and can be used
with 6 or 12 or 24 parallel reaction stations.
Cryoplongeur TC100E avec Cool CarouselThe immersion cooler TC100E
allows a quick and a controlled cooling
of the liquid inside the Cooled Carousel Reservoirs
and to garantee a constant temperature
(T°C max: -100°C) with an accuracy of +/- 0.5k.
The combination of these two systems ensures the stability
of temperature of the medium and an effective stirring
over an unlimited reaction time.

 

For more information:

In all of this, to help you push back the limits of your syntheses because of the existing tools, contact Interchim®.

Thanks to our big network of suppliers everywhere in the world, Interchim will be always able to find the best solution with innovative productivity tools to answer exactly to the needs requested by your applications.

Caroussel_6_Plus_interchim_blog1218Caroussel 12 PlusHuber_Temperature_Control_interchim_blog1218

More information

More information

More information

Feel free to contact the technical support at +33 4 70 03 73 01 or by email at interfine@interchim.com.



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Lead Diversification Tool Box from Hepatochem


Lead Diversification tool box

Illustration_interchim_blog0618

HepatoChem has developed several kits for lead diversification for the C-H functionalization. This chemistry offers many possible transformations including hydroxylation, acetoxylation, methoxylation, and halogenation among others. This chemistry can be sometimes difficult.
The HepatoChem kits is offering you a rapid, practical and cost-effective solution for analogues obtaining. They enable the parallel screening of a selected set of catalytic conditions focusing on generating diversity with an approach totally orthogonal and complementary to conventional synthetic methods.

HepatoChem proposes different kits:

  • Alkoxylation and Acetoxylation kits
  • Fluorination kit
  • Biomimetic Oxidation kit
  • Sulfinate Alkylation reagent kit
  • Photocatalytic alkylation diversification kit

 

Alkoxylation and Acetoxylation Kits

Diversity Kit : 4 different functionalizations

C-H Alkoxylation is one of the most C-H functionalization described in literature. HepatoChem kit is designed to enable conveniently the screen of both Alkoxylation and Acetoxylation reaction conditions. It uses PdOAc2 as catalyst with several oxidants and additives.

Kit HCK1007-01-001 (article 9H4350)
Substrate solution is prepared in DMF (to facilitate the screening of solvents) and added to all four for solvents. Screen the four solvents (methanol, ethanol, isopropanol and acetic acid) with three reaction conditions (different salts). 10mol% Pd(OAc)2, 1 equiv PhI(OAc)2.

TableauKitHCK1007-01-001_interchim_blog0618

 

Salt Effect on C-H functionalization

Optimisation Kit: 5 differents salts

It has been reported that salt can influence C-H functionalization. HepatoChem kit is designed to enable the screen of several salts simultaneously. This kit contains 5 different salts CuOAC2, Ag2CO3, K2CO3, Cs2CO3, MgSO4.

Kit HCK1007-01-002 (article 9H4360)
Screen 1 solvent with 12 reaction conditions. 10 mol% PdOAc2, 1 or 2 equivalents of PhIOAc2 with 5 differents salts. Prepare one solution in solvent or mixture in DMF if solubility issues.
Tableau Kit HCK1007-01-002

 

Fluorination Kit

Fluorination is one of the most interesting C-H functionalization described in literature. HepatoChem kit is designed to screen fluorination reaction conditions using PdOAc2  as catalyst in presence of common fluorine sources : Silver Fluoride AgF, 1-fluoro-2,4,6-trimethyl-pyridinium triflate (TMPyF), SelectFluor®, N-fluorobenzenesulfonimide (NFSI) and Bis(tert-butylcarbonyloxy iodobenzene (PhIOPiv).

Kit HCK1008-01-001 (article APQ9X0)
This kit includes 2 sets of reagents ; catalyst and oxidant are mixed in the same vial

12 conditions with AgF, TMPyF, Selectfluor and NFSI

Kit HCK1008-01-001

 

Biomimetic Oxidation Kits

HepatoChem has developed a revolutionary way to screen, optimize, and produce metabolites directly from drug candidates. The BMO kit exploits an optimized panel of catalytic chemical reaction conditions with organometallic catalysts. This tool enables to mimic the suite of cytochrome P450 enzymes (CYP) present in human hepatocytes.
HepatoChem BMO kits enable, in three simple steps, synthesis of metabolites directly from the parent drug.

Biomimetic Oxidation Kits

BMO Screening kit : HCK1001-01-001 (article 9H4040)

Perform the primary screen, select the desired metabolites wells. Then order the corresponding optimization kit.
The complete kit contains all solvents and reagents for 2×25 screening reaction conditions (2 plates included).

BMO Optimization kit : HCK1001-02-XXX (article 9H4050)
Perform the optimization kit, identify the best production conditions and then order the corresponding production kit.
The complete kit contains solvents and reagents for the optimization of selected screening reaction conditions (1 plate included).

BMO Production kits : HCK1001-03-XXX-02 (article 9H4060)
and HCK1001-03-XXX-10 (article 9H4070)

You can scale-up and produce your metabolite
The complete kit includes all solvents and reagents for your metabolite at 12.5µmol scale or more.

 

Sulfinate Alkylation Reagent Kit

The sulfinate alkylation reaction described by Prof. Baran is a powerful late stage functionalization tool. HepatoChem kit enables to produce analogues of the lead compound in mg quantities using 6 different alkylation reagents. Each vials contains 100µmol of sulfinate alkylation reagent and a stirring bar to react with 50µmol of substrate. The C-H functionalization will mainly occur on electron-deficient heteroarenes at one or several positions.

Kit HCK1013-01-001 (article AYHDQ0)
kit content: 2 reaction vials of each reagents (100µmol), 12 reaction vials total

Sulfinate Alkylation Reagent Kit


Tableau Sulfinate Alkylation Reagent Kit

 

Photocatalytic Alkylation Diversification Kit

A photoredox kit is also available for the C-H functionalization

The trifluoroborate alkylation reaction (Minisci reaction) described by Prof. Molander is a powerful late stage functionalization tool. HepatoChem kit enables to produce in one step 8 different analogues of a lead compound in mg quantities. C-H functionalization will mainly occur on electron-deficient heteroarenes at one or several positions.

Kit HCK1016-01-001 (article AYQRA0)
Kit contents (HCK1016-01-001) : 2 reaction vials of each BF3K reagents (75µmol) and K2S2O8 (100µmol), 2 vials of photocatalysts and 2 vials of TFA, 16 reaction vials total

KitHCK1016-01-001_interchim_blog0618

Tableau KitHCK1016-01-001



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Let the magic happen : Merry christmas from France


The end of the year brings us no greater joy than the opportunity to wish you a Merry Christmas ! May it be a wonderful season for you and yours. Thank you for being part of this magic throughout the year. 🙂



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puriFlash monolith columns


The purification of compounds is always a compromise between desired purity, the sample load and the duration of methods. To improve efficiency in obtaining pure compounds, chemists must find the best balance between purity, duration of the method, and environmental considerations. This delicate balance is often necessary for both raw products and final purification.
Due to their particular structure, the puriFLash® Monolith columns provide a great help for all the points on which a balance must be implemented.

What is a puriFlash® monolith column?

Interchim® Peptides monolith column is a pre-packed column with the novel silica gel for reversed-phase liquid chromatography that will permit high-speed processing only with a medium to low back pressure.

Microsoft PowerPoint - BioProcess Poster v3 Final.pptx

How puriFlash®monolith columns can provide best results?

In the pores of this monolith, there are two structures (Macro and micro pores), which allow a faster and deeper diffusion of the solvent inside the particles. That conduces to a more effective purification, especially of macromolecules such as peptides, with an extremely low pressure.

Particle of 30µm which provide equivalent result of 15µm and less pressure

When used with the optimum flow rates, these 30μm phase-fill columns will give you at least 15μm phase results, as shown in the comparison below.

ColonnespuriFlashMonolith2_interchim_blog0518

Ultra-High throughput

Increase the flow-rate of purifications to the limit pressure of your columns and significantly reduce the time of purifications.
As these columns generate less pressure, it becomes possible to use flow rates higher than the optimum flow of your columns, without losing the separation’s quality for better productivity. This example shows that it is possible to use 10x the optimum flow without losing the quality of separation. This product therefore allows better productivity.

ColonnespuriFlashMonolith3_interchim_blog0518

This advantage can even be used when a purification requires to stack columns for difficult purifications. Then, it will be possible not only to stack columns, but also to work at a higher flow rate than the optimum, which is not possible with conventional silica.

Example :
Sample:
1- GLY-TYR 238
2- VAL-TYR-VAL 380
3- Met-Enkephalin 574
4- Angiotensin 1 000
5- Cytochrome c from bovine heart 11749

Method :
Solvant A : Water + 0.1%TFA
Solvent B : ACN + 0.1%TFA

ColonnespuriFlashMonolith4_interchim_blog0518

Gradient : 5 to 40% d’ACN in 33 :45
Débit : 15 mL/min
Pression : 4 bar (monolith)
7 bar (PF-15C18N-F0025)

For this application, the two columns give a similar result.
The compounds 3 and 4 are co-eluted.

 

ColonnespuriFlashMonolith5_interchim_blog0518

Gradient : 5 to 40% d’ACN in 66 :30
Débit : 15 mL/min
Pression : 4 bar (monolith)
13 bar (PF-15C18N-F0025)

With the stack of two columns we get to separate compounds 3 and 4 but the run time is then doubled exceeding the hour!

 

ColonnespuriFlashMonolith6_interchim_blog0518

Gradient : 5 to 40% d’ACN in 16 :30
Débit : 60 mL/min
Pression : 17 bar (Monolith)
Impossible avec PF-15C18N-F0025

When increasing the flow-rate, even slightly, the column PF-15C18N-F0025 generates too much pressure, so it is not possible to significantly reduce the run time.
On the contrary, the monolith column makes it possible here to increase the flow rate to 60mL / min (4 times the optimum flow rate) and makes the purification time to 16min.
The time saving is important.

Less toxicity

Thanks to the pressure, it’s possible to use viscous solvent as isopropanol. Free from toxics solvents as acetonitrile and methanol.
In this application, eluent solvent is IPA/Water, 1:1, we see that the generated pressure is under max pressure of F0025 column.

ColonnespuriFlashMonolith7_interchim_blog0518

 

Enhanced Performance with Any System!

Even in the reverse phase purification, the pressure of Interchim® puriFlash® monolith column is as low as 2 bar or less, at a standard flow rate and can be adapted to any low / medium pressure machine like puriFlash® machines. Moreover, it is quite easy to improve separation performance by stacking 2 or more columns.

Why to choose puriFlash®monolith columns?

As the different results show, the use of puriFlash® monolith columns will help you to:
  – save up to 80% of run-time on your purifications and increase your productivity.
  – use columns with a particle size of 30 μm and obtain results at least equivalent
     to 15 μm columns.
  – get rid of toxic solvents such as acetonitrile and methanol, and even use solvents
     generating high back pressure such as isopropanol.
  – use small particle size columns on low pressure systems for better performance.

 

Learn more :

Find the complete list of columns here.



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Analytica 2018, here we go !


Analytica 2018 is coming ! We look forward to welcoming you to our booth ! 🙂

See you in Germany or follow us with our social medias!

Analytica 2018 - Interchim



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Bring Your Chemistry to Light with the PhotoRedOx Box


PhotoRedOx Setup

Interest in photochemistry has been growing exponentially in recent years. Numerous new applications using visible-light photoredox catalysis have been discovered. These catalytic systems can perform many types of bond formations using various substrates which are valuable new tools for synthetic chemists.
However photoredox chemistry setup necessitates to the use of a light source (blue light) and apparatus that are not standard yet in an organic chemistry laboratory. Many chemists have made their own setup and tried to reproduce literature chemistry with more or less success. As a result the implementation of photoredox chemistry is slow and organic chemists are still hesitant to try these important new tools. Therefore, the need for a simple and robust device to perform visible-light photoredox catalysis has become increasingly important.

EvoluChem™ PhotoRedOx Box

The EvoluChem™ PhotoRedOx Box was designed with one main objective: To allow any chemist to easily perform multiple photoredox reactions in a reproducible environment. Our photochemistry device provide an even light distribution to all reaction samples allowing consistent and reproducible reactions. A cooling fan allows even temperature distribution and keeps the chamber near room temperature during long reaction runs. The device easily fits on standard stir plates, allowing for consistent stirring. Sample holders are compatible with vials ranging from 0.3 ml to 20 ml vials.

Unique Design

Schema PhotoRedOxThe PhotoRedOx Box is using a unique geometry of mirrors to irradiate multiple samples simulatanously for parallel chemistry setup while limiting the thermal effect of the light source. This design results into a compact and efficient photoredox device which can be easely set on any standard stir plate.
The removable lamp adapter allows easy switching from the standard kessil™ blue 34W LED lamp to many other light sources.

Fit multiple vial formats

PhotoRedOx_Box_interchim_blog0218Organic chemists needs to be able to use different reaction vial sizes depending on the scale and the number of the reaction to be performed. The PhotoRedOx Box can virtually fit any type of vials including 0.3ml crimped vials (6 x 32mm), 2ml HPLC vials (12 x 32mm), 1DRAM (15 x 45mm), Microwave vial 2-5mL (17 x 83mm), 2DRAM (17 x 60mm) and 20ml scintillation vials (28 x 61mm).

 

This feature allows quick and consistent scale up from screen reactions to larger scale with preset sample positions removing the guess work on sample placement distance from the light source. When using 0.3 ml vials, 32 reactions can be performed in parallel in the photochemical device. At 20 ml, two reactions can be run in duplicate.

Available Holders

PhotoPortoirsRedOx_Box_HCK1006-01-017_interchim_blog0218PhotoPortoirsRedOx_Box_HCK1006-01-018_interchim_blog0218PhotoPortoirsRedOx_Box_HCK1006-01-019_interchim_blog0218PhotoPortoirsRedOx_Box_HCK1006-01-020_interchim_blog0218PhotoPortoirsRedOx_Box_HCK1006-01-021_interchim_blog0218

Reproducibility

With the EvoluChem photomethylation kit, we have demonstrated the reproducibility of both the photomethylation kit and the device. Using a photomethylation of buspirone as test reaction, 16 vials spread through the 0.3 ml vial sample holder for Trial #1 results in 53% (+/-2 %) conversion. See figure. For a second trial with 16 reaction vials we observed an average conversion of 56% (+/-2 %) for the mono-methylated product.

Test rection (Methylation)

Pourcentage de produit de mono-méthylation par position des flacons réactionnels

Reaction conditions:

Each reaction vial contains Ir(dF-CF3-ppy)2(dtbpy)[PF6] (0.1 μmol), tert-butylperacetate solution (12.5 μmol) and a stir bar sealed under inert atmosphere. To each vial was added 50 μl of 0.05 M buspirone solution in 1:1 trifluoroacetic acid/acetonitrile sparged with nitrogen stream. Reaction mixture irradiated with Kessil 34 W blue LED for 18 hr using EvoluChem photochemical device.

PhotoRedOx Flow Reactor

PhotoFlowReactorRedOx_Box_interchim_blog0218The common limitation to scaling up photoredox chemistry is due to the low penetration of the light in to the reaction mixture (few mm) which prohibits the use of large reaction vessels. Surface area is key to shorten reaction time. It is possible to significantly increase the surface area by running the reaction in flow. This will decreases the reaction time and allows to be run in continuous mode for scale-up.

To solve this challenge, we designed a flow reactor that can be used in the PhotoRedOx Box. This flow reactor is using PFA tubing and has volume of 2 ml. Comparing reactions in flow and in batch we observed significant decrease in reaction time.

SchemaPhotoRedOx-FR-3_interchim_blog0218

Reaction protocol

In a 4-ml vial equipped with a Teflon septa were weighed NiCl2-dme (1.1 mg, 5 μmol, 0.05 mol %) and dtbbpy (1.3 mg, 5 μmol, 0.05 mol %). 1 ml of dry MeOH was added to the vial and the vial was stirred on an orbital shaker until complete dissolution. The solution was evaporated to dry at room temperature. Then Ir(dF-CF3-ppy)2(dtbpy) (1.1 mg, 1 μmol, 0.05 mol %), and 4-bromoacetophenone (9.95 mg, 100 μmol, 1 equiv.) were added. 1 ml of dry acetonitrile was added followed by Et3N (21 μmol, 300 μmol, 3 equiv.) and aniline (4.65 mg, 100 μmol, 1equiv.). The solution was sparged with nitrogen via submerged needle for 5 minutes.
Several batches of 100 μl of solution were successively injected to the flow reactor placed in EvoluChem PhotoRedOx Box with blue Kessil LED using an injection module (Gilson) and the samples were circulated using a HLPC pump at different flow rates to allow residence time of 5, 10, 15, 20 and 30 min. Reaction completion was monitored by LC-MS using the ratio bromoacetophenone/product.

SchemaPhotoRedOx-FR-4_interchim_blog0218

SchemaPhotoRedOx-FR-5_interchim_blog0218

Reaction protocol

In a 4-ml vial equipped with a Teflon septa were weighed NiCl2-dme (1.1 mg, 5 μmol, 0.1 mol %) and dtbbpy (1.3 mg, 5 μmol, 0.1 mol %). 1 ml of dry MeOH was added to the vial and the vial was stirred on an orbital shaker until complete dissolution. The solution was evaporated to dry at room temperature. Then Ir(dF-CF3-ppy)2(dtbpy) (1.1 mg, 1 μmol, 0.1 mol %), and 4-bromoacetophenone (4.98 mg, 50 μmol, 1 equiv.) were added. 1 ml of dry acetonitrile was added followed by 2,6 lutidine (17.5 μmol, 150 μmol, 3 equiv.) and potassium benzyltrifluoroborate (9.90 mg, 50 μmol, 1 equiv.). The solution was sparged with nitrogen via submerged needle for 5 minutes.
Several batches of 100 μl of solution were successively injected to the flow reactor placed in EvoluChem PhotoRedOx Box with blue Kessil LED using an injection module (Gilson) and the samples were circulated using a HLPC pump to allow residence time of 30 min. Reaction completion was monitored by LC-MS using the ratio bromoacetophenone/product.

To know more :

Acces directly to our products dedicated to PhotoRedox on our website.



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Iridium and Nickel Photoredox kits from HepatoChem


HepatoChem-interchim-photochemstry

 

In recent years photoredox chemistry has become a powerful tool for chemical synthesis. Many reactions conditions have been reported in the literature using a wide range of catalysts and reagents. However, often these reactions are highly substrate, solvent and base specific. In order to facilitate the screening of common photochemistry reactions, HepatoChem has released a series of kits combining common Iridium, Nickel, ligand and base combinations to achieve successful cross-coupling transformations.

Iridium/Nickel catalysis versatility

Depending on the ligand, base and solvent, the Ir/Ni catalytic systems can perform different cross-coupling reaction.

HepatoChem_photochemistry_c-c_coupling_interchim_blog0717HepatoChem_photochemistry_irridium_catalyst_nickel_ligands_interchim_blog0717

Several kits available

HepatoChem_photochemistry_kits_photoredox_interchim_blog0717

Standard Protocol

5 µmol of substrates in 100 µl solvent with Ir catalyst (2 mol %),  NiCl2•dme (10 mol %), ligand (10 mol %),  and 3 equivalent of base.

Features

  • 0.3 ml vial with crimp cap and stirring bar
  • Specifically designed for photochemistry device
  • Pre-weighed reagents and catalysts
  • Temperature maintained at RT
  • Pre-designed or custom arrays available
  • Reagents are packaged under inert atmosphere

Know more about the Iridium/Nickel Photoredox kits from HepatoChem



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Processing unstable intermediates with Flow Chemistry


The art of chemical synthesis continues to evolve through innovation in instrumentation, Interchim works with many companies to offer this enabling technology to leading research scientists across Europe.

One such technology is continuous flow chemistry, and in this area, Interchim collaborates with Uniqsis, a market leader in meso scale flow chemistry. This is a complementary technique to batch and microwave for seamless reaction optimisation, synthesis and scale-up from milligrams to 10 Kg per day.

Interchim offers a wide range of flow chemistry products to make this technique accessible to novices while at the same time catering for complex multi-step fully automated reactions sequences for library synthesis.

Flow Chemistry offers several benefits

Faster reactions

  • by superheating  at elevated pressure, reactions run more quickly (Arrhenius equation)
  • batch reactions that take several hours can often be performed in minutes, analogous to microwave

Improved safety

  • small reactor volumes minimise risk associated with hazardous intermediates and highly exothermic chemistry

High reproducibility

  • precise control of mixing and reaction temperature often difficult in batch chemistry

Scalable

  • continuous processing on a mesoscale can deliver 100s g to 10 Kg per day

Solvents

  • more choice- superheating
  • easier to clean-up – saves time and money
  • lowest cost
  • best solubility
  • least damaging to the environment

To give you an idea on how to minimise risk associated with hazardous intermediates with a small reactor volume, we describe a Curtius Rearrangement carried out with a The FlowSyn™.

Flow_chemistry_FlowSyn_Interchim_blog_0317

Objective:

The Curtius rearrangement is a useful reaction in synthesis that converts carboxylic acids into their corresponding reversed amino derivatives.
However, the reaction requires the formation of potentially explosive acyl azides as the precursor to isocyanates that undergo nucleophilic attack to afford the reaction products. dppa_FlowSyn_Interchim_blog_0317Under conventional ‘batch’ conditions, the scale of the reaction is therefore often limited for safety reasons. This can present a bottleneck in terms of scale-up.

Flow chemistry offers an attractive alternative whereby the acyl azide intermediate is continuously processed through to product, preventing its accumulation.

Method:

System solvent: Acetonitrile.
Stock solution A: 4-Nitrobenzoic acid (925 mg; 5.05 mmol), triethylamine (1.40 mL; 10.0 mmol) and allyl alcohol (1.02 μL; 15.0 mmol) in MeCN (50 mL).
Stock solution B: Diphenylphosphorylazide (DPPA: 1.10 mL; 5.1 mmol) in MeCN (50 mL).

A 100 psi chemically inert fixed back-pressure regulator was fitted and used in all experiments.

Using Automated Experiment Setup

FlowSyn™ is equipped with a program that allows unattended operation and is able to run a flow experiment automatically, stopping and cleaning the instrument when the reaction is complete.

1- FlowSyn™ was fitted with a 14 mL HT PTFE tubing reactor cassette, and the heating unit was tensioned to ensure optimal thermal contact.

systemconf_Flow_chemistry_FlowSyn_Interchim_blog_0317

2- A 10 cm x 15 mm Column reactor was filled with a [1:1] mixture of Amberlyst A-21 and Amberlyst H-15 resins, and the ‘Col Vol’ was set to 3.0 mL in the Configuration Screen.

column_reactor_Flow_chemistry_FlowSyn_Interchim_blog_0317

3 – A 100 psi fixed BPR was connected in-line to the outflow from the tubing reactor before the collection valve.

Flow_chemistry_FlowSyn_Interchim_blog_03172

4 – The pumps and inlet lines were primed.

5 – The following flow parameters were entered into the ‘Auto Set Up’ screen.

systemconf2_Flow_chemistry_FlowSyn_Interchim_blog_0317

6 – Upon pressing ‘Run Experiment’, FlowSyn™ equilibrates to the set temperature and then runs the flow experiment, before finally cleaning the system by flushing with system solvent (‘Wash’).

7 – The collected product solution was concentrated in vacuo to leave allyl-4-nitrophenyl carbamate as a white solid (198 mg; 88%).

UVLC-MS (ESI +ve): (m/z 223.1 (MH+)); Rt = 3.60 min, >99%;

IR (ATR): 3380 (s), 1730 (s),1685 (m), 1610 (m), 1600 (m), 1545 (s), 1508 (s), 1495 (s), 1320 (s), 1305 (s),1205 (s), 1110 (s), 1050 (s), 945 (s), 850 (s), 765 (s), 750 (s), cm−1.

1H NMR (d3-MeCN, 400 MHz): dH 8.28 (1H, s), 8.15 (2H, d, J = 9.2 Hz), 7.65 (2H, d, J = 9.2 Hz), 5.98 (1H, dt, J = 17.3, 10.2, 5.8 Hz), 5.40 (1H, ddt, J = 17.2, 1.6, 1.6 Hz), 5.30 (1H, ddt, J = 10.8, 1.6, 1.6 Hz), 4.65 (2H, d,J = 5.6 Hz)

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In this specific case flow chemistry is an excellent alternative to push back the limits of the conventional batch chemistry and to overcome a bottleneck in terms of scale-up.

With our range of flow chemistry systems, we offer modular starter systems to fully integrated fully automatic system.

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The FlowLab can offer up to 3 reagent channels,  2 reactor stations and has its own software program for single experiments. It also has the option for an inline UV/VIS detector system to see when the reaction has reached steady state.

All of the reagent have been specially designed for flow chemistry and can deliver 10 ml/min or 50 ml/min with the prep heads at up to 100 bar. Reactions can be carried out in the range -85°C to 300°C.

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Purification cost PF-15SIHP vs IR-50SI columns


Purification by liquid chromatography is always a challenge and there is often a compromise to obtain the desired purity, loading and throughput.
To improve efficiency in delivering pure compounds, chemists may balance between purity, run time and environmental considerations.
This delicate balance is often necessary for both crude and final purification.

The Ultra Performance Flash Purification (UPFP) concept achieves accelerated throughput by reducing the time and cost per sample of the purification process with increased confidence. What differentiates UPFP from Flash chromatography is the combination of advanced machine technology, built to last and mastery of small particle spherical silica puriFlash® columns which offers significant benefits over the traditional flash grade silica.

Conditions:

  • Device: puriFlash® 450
  • Solvents: A-Cyclohexane, B-Ethyl acetate
  • Injection Mode: Liquid injection
  • Crude sample mixture: 400mg of each Phthalate
  • Injection volume: 3.2mL
  • UV Detection: 254nm

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Purification Cost:

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  • Cyclohexane 1L price (Cat price): 25.10€
  • Ethyl Acetate 1L price (Cat price): 18.70€
  • Labor cost per hour: 75€
  • Solvent recycling without halogen compound (Cat price): 0,00035€/mL
  • Silica columns recycling (Cat price): 0,0009€/mL

Conclusion :

A 15µSIHP-F0040 column gives a better result with greater resolution, efficiency, loading capacity and improved retention versus a IR-50SI column.
Using a 15µSIHP, reduce run time by 45%, improve in time for the purification by 114%, reduce the solvent consumption by 59% and improve in cost for the purification by 26%. Lower collection volume means a decrease of the evaporation time.

If the sufficient selectivity is reached, the 15µSIHP allows to achieve greater fraction purity. The best ratio cost/productivity is obtained with 15µm silica.



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