The authors wish to acknowledge start-up funding from The University of Toledo, as well as funds from the American Chemical Society&#39;s Herman Frasch Foundation in partial support of this work. Mr. Thomas Kina is acknowledged for his assistance with developing a suitable pressure gauge for measuring the reaction pressures. Mr. Steve Modar is thanked for useful discussions.

CAUTION: 1) The following protocols have been deemed safe through repeated trials. However, caution should be exercised when sealing vials, throughout the reaction, and especially when opening the reactions, as inhomogeneity in the reaction vials may lead to equipment failure. Vials should be inspected for physical defects prior to use. Vials should be placed behind some form of blast shield or hood sash immediately after sealing to prevent incidents should the vials fail. 2) Although there is little chance for asphyxiat...

The use of CO2 as a directing group for C-H activation of Lewis basic substrates is currently the focus of United States Provisional Patent #62/608,074.

Using the van der Waals Equation of State, the approximate pressure of these systems can be calculated45
Eq. 1:&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;<img alt="Equation" src="/files/ftp_upload/58281/58281eq1.jpg" />
Under the conditions in Protocol 1, we can assume 26.3 mg of CO2 gives n =5.98 x 10-4 mols
<img alt="Equation 1b" src="/files/ftp_upload/5828...

The use of gaseous compounds in chemical reactions typically requires specialized equipment and procedures1,2. At bench scale, some gases can be added directly from a tank using a high pressure regulator3. An alternative method is to condense the gas under cryogenic conditions4,5. Although useful, these strategies require the use of specialized pressure reactors with valves, which can be cost prohibitive for running numerous reactions in parallel. This can therefore greatly slow the rate at which reaction screening can proceed. As a result, chemists have found it desirable to introduce these compounds using alternative methods. Ammonia can be added to reactions using different ammonium carboxylate salts, taking advantage of the weak equilibrium between these salts and free ammonia6. Transfer hydrogenation is an important strategy for reduction reactions of olefins, carbonyl, and nitro groups that circumvents the use of flammable hydrogen gas with compounds such as ammonium formate or hydrazine as carriers of H27. Another gas of interest in this area is carbon monoxide8 &#8211; CO can be generated in situ by liberation from metal carbonyl complexes9,10, or alternatively it can be generated by decarbonylation from sources such as formates and formamides11,12,13 or chloroform14,15.
One gas which has not enjoyed significant development in this respect is carbon dioxide16. One reason for this is that many transformations that involve CO2 also require high temperatures and pressures, and thus are automatically relegated to specialized reactors17,18. Recent efforts to develop more reactive catalysts, however, have facilitated running many of these reactions under atmospheric pressures of CO219,20,21,22. We recently discovered a reaction in which carbon dioxide could be used to mediate the &#947;-C(sp3)&#8211;H arylation of aliphatic amines23. This strategy was expected to combine the benefits of a static directing group approach including amide24,25,26,27,28, sulfonamide29,30,31,32, thiocarbonyl33,34, or hydrazone35-based directing groups (chemical robusticity), with the ease of a transient directing group (decreased step economy)36,37,38,39.
Although the reaction could occur under atmospheric pressure of CO2, the need for a Schlenk set-up to screen reactions proved prohibitively slow. Furthermore, increasing the pressure slightly led to improved reaction yields, but could not be easily achieved using a Schlenk line. We therefore sought an alternative strategy, and subsequently identified that dry ice could be easily used as a solid source of CO2 that could be added to a variety of reaction vessels to introduce the necessary amount of carbon dioxide to achieve moderate pressures (Figure 1). Though underutilized in synthesis, a similar strategy is fairly common as a method to generate liquid CO2 for chromatography and extraction applications40,41,42,43,44. Utilizing this strategy allowed our group to rapidly screen large numbers of reactions in parallel, while the ability to access moderate CO2 pressures of between 2-20 atmospheres were critical to improving the yields of the reactions. Under these conditions, both primary (1&#176;) and secondary (2&#176;) amines can be arylated with electron rich and electron poor aryl halides.

<table>
	<tbody>
		<tr>
			<td>7.5 mL Sample Vial with Screw Cap (Thermoset)</td>
			<td>Qorpak</td>
			<td>GLC-00984</td>
			<td>Can be reused.</td>
		</tr>
		<tr>
			<td>40 mL Sample Vial with Screw Cap (Thermoset)</td>
			<td>Qorpak</td>
			<td>GLC-01039</td>
			<td>Can be reused.</td>
		</tr>
		<tr>
			<td>Pressure Tube, #15 Thread, 7&#34; Long, 25.4 mm O.D.</td>
			<td>Ace Glass</td>
			<td>8648-06</td>
			<td>Can be reused.</td>
		</tr>
		<tr>
			<td>Pie-Block for 2 Dram Vials</td>
			<td>ChemGlass</td>
			<td>CG-1991-P14</td>
			<td>Can be reused.</td>
		</tr>
		<tr>
			<td>Pie-Block for 10 Dram Vials</td>
			<td>ChemGlass</td>
			<td>CG-1991-P12</td>
			<td>Can be reused.</td>
		</tr>
		<tr>
			<td>3.2 mm PTFE Disposable Stir Bars</td>
			<td>Fisher</td>
			<td>14-513-93</td>
			<td>Can be reused.</td>
		</tr>
		<tr>
			<td>C-MAG HS 7 Control Hotplate</td>
			<td>IKA</td>
			<td>20002695</td>
			<td></td>
		</tr>
		<tr>
			<td>Analytical Weighing Balance</td>
			<td>Sartorius</td>
			<td>QUINTIX2241S</td>
			<td></td>
		</tr>
		<tr>
			<td>Double-Ended Micro-Tapered Spatula</td>
			<td>Fisher Scientific</td>
			<td>21-401-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Hei-VAP Advantage - Hand Lift Model with G5 Dry Ice Condenser Rotary Evaporator</td>
			<td>Heidolph</td>
			<td>561-01500-00</td>
			<td></td>
		</tr>
		<tr>
			<td>Bump Trap 14/20 Joint</td>
			<td>ChemGlass</td>
			<td>CG-1322-01</td>
			<td></td>
		</tr>
		<tr>
			<td>tert-Amyl amine</td>
			<td>Alfa Aesar</td>
			<td>B24639-14</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>2-Methyl-N-(3-methylbenzyl)butan-2-amine</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Prepared from reductive amination of tert-amyl amine and 3-tolualdehyde in the presence of sodium borohydride in methanol.</td>
		</tr>
		<tr>
			<td>Palladium Acetate</td>
			<td>Chem-Impex International, Inc.</td>
			<td>4898</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Silver Trifluoroacetate</td>
			<td>Oakwood Chemicals</td>
			<td>007271</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Phenyl Iodide</td>
			<td>Oakwood Chemicals</td>
			<td>003461</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Acetic Acid</td>
			<td>Fisher Chemical</td>
			<td>A38</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>1,1,1,3,3,3-Hexafluoroisopropanol</td>
			<td>Oakwood Chemicals</td>
			<td>003409</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Deionized Water</td>
			<td></td>
			<td></td>
			<td>Obtained from in-house deionized water system.</td>
		</tr>
		<tr>
			<td>Dry Ice</td>
			<td>Carbonic Enterprises Dry Ice Inc.</td>
			<td></td>
			<td>Non-food grade dry ice.</td>
		</tr>
		<tr>
			<td>Concentrated Hydrochloric Acid</td>
			<td>Fisher Chemical</td>
			<td>A144SI</td>
			<td>Diluted to a 1.2 M solution prior to use.</td>
		</tr>
		<tr>
			<td>Diethyl Ether, Certified</td>
			<td>Fisher Chemical</td>
			<td>E138</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Hexanes, Certified ACS</td>
			<td>Fisher Chemical</td>
			<td>H292</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Saturated Ammonium Hydroxide</td>
			<td>Fisher Chemical</td>
			<td>A669</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Dichloromethane</td>
			<td>Fisher Chemical</td>
			<td>D37</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>Sodium Sulfate, Anhydrous</td>
			<td>Oakwood Chemicals</td>
			<td>044702</td>
			<td>Used as received.</td>
		</tr>
		<tr>
			<td>250 mL Separatory Funnel</td>
			<td></td>
			<td></td>
			<td>Prepared in-house by staff glassblower.</td>
		</tr>
		<tr>
			<td>100 mL Round Bottom Flask</td>
			<td></td>
			<td></td>
			<td>Prepared in-house by staff glassblower.</td>
		</tr>
		<tr>
			<td>Scientific Disposable Funnel</td>
			<td>Caplugs</td>
			<td>2085136030</td>
			<td></td>
		</tr>
		<tr>
			<td>Borosilicate Glass Scintillation Vials, 20 mL</td>
			<td>Fisher Scientific</td>
			<td>03-337-15</td>
			<td></td>
		</tr>
		<tr>
			<td>5 mm O.D. Thin Walled Precision NMR Tubes</td>
			<td>Wilmad</td>
			<td>666000575</td>
			<td></td>
		</tr>
		<tr>
			<td>Chloroform-d</td>
			<td>Cambridge Isotope Laboratories, Inc.</td>
			<td>DLM-7</td>
			<td>Used as received.</td>
		</tr>
	</tbody>
</table>

achieving moderate pressures in sealed vessels using dry ice as a solid co2 source

Herein is presented a general strategy to perform reactions under mild to moderate CO2 pressures with dry ice. This technique obviates the need for specialized equipment to achieve modest pressures, and can even be used to achieve higher pressures in more specialized equipment and sturdier reaction vessels. At the end of the reaction, the vials can be easily depressurized by opening at room temperature. In the present example CO2 serves as both a putative directing group as well as a way to passivate amine substrates, thereby preventing oxidation during the organometallic reaction. In addition to being easily added, the directing group is also removed under vacuum, obviating the need for extensive purification to remove the directing group. This strategy allows the facile &#947;-C(sp3)-H arylation of aliphatic amines and has the potential to be applied to a variety of other amine-based reactions.

Following these protocols, it is possible to charge a reaction vial with an appropriate amount of carbon dioxide to achieve chemical reactions that require CO2 atmospheres. The pressure achieved in Step 1 is calculated to be approximately 3 atmospheres (see discussion for determination of this value), although due to partial solvation, the observed pressure is in the vicinity of 2 atmospheres at room temperature, and should be approximately 2.6 atmospheres under the reaction co...

Watch this Scientific Journal Video about Achieving Moderate Pressures in Sealed Vessels Using Dry Ice As a Solid CO2 Source at JoVE.com

Achieving Moderate Pressures in Sealed Vessels Using Dry Ice As a Solid CO2 Source

Here we present a protocol for performing reactions in simple reaction vessels under low-to-moderate pressures of CO2. The reactions can be performed in a variety of vessels simply by administering the carbon dioxide in the form of dry ice, without the need for costly or elaborate equipment or set-ups.

Achieving Moderate Pressures in Sealed Vessels Using Dry Ice As a Solid CO2 Source

Herein is presented a general strategy to perform reactions under mild to moderate CO2 pressures with dry ice. This technique obviates the need for ...

This method can help address a key challenge in the field of synthetic organic chemistry, namely how to perform reactions under carbon dioxide atmosphere quickly and easily. The main advantage of this technique is that it allows reactions to be performed under carbon dioxide atmospheres above ambient pressures without the need for expensive, specialized equipment. Though this method can be useful for direct CH arylation it can also be applied to other reactions such as CH capitulation, or converting car epoxides into syntha carbonates.Generally individuals new to this matter will struggle because they will fail to properly exfoliate the dry ice prior to addition or will take too long to seal the vile. To begin add a stir bar to a dry 7.5 milliliter vile and add 6.7 milligrams of palladium acetate to the vile. Next ad 99.9 milligrams of silver trifluoroacetate 92.3 milligrams of phenyl iodide and 26.3 milligrams of tert-amylamine to the vile.Then add 1 milliliter of acidic acid and 21.7 microliters of deionized water to the vile. The key to success is to ensure that the appropriate amount of dry ice is added in a timely manner and that only dry ice not deposited water is added to the reaction vessel. After weighing out 26.3 milligrams of dry ice immediately add the ice and seal the vile with a PTFE lined cap.Before setting up the reaction it is important to confirm a good fit between the cap and the vessel to prevent a traumatic loss of carbon dioxide pressure before or during the reaction. Stir the seal reaction vile for 15 minutes at room temperature. Then transfer the reaction vessel to a preheated 110 degree Celsius plate for a 14 hour stirring incubation.The next morning open the vile after cooling to vent the CO2. To perform a reaction in a 7.5 milliliter vile with air excluded add a stir bar and the same reagents and solutions as just demonstrated to a dry 7.5 milliliter vile. After the deionized water has been added tear the vile on a balance and add approximately 98 milligrams of dry ice.Allow the CO2 to sublimate off until a final mass of approximately 26 milligrams is achieved. Followed by immediate sealing of the file with a PTFE lined cap. Then stir the sealed reaction vile for 15 minutes at room temperature followed by an overnight stirring incubation at 110 degrees Celsius as just demonstrated.To perform an air not excluded reaction in a 35 milliliter pressure tube add a stir bar to a dry 35 milliliter pressure tube. And add 6.7 milligrams of palladium acetate to the tube. Add 132.5 milligrams of silver trifluoroacetate 183.6 milligrams of phenyl idodide and 57.4 milligrams of the secondary amine starting material to the pressure tube as well as 1 milliliter of acidic acid and 1 milliliter of hexafluoroisopropanol Next add 21.7 milliliters of deionized water to the pressure tube followed by 1.32 grams of dry ice.Immediately seal the tube with an appropriate Teflon screw cap. And stir the sealed reaction vessel for 15 minutes at room temperature. Then transfer the reaction vessel to a 90 degree Celsius hot plate for a 24 hour stirring incubation.Upon cooling place a towel or padded glove over the cap and carefully open the pressure tube to vent the CO2. Under the 7.5 milliliter vile air not excluded reaction conditions two methyl for phenyl butanoate can be obtained as an oil at a 69 to 72 percent yield demonstrating a proton nuclear magnetic resonance spectrum consistent with the desired product. The reactions can also be performed in pressure reaction tubes.Allowing the synthesis of two methyl and three methyl benzol four phenyl butanoate two amine at a 40 percent yield. While attempting this procedure it is important to remember to be quick while measuring out the dry ice. This technique will allow researchers in the field of synthetic chemistry to study reactions involving moderate pressure of carbon dioxide without the need for complicated and often expensive equipment increasing the number of reactions that can be run in parallel.Don't forget that working with pressurized vessels can be extremely hazardous and the precautions such as using blast shields or working behind hood sashes should always be taken while performing this procedure.

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Research

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Chemistry

9.8K vues.  University of Toledo. This method can help address a key challenge in the field of synthetic organic chemistry, namely how to perform reactions under carbon dioxide atmosphere quickly and easily. The main advantage of this technique is that it allows reactions to be performed under carbon dioxide atmospheres above ambient pressures without the need for expensive, specialized equipment. Though this method can be useful for direct CH arylation it can also be applied to other reactions such as CH capitulation, or con...