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

Summary

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.

Abstract

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 γ-C(sp³)-H arylation of aliphatic amines and has the potential to be applied to a variety of other amine-based reactions.

Introduction

The use of gaseous compounds in chemical reactions typically requires specialized equipment and procedures^1,2. 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 conditions^4,5. 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 – CO can be generated in situ by liberation from metal carbonyl complexes^9,10, or alternatively it can be generated by decarbonylation from sources such as formates and formamides^11,12,13 or chloroform^14,15.

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 reactors^17,18. Recent efforts to develop more reactive catalysts, however, have facilitated running many of these reactions under atmospheric pressures of CO₂^19,20,21,22. We recently discovered a reaction in which carbon dioxide could be used to mediate the γ-C(sp³)–H arylation of aliphatic amines²³. This strategy was expected to combine the benefits of a static directing group approach including amide^{24,25,26,27,28}, sulfonamide^29,30,31,32, thiocarbonyl^33,34, 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 applications^{40,41,42,43,44}. 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°) and secondary (2°) amines can be arylated with electron rich and electron poor aryl halides.

Protocol

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 asphyxiation due to the small quantities of CO₂ used, reactions should be set-up as well as opened in a well-ventilated area or in a fume hood. 3) Dry ice is a cryogen and can cause serious tissue damage. Care should therefore be exercised while manipulating it to avoid frostbite, such as limiting direct contact or using cryogenic gloves. 4) Dry ice will condense water vapor, meaning that prior to use, the dry ice should be mechanically exfoliated to ensure the mass is of CO_2(s) only. This can be achieved by simply rubbing the dry ice between one’s fingers, or more safely, rubbing it between one’s fingers with a protective layer such as a glove or towel.

1. Reaction in a 7.5 mL Vial (Air Not Excluded)

1. Add a stir bar to a dry 7.5 mL vial.
2. Add palladium acetate (6.7 mg, 0.03 mmol) to the vial.
3. Add silver trifluoroacetate (99.9 mg, 0.45 mmol) to the vial.
4. Add phenyl iodide (92.3 mg, 0.45 mmol) to the vial.
5. Add tert-amyl amine (26.3 mg, 0.30 mmol) to the vial.
6. Add acetic acid (1.0 mL) to the vial.
   Note: The ratio of solution volume to vial size is important, as the immediate sublimation of CO₂ upon addition of dry ice can mechanically displace solvent if too much is used relative to the size of the reaction vessel.
7. Add deionized water (21.7 μL, 12.1 mmol) to the vial.
8. Weigh dry ice (26.3 mg, 0.60 mmol), and immediately add the dry ice to the vial, while ensuring to also immediately seal the vial with a PTFE-lined cap.
   Note: The whole operation should be performed within approximately 5 seconds to prevent sublimation and escape of the small amount of CO₂ added (this is slowed by the formation of frozen acetic acid around the dry ice). The amount of CO₂ added will be an approximate value, and in our hands a deviation of a few mg is permissible.
9. Stir the sealed reaction vial for 15 minutes at room temperature.
10. Transfer the reaction vessel to a pre-heated plate at 110 °C and stir for 14 hours before allowing to cool.
11. Upon cooling, carefully open the vial to vent CO₂.
12. Remove all of the volatiles in vacuo.
    Note: This operation can be performed in the vial, or the solution can be transferred to a larger round bottom flask.
13. Add 1.2 M HCl_(aq) (6 mL) to the reaction mixture and stir open to air for 15 minutes.
14. Transfer the aqueous fraction to a separatory funnel, washing with additional 1.2 M HCl (4 mL), and extract with a 1:1 diethyl ether/hexanes mixture (3 x 8 mL).
    Note: This organic wash contains excess phenyl iodide and other neutral by-products, and can be disposed of.
15. Neutralize and make basic the aqueous solution by addition of saturated NH₄OH_(aq) (10 mL is a good starting point).
16. Extract the aqueous layer with dichloromethane (2 x 10 mL).
17. Dry the combined organic fractions over Na₂SO₄, then filter into a tared sample vial.
18. Evaporate the solvent in vacuo, giving the product (2-Methyl-4-phenyl-butanamine) as a yellow oil.

2. Reaction in a 7.5 mL Vial (Purging Conditions – Air Excluded)

1. Add a stir bar to a dry 7.5 mL vial.
2. Add palladium acetate (6.7 mg, 0.03 mmol) to the vial.
3. Add silver trifluoroacetate (99.9 mg, 0.45 mmol) to the vial.
4. Add phenyl iodide (92.3 mg, 0.45 mmol) to the vial.
5. Add tert-amyl amine (26.3 mg, 0.30 mmol) to the vial.
6. Add acetic acid (1.0 mL) to the vial.
   Note: The ratio of solution volume to vial size is important, as the immediate sublimation of CO₂ upon addition of dry ice can mechanically displace solvent if too much is used relative to the size of the reaction vessel.
7. Add deionized water (21.7 μL, 12.1 mmol) to the vial.
8. Tare the vial on a balance, add approximately 98 mg of dry ice, and then allow the CO₂ to sublimate off until a final mass of approximately 26 mg is achieved, followed by immediately sealing the vial with a PTFE-lined cap.
   Note: If desirable, this step can be performed with a greater mass of dry ice to further exclude air from the vial. It is noteworthy that this may introduce water, and thus may not be the most effective strategy for water sensitive reactions.
9. Stir the sealed reaction vial for 15 minutes at room temperature.
10. Transfer the reaction vessel to a pre-heated plate at 110 °C and stir for 14 hours before allowing to cool.
11. Upon cooling, carefully open the vial to vent CO₂.
12. Remove all of the volatiles in vacuo.
    Note: This operation can be performed in the vial, or the solution can be transferred to a larger round bottom flask.
13. Add 1.2 M HCl_(aq) (6 mL) to the reaction mixture, and stir open to air for 15 minutes.
14. Transfer the aqueous fraction to a separatory funnel, washing with additional 1.2 M HCl (4 mL), and extract with a 1:1 diethyl ether/hexanes mixture (3 x 8 mL).
    Note: This organic wash contains excess phenyl iodide and other neutral by-products, and can be disposed of.
15. Neutralize and make basic the aqueous solution by addition of saturated NH₄OH_(aq) (10 mL is a good starting point).
16. Extract the aqueous layer with dichloromethane (2 x 10 mL).
17. Dry the combined organic fractions over Na₂SO₄, then filter into a tared sample vial.
18. Evaporate the solvent in vacuo, giving the product (2-Methyl-4-phenyl-butanamine) as a yellow oil.

3. Reaction in a 40 mL Vial (Air Not Excluded)

1. Add a stir bar to a dry 40 mL vial.
2. Add palladium acetate (33.5 mg, 0.15 mmol) to the vial.
3. Add silver trifluoroacetate (499.5 mg, 2.25 mmol) to the vial.
4. Add phenyl iodide (461.5 mg, 2.25 mmol) to the vial.
5. Add tert-amyl amine (131.5 mg, 1.5 mmol) to the vial.
6. Add acetic acid (5.0 mL) to the vial.
   Note: The ratio of solution volume to vial size is important, as the immediate sublimation of CO₂ upon addition of dry ice can mechanically displace solvent if too much is used relative to the size of the reaction vessel.
7. Add deionized water (108.5 μL, 6.02 mmol) to the vial.
8. Weigh dry ice (131.5 mg, 3.0 mmol), and immediately add the dry ice to the vial, while ensuring to also immediately seal the vial with a PTFE-lined cap.
   Note: The whole operation should be performed within approximately 5 seconds to prevent sublimation and escape of the small amount of CO₂ added (this is slowed by the formation of frozen acetic acid around the dry ice). The amount of CO₂ added will be an approximate value, and in our hands a deviation of a few mg is permissible.
9. Stir the sealed reaction vial for 15 minutes at room temperature.
10. Transfer the reaction vessel to a pre-heated plate at 110 °C and stir for 14 hours before allowing to cool.
11. Upon cooling, carefully open the vial to vent CO₂.
12. Remove all of the volatiles in vacuo.
    Note: This operation can be performed in the vial, or the solution can be transferred to a larger round bottom flask.
13. Add 1.2 M HCl_(aq) (30 mL) to the reaction mixture and stir open to air for 15 minutes.
14. Transfer the aqueous fraction to a separatory funnel, washing with additional 1.2 M HCl (20 mL), and extract with a 1:1 diethyl ether/hexanes mixture (3 x 8 mL).
    Note: This organic wash contains excess phenyl iodide and other neutral by-products, and can be disposed of.
15. Neutralize and make basic the aqueous solution by addition of saturated NH₄OH_(aq) (10 mL is a good starting point).
16. Extract the aqueous layer with dichloromethane (2 x 20 mL).
17. Dry the combined organic fractions over Na₂SO₄, then filter into a tared sample vial.
18. Evaporate the solvent in vacuo, giving the product (2-Methyl-4-phenyl-butanamine) as a yellow oil.

4. Reaction in a 35 mL Pressure Tube (Air not excluded)

1. Add a stir bar to a dry 35 mL pressure tube.
2. Add palladium acetate (6.7 mg, 0.03 mmol) to the pressure tube.
3. Add silver trifluoroacetate (132.5 mg, 0.6 mmol) to the pressure tube.
4. Add phenyl iodide (183.6 mg, 0.9 mmol) to the pressure tube.
5. Add 2-methyl-N-(3-methylbenzyl)butan-2-amine (57.4 mg, 0.3 mmol) to the pressure tube.
6. Add acetic acid (1.0 mL) to the vial, followed by 1,1,1,3,3,3,-hexafluoroisopropanol (1.0 mL).
   Note: The ratio of solution volume to vial size is important, as the immediate sublimation of CO₂ upon addition of dry ice can mechanically displace solvent if too much is used relative to the size of the reaction vessel.
7. Add deionized water (21.7 μL, 1.2 mmol) to the pressure tube.
8. Weigh dry ice (1.32 g, 30 mmol), and immediately add the dry ice to the pressure tube, while ensuring to also immediately seal the pressure tube with the appropriate Teflon screw cap.
   Note: The whole operation should be performed within approximately 5 seconds to prevent sublimation and escape of the small amount of CO₂ added (this is slowed by the formation of frozen acetic acid around the dry ice). The amount of CO₂ added will be an approximate value, and in our hands a deviation of a few mg is permissible.
9. Stir the sealed reaction vessel for 15 minutes at room temperature.
10. Transfer the reaction vessel to a pre-heated plate at 90 °C and stir for 24 hours before allowing to cool.
11. Upon cooling, put a towel or padded glove over the cap, and carefully open the pressure tube to vent CO₂.
12. Remove all of the volatiles in vacuo.
    Note: This operation can be performed in the pressure tube with an appropriate adaptor, or the solution can be transferred to a larger round bottom flask.
13. Add 1.2 M HCl_(aq) (12 mL) to the reaction mixture and stir open to air for 15 minutes.
14. Transfer the aqueous fraction to a separatory funnel, washing with additional 1.2 M HCl (8 mL), and extract with a 1:1 diethyl ether/hexanes mixture (3 x 8 mL).
    Note: This organic wash contains excess phenyl iodide and other neutral by-products and can be disposed of.
15. Neutralize and make basic the aqueous solution by addition of saturated NH₄OH_(aq) (10 mL is a good starting point).
16. Extract the aqueous layer with dichloromethane (2 x 10 mL).
17. Dry the combined organic fractions over Na₂SO₄, then filter into a tared sample vial.
18. Evaporate the solvent in vacuo, giving the product (2-Methyl-N-(3-methylbenzyl)-4-phenylbutan-2-amine) as a yellow oil.

Results

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...

Discussion

Using the van der Waals Equation of State, the approximate pressure of these systems can be calculated⁴⁵

Eq. 1:          

Under the conditions in Protocol 1, we can assume 26.3 mg of CO₂ gives n =5.98 x 10^-4 ...

Materials

List of materials used in this article

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