1. Procedure (Note 1)
A.
[13C]Methyl-p-toluenesulfonate: (1).
2 A 250-mL, single-necked round-bottomed flask equipped with a Teflon-coated magnetic stirbar (35 mm x 15 mm, oval) is charged with
sodium hydroxide (30.3 g, 758 mmol, 5 equiv) (
Note 2). The flask is placed in an ice bath and
water (50 mL) (
Note 3) is added in one portion with stirring.
[13C]Methanol (5.00 g, 151.5 mmol, 1 equiv) (
Note 4) is weighed in a 12 mL syringe and slowly added to the hydroxide solution at 0 °C.
p-Toluenesulfonyl chloride (
TsCl) (34.7 g, 182 mmol, 1.2 equiv) (
Note 5) is weighed into a 250 mL single-necked conical flask equipped with a Teflon-coated magnetic stirbar (30 mm x 15 mm, oval).
Tetrahydrofuran (40 mL) (
Note 6) is added to this flask and stirred under nitrogen until all the
TsCl dissolves. This solution is added over five min via cannulation under nitrogen to the
NaOH reaction flask, which is cooled in an ice bath. The conical flask is rinsed with
THF (5 mL), which is then added to the round-bottomed flask. The internal sides of the RBF are then rinsed with additional
THF (5 mL) via syringe before sealing with a rubber septum and venting with a small needle (Figure 1A). The ice-bath is removed and the mixture is allowed to warm to 25 °C with stirring over 20 h (
Note 7). The reaction is neutralized by the slow addition of
acetic acid (33 mL, 576 mmol, 3.8 equiv) (
Note 8) at 0 °C over 5 min. The reaction mixture is left unstirred for 20 min at 0 °C to induce crystallization of sodium acetate (
Note 9). The reaction mixture is then filtered through a sintered glass funnel (100 mm tall, 50 mm wide) to remove solid sodium acetate and the filtrate layers of
THF and
water are separated in a 250 mL separating funnel. The aqueous phase is extracted with
ethyl acetate (2 x 60 mL) (
Note 10). The filter cake is dissolved in
water (150 mL) along with residue in the reaction flask and extracted with
ethyl acetate (2 x 60 mL). The organic phases are combined, transferred to a 500 mL separating funnel, washed with sat. aq.
Na2CO3 (100 mL) (
Note 11) and sat. aq.
NaCl (100 mL) (
Note 12), dried over
Na2SO4 (~40 g) for 10 min (
Note 13), and filtered through a sintered glass funnel (100 mm tall, 50 mm wide) into a 1 L round-bottomed flask. The sodium sulfate is placed on the same sintered glass funnel and rinsed using additional
ethyl acetate (40 mL). The organic solvent is concentrated by rotary evaporation at 40 °C (150 to 7 mmHg). A clear, colorless oil is obtained and transferred to a 250 mL round-bottomed flask with
diethyl ether rinsings (~50 mL) (
Note 14) and concentrated by rotary evaporation at 40 °C (600 to 7 mmHg). Additional
diethyl ether (~50 mL) is added and the concentration repeated to give 27.1 g (96%) of a slightly yellow oil (Figure 1B) (Notes
15 and
16).
Figure 1. (A) Reaction Assembly for Step A; (B) Product after work-up and concentration (photos provided by submitters)
B.
N-[13C]Methyl benzophenone imine (2). A dry 500 mL, two-necked round-bottomed flask equipped with a Teflon-coated magnetic stirbar (35 mm x 15 mm, oval), a nitrogen inlet and a rubber septum, is filled with a nitrogen atmosphere and maintained this way over the course of the reaction. The flask is charged with anhydrous
THF (175 mL) (
Note 17) and cooled to -78 °C (
Note 18).
n-Butyllithium (68 mL, 2.45 M in hexanes, 167 mmol, 1.10 equiv) (Notes
19 and
20) is added to the cooled
THF with efficient stirring (
Note 21).
Benzophenone imine (29 mL, 174 mmol, 1.15 equiv) is dissolved in
THF (40 mL), and the solution is added via cannulation over a period 10 min to give a blue solution (
Note 22). The
benzophenone imine flask is rinsed with
THF (10 mL) and added to the reaction flask (Figure 2A).
[13C]Methyl p-toluenesulfonate (
1) is dissolved in
THF (40 mL) and added via cannulation using a double-ended needle over 10 min to the cold (-78 °C) solution. The methyl
p-toluenesulfonate flask is rinsed with
THF (10 mL), which is added to the reaction flask. The stir-rate is increased to facilitate a mild vortex (
Note 23) and the flask is transferred to a large ice-bath and allowed to warm to 0 °C over 20 min (
Note 24). The flask is placed in a large water bath at 23 °C for a further 45 min. The reaction is quenched with
water (5 mL), transferred to a 1 L separatory funnel and partitioned with
water (200 mL) and Et
2O (200 mL) (
Note 25). The layers are separated and the aqueous layer is back extracted with Et
2O (50 mL). The combined organic layers are washed with sat. aq.
Na2CO3 (100 mL), sat. aq.
NaCl (100 mL), dried with
Na2SO4 (~40 g) for 10 min, and filtered through a sintered glass funnel (100 mm tall, 50 mm wide) into a 1 L round-bottomed flask. The
sodium sulfate is washed in the same sintered glass funnel using additional Et
2O (40 mL). The bright yellow solution is concentrated
in vacuo (600 to 7 mmHg, 40 °C) to give a yellow oil (35 g). The oil is treated with petroleum ether (250 mL, bp 35-60 °C) (
Note 26) to give a cloudy solution, which is placed in a fridge (4 °C) for 20 h. A short pad of Celite
TM 545 (3 cm deep) (
Note 27), which is first wetted with 50 mL of petroleum ether, is prepared in a 60 mL glass funnel (medium frit). The mixture is then filtered through the Celite
TM into a 500 mL round-bottomed flask using petroleum ether (150 mL). The solution is concentrated
in vacuo (40 °C, 500 to 120 to 7 mmHg) to give a yellow oil (32 g) (Figure 2B) (
Note 28). This material is used directly in the next reaction without further purification (
Note 29).
Figure 2. (A) Reaction Assembly for Step B; (B) Product after work-up and concentration (photos provided by checkers)
F.
Trimethylsilyldiazo[13C]methane (6). Trimethylsilyl[
13C]-amine hydrochloride (10 g) is transferred to a 125 mL Erlenmeyer flask.
Diethyl ether (30 mL) (
Note 14) is added, followed by a freshly prepared solution of 2M aq
NaOH (40 mL) (
Note 2). The biphasic solution is swirled until all solids are dissolved, and the colorless solution is transferred to a 250 mL separatory funnel. The Erlenmeyer flask is rinsed with additional 2M
NaOH solution (30 mL) and ether (10 mL), both of which are added to the separatory funnel. The aqueous layer is saturated with
NaCl (15.4 g, 0.22 g per mL of 2N
NaOH solution). The organic layer is removed and the aqueous layer is extracted with ether (2 x 25 mL). The combined organic extracts are dried over
Na2SO4 (5 g) for 10 min, then filtered through a sintered funnel to a 250 mL round-bottomed flask. The
Na2SO4 is rinsed with ether (10 mL). The colorless solution is stirred using a Teflon-coated magnetic stirbar (35 mm x 15 mm, oval). The flask is placed in an oil bath and fitted with a Vigreux column, short condenser and collection flask (
Note 53) (Figure 6A and 6B).
Diethyl ether is slowly distilled from the colorless solution at 46 °C for 4 h, then at 48 °C for another 4 h. The remaining colorless solution is stored at -10 °C overnight.
Figure 6. (A) Vigreux column used by the checker; (B) Vigreux column
showing indents (photos provided by checkers)
Trimethylsilyl[
13C]methylamine as a solution in
diethyl ether in a 250 mL round-bottomed flask is placed in a water bath. Anhydrous 2-Me-THF (45 mL) (
Note 54) is added followed by
3-nitrophenol (1 g) (
Note 55) and
2,2-diethyl-1,3-propanedinitrite (
5) (20 mL). A yellow solution is obtained. The single-necked round-bottomed flask is fitted with a nitrogen gas adapter and stirred at 25 °C for 1 h. The nitrogen gas adapter is removed and replaced with a Vigreux column (
Note 53), which is a topped with a gas adapter connected to a series of two solvent traps via Tygon tubing. The second solvent trap is connected to a digitally controlled (vacuum control V-850) vacuum pump (Buchi V-700) (
Note 56) (Figure 7A-B).). The first trap is cooled at -78 °C in a dry-ice/
acetone bath, while the second is cooled with liquid nitrogen (Figure 7).
Figure 7. (A) Set-up for distillation step (photo provided by checker);
(B) Diagram of set-up for distillation step (diagram from submitter)
The distillation is started at room temperature and the vacuum slowly lowered to 75 mmHg (75 mmHg/5 min) in 45 min. Gas evolution starts around 360 mmHg, and the evolution (bubbling) is rapid at about 80 mmHg. The vacuum is left at 20 mmHg for 30 min, then at 15 mmHg for another 30 min. The bright yellow distillate (
Note 57) is warmed to 25 °C and transferred to a 250 mL separatory funnel and rinsed with 2 mL of 2-Me-THF. The solution is washed with sat. aq.
NaCl (2 x 10 mL), dried for 10 min over
MgSO4 (2 g) (
Note 58), gravity filtered through a sintered funnel, and rinsed with 2-MeTHF (3 mL). A total of about 50 mL of the product (
Note 59) solution was obtained, and the solution is stored over molecular sieves (
Note 60). The concentration of the trimethylsilyl[
13C]methane is determined by Q NMR comparison to
bibenzyl (
Note 61) to be 0.66 M, which indicates the formation of ca. 33 mmol of the product. The reaction flask contains 37 mL of undistilled deep yellow solution (
Note 62).
2. Notes
1. Prior to performing each reaction, a thorough hazard analysis and risk assessment should be carried out with regard to each chemical substance and experimental operation on the scale planned and in the context of the laboratory where the procedures will be carried out. Guidelines for carrying out risk assessments and for analyzing the hazards associated with chemicals can be found in references such as Chapter 4 of "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at
https://www.nap.edu/catalog/12654/prudent-practices-in-the-laboratory-handling-and-management-of-chemical. See also "Identifying and Evaluating Hazards in Research Laboratories" (American Chemical Society, 2015) which is available via the associated website "Hazard Assessment in Research Laboratories" at
https://www.acs.org/content/acs/en/about/governance/committees/chemicalsafety/hazard-assessment.html. In the case of this procedure, the risk assessment should include (but not necessarily be limited to) an evaluation of the potential hazards associated with (
[13C]methanol,
p-toluenesulfonyl chloride,
tetrahydrofuran,
acetic acid,
ethyl acetate,
sodium carbonate,
sodium sulfate,
diethyl ether,
n-butyllithium,
benzophenone imine, petroleum ether,
diisopropylamine,
chlorotrimethylsilane,
acetone,
methyl tert-butyl ether,
palladium on
carbon,
hydrogen gas, 2 M
hydrogen chloride (
HCl) in
diethyl ether,
isopropanol,
sodium chloride,
2-methyltetrahydrofuran,
3-nitrophenol,
sodium nitrite and
2,2-diethyl-1,3-propanediol). Step D involves the use of hydrogen gas, this is highly flammable and explosive, keep away from all sources of heat and potential sources of electrical sparks. Step D also involves the use of
palladium on
carbon, this can be pyrophoric, especially after use in a hydrogenation reaction. The filtration should be conducted under a flow of nitrogen and the filter cake should never be allowed to become completely dry. Once the filtration is complete, the
palladium on
carbon residue should be immediately moistened with
water to prevent spontaneous ignition. Step E involves the preparation of
2,2-diethyl-1,3-propanedinitrite, alkyl nitrates are known vasodilators and should not be removed from the fume hood unless stored in a well-sealed container. Step F involves the preparation of
trimethylsilyldiazo[13C]methane, this should be regarded as highly toxic and must be handled with all precautions appropriate for work with highly toxic substances. Ensure fume cupboard is working correctly before commencing use/preparation of this reagent and do not remove it from the fume cupboard unless stored in a well-sealed container. An emergency quenching solution of methanol:
acetic acid 10:1 should be on hand in the case of a spill.
2.
Sodium hydroxide (pellets, 98.9%) was purchased from Fisher Scientific and used as received.
3. Deionized
water was used.
4. The checkers used
[13C]methanol purchased from Sigma-Aldrich with 100% purity by GC and 99%
13C-labelled.
[13C]Methanol was purchased by the submitters from CK-isotopes (98% purity, 99%
13 C-labelled) and used as received.
5. The checkers used
p-toluenesulfonyl chloride purchased from Sigma-Aldrich (99%). The submitters purchased
p-toluenesulfonyl chloride (99%) from Acros Organics and used the material as received.
6. The checkers used
tetrahydrofuran purchased from Sigma-Aldrich (>99.9% with 250 ppm BHT).
Tetrahydrofuran (>99% with 250 ppm BHT) was purchased by the submitters from Fisher Scientific and used as received.
7. Vigorous stirring with a large stir bar is essential to facilitate efficient mixing. The submitters reported stirring at 800 rpm to achieve a mild vortex.
8.
Acetic acid (>99.5%) was purchased from Sigma Aldrich and used as received.
9. The reaction flask may be scratched with a spatula to initiate crystallization.
10.
Ethyl acetate (>99%) was purchased from Fisher Scientific and used as received.
11.
Sodium carbonate (>99%) was purchased from Fisher Scientific and used as received.
12.
Sodium chloride (99%) was purchased from Fisher Scientific and used as received.
13.
Sodium sulfate (anhydrous, granular, 99%) was purchased from Fisher Scientific and used as received.
14.
Diethyl ether (>99%) was purchased from Fisher Scientific and used as received.
15. Characterization data for
[13C]Methyl p-toluenesulfonate (
1):
1H NMR
pdf(400 MHz, CDCl
3) δ : 2.46 (s, 3H), 3.74 (d,
J = 150 Hz, 3H), 7.36 (d,
J = 8.5 Hz, 2H), 7.79 (d,
J = 8.5 Hz, 2H);
13C {
1H} NMR
pdf(101 MHz, CDCl
3) δ: 21.6, 56.1, 128.1, 129.9, 132.2, 144.9.
16. The weight percent (wt%) purity was determined to be 98.4 wt% by quantitative
1H NMR (Q NMR) using dimethylsulfone (99.96 wt%) purchased from Sigma Aldrich as an internal standard
.
17. The checkers used
THF (anhydrous, >99.9% stabilized with 250 ppm BHT) purchased from Sigma-Aldrich.
Tetrahydrofuran (>99.8%, unstabilized) was purchased by the submitters from Fisher Scientific and dried by passage through an activated alumina column under argon.
18. The submitters used an insulated bucket filled with dry ice and
acetone to maintain the temperature at -78 °C.
19. The checkers used
n-butyllithium (2.5 M in hexanes) from Acros Organics. The certificate of analysis indicated 2.67 M. The
n-butyllithium solution was used as received and was not titrated.
n-Butyllithium (2.5 M in hexanes) was purchased by the submitters from Acros Organics and titrated before use (Note 20).
20. Freshly titrated
n-butyllithium in hexanes (167 mL) should be used, although the volume required will depend on the concentration of the
n-butyllithium solution. The submitters titrated
n-butyllithium against
diphenylacetic acid (2 mmol) in
tetrahydrofuran (15 mL) at room temp (approx. 20 °C in a
water bath) until the appearance of a consistent yellow color.
3 The titration was performed in duplicate.
21. The submitters stirred the reaction at 340 rpm, which resulted in a slight vortex being visible.
22. The checkers purchased
benzophenone imine (98%) from Oakwood Products, Inc.
Benzophenone imine (98%) was purchased by the submitters from Fluorochem and used as received. The submitters report the solution to be a dark red color.
23. The submitters stirred the reaction at 500 rpm, which resulted in a mild vortex being visible.
24. The color of the reaction at this stage can vary from red to blue to black with no noticeable effect on yield or purity after the quench and workup.
25. As the product imine is susceptible to hydrolysis the work-up should be conducted swiftly. An insoluble white precipitate may form at this stage, in such cases the workup should be followed as normal, any precipitate remaining in the organic layer after separation will be removed by filtration.
26. Petroleum ether (bp 35-60, ACS reagent) was purchased from Sigma-Aldrich.
27. The checkers used Celite
TM 545 from Fisher, rinsed with petroleum ether before use. Kieselguhr washed with acid was purchased from Fisher Scientific by the submitters and used as received.
28.
N-[
13C]Methyl benzophenone imine, relevant NMR resonances in crude material:
1H NMR
pdf(400 MHz, CDCl
3) δ : 3.25 (d,
J = 135 Hz, 3H), 7.15-7.19 (m, 2H), 7.29-7.50 (m, 6H), 7.56-7.62 (m, 2H);
13C {
1H} NMR
pdf(101 MHz, CDCl
3) δ : 41.5, 127.8, 128.0, 128.2, 128.3, 128.5, 129.8, 136.5 (d,
J = 6.1 Hz), 139.8 (d,
J = 7 Hz), 169.6 (d,
J= 3.9 Hz).
29. The submitters found this compound to be sensitive to chromatographic media, undergoing hydrolysis to benzophenone, which has an identical R
f to that of the desired product in numerous solvent systems. Distillation is difficult due to the similar boiling points of the starting material and product. If this material were required in pure form the submitters would recommend using equimolar amounts of starting materials rather than the ratios employed here.
30. The checkers used
diisopropylamine (redistilled, 99.95%) from Sigma-Aldrich without further purification.
Diisopropylamine (>99.5%) was purchased from Sigma Aldrich by the submitters and was purified by distillation over calcium hydride under N
2 before use.
31. The checkers used a dry ice/
acetone bath (-78 °C), followed by a dry ice/chloroform bath (-60 °C). The submitters utilized an insulated bucket filled with ethanol and cooled with an immersion cooler. An overhead mechanical stirrer with a propeller type paddle (35mm) was used by the submitters to stir the cooling bath.
32. The checkers used TMSCl from Sigma-Aldrich (≥ 99.0% (GC)) without purification.
Chlorotrimethylsilane (98%) was purchased from Sigma Aldrich by the submitters and purified by distillation over calcium hydride under N
2 before use.
33. At higher temperatures, such as -30 °C, double silylation of the imine methyl group is much more prominent. As such, the reaction was examined at -45 °C and found to provide a product ratio of 0:96:4 (starting material : product : disilylated material), demonstrating some flexibility with temperature control.
34.
Acetone (>99%) was purchased from Fisher Scientific and used as received.
35. Quenching with
water or an organic alcohol caused protodesilylation; therefore,
acetone should be used to quench the reaction.
36. The checker used a 3 cm tall plug of Celite
TM 545 filter aid (not acid-washed) powder from Fisher, and the Celite
TM was rinsed with petroleum ether (50 mL) before use. The submitters used "Kieselgur washed with acid" for filtration to remove lithium chloride. Other filter aids may provide similar results; however, an aqueous workup should be avoided as protodesilylation can occur.
37. The crude material is a mixture of starting material, product and disilylated material, which contain
1H NMR (CDCl
3) resonances at 3.26, 3.31, and 3.04 ppm, respectively. The ratio of products (based solely on these three compounds) can be determined by the following calculation; Product % = (b/2)*100/((a/3)+(b/2)+(c/1)). Where a = starting material, b = product and c = disilylated material by integration of their respective
1H NMR peaks.
38.
N-[
13C]Methyl(trimethylsilyl)benzophenone imine, relevant peaks in crude material:
1H NMR
pdf(400 MHz, CDCl
3) δ : 0.2 (d,
J =1.5 Hz, 9H), 3.27 (d,
J = 127.5 Hz, 2H), 7.11 (m, 2H), 7.28-7.30 (m, 2H), 7.36-7.50 (m, 3H), 7.50-7.53 (m, 2H);
13C {
1H} NMR
pdf(101 MHz, CDCl
3) δ : -0.1 (d,
J = 3.6 Hz), 130.0, 130.1, 130.2, 130.5, 130.6, 131.3, 138.9 (d,
J = 5.7 Hz), 142.7 (d,
J = 6.7 Hz), 167.0 (d,
J = 4.2 Hz).
39. The submitters found this compound to be sensitive to chromatographic media, undergoing hydrolysis to benzophenone, which has an identical R
f to the desired product in numerous solvent systems. Vacuum distillation caused decomposition of the product to give a black tar.
40. The submitters performed the hydrogenolysis using the following procedure. The 500 mL, single-necked round-bottomed flask containing
N-[13C] methyl(trimethylsilyl)-benzophenone imine from the previous step is equipped with a Teflon-coated magnetic stir bar (35 mm x 15 mm, oval), flushed with nitrogen gas and charged with
methyl tert-butyl ether (200 mL). Stirring is commenced and
palladium on
carbon (7.3 g, 10% wt/wt
Pd on
carbon, 6.8 mmol, 5 mol%
Pd) (
Note 42) is added followed by additional
methyl tert-butyl ether (70 mL) (
Note 41) to rinse the sides of the flask. The flask is sealed with a rubber septum and a double walled hydrogen balloon is added (Notes
63 and
64) (Figure 8A and 8B). The flask is flushed with
hydrogen by piercing the rubber septum with a small needle (40 mm, gauge 20) as an outlet. After 15 min the outlet needle is removed, the hydrogen balloon is refilled and the reaction left under this pressure at room temperature (23 °C) overnight. The following morning the balloon is replaced with a freshly made hydrogen balloon. This balloon should be refilled once more in the before being left over a second night. The following morning the reaction is checked by TLC (Notes
65,
66, and
Note 67) (Figure 8C and 8D).
Figure 8. (A) Reaction Assembly for Step D; (B) Double walled hydrogen balloon; (C) TLC of starting material stained with I2. (D) TLC at end of reaction stained with I2; (E) Filtration of reaction mixture under a blanket of N2 gas to give a clear solution (photos provided by the submitters)
Once complete, the remaining
hydrogen gas is released slowly in the fume hood, the flask is flushed with nitrogen and the crude mixture filtered through a ~2 cm pad of kieselgur into a 1 L round-bottomed flask under an inverted funnel dispensing nitrogen gas (Figure 8E). The kielselgur is washed with methyl
tert-butyl ether (MTBE) (2 x 50 mL).
Water (~5 mL) is added to the used kieselgur pad, which is then disposed of as heavy metal waste. The clear, near-colorless filtrate obtained is degassed with stirring and gentle nitrogen bubbling over 10 min to remove any ammonia or methylamine side products (Figure 9A). Bubbling is suspended and the 1 L round-bottomed flask is equipped with a Teflon-coated magnetic stirbar (35 mm x 15 mm, oval) and placed in a
water bath at room temperature. A 250 mL separating funnel is charged with 2 M
HCl in Et
2O (89 mL, 178 mmol, 1.3 equiv) (Note 45). The
HCl solution is then slowly added via the 250 mL separating funnel to the reaction mixture over ~15-20 mins with slow stirring (
Note 46) (Figure 9B). The resulting suspension is filtered through a sintered glass funnel (
Note 47) to collect the solid trimethylsilylmethylamine hydrochloride salt. MTBE (30 mL) is added to the solid and the mixture stirred to form a slurry before removal of the solvent by further vacuum filtration and collection of the product as a fluffy white solid (15 - 17 g) (
Note 48).
Figure 9: (A) Degassing of reaction mixture with N2 bubbling through a needle. (B) Set-up for addition of 2 M HCl in Et2O to reaction mixture. (C) Suspension after recrystallization step. (D) Crystals collected by filtration. (E) Product in a 100 mL screw cap flask
The product is transferred to a 1 L single-necked round-bottomed flask and suspended in
isopropanol (~105 mL, 6 mL/g of crude material) (
Note 49). The suspension is heated to ~80 °C with a heat gun and swirling by hand to give a clear solution with a slight yellow coloration. This hot solution is swirled by hand while warm (~40 °C) MTBE (~313 mL, 18 mL/g of crude material) is added slowly. Material begins to precipitate before the MTBE addition is complete. The resulting suspension is allowed to cool to room temperature over 30 min, placed in a freezer (-20 °C) and left overnight (16 h). The resulting suspension is filtered with suction through a sintered glass funnel to collect the solid trimethylsilylmethylamine hydrochloride salt (
Note 47) (Figure 9C-D). The resulting white crystalline solid is washed with MTBE (50 mL) then dried with suction under an inverted funnel dispensing nitrogen gas for 20 min. The white crystalline solid (13.0-14.5 g, 61-68% yield from methanol) is transferred to a 100 mL screw cap flask for storage (Figure 9E) (Notes
50 and
51).
41. The checkers used
methyl tert-butyl ether purchased from Sigma-Aldrich (ACS reagent, > 99%).
Methyl tert-butyl ether (99%) was purchased by the submitters from Acros Organics and used as received.
42.
Palladium on
carbon (10 wt. % loading, matrix activated carbon support) was purchased from Sigma Aldrich and used as received.
43.
Hydrogen gas (>99%) was purchased from BOC gases.
44. The checkers used Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLCMS) using a medium polar method: run time 3.0 min, gradient 95%
water (0.1% formic acid) and 5% MeCN to 5%
water in 2.1 min, hold to 3 min at 5%
water, flow 2.5 mL/min; column: BEH C18 (2.1 mm × 50 mm, 1.7 μm),
m/z 120-1000, 0.3 μL injection. The starting material showed at 1.03 min, MH
+ = 269. A new peak was observed at 1.85 min corresponding to diphenylmethane (UV active), though no mass peak was observed.
45. 2M
HCl in
diethyl ether was purchased by the checkers from Sigma-Aldrich. The submitters purchased 2M
HCl in
diethyl ether from VWR (Alfa Aesar brand) and used the material as received.
46. The submitters stirred the mixture at 360 rpm until the slurry became too thick for magnetic stirring, at which point gentle swirling by hand was sufficient.
47. A fine porosity sintered glass funnel is required to avoid the frit becoming blocked. The submitters used grade 3, (16-40 μm pore size), 65 mm diameter, 60 mm high. The filtration is slow but can be accelerated by gently stirring the product slurry with a spatula.
48. The purity of product (
1H NMR
pdf and
13C NMR
pdf) obtained at this stage varied from 90-95% by QNMR with dimethylsulfone (see
Note 51 for Q NMR of purified material); therefore, further purification by a trituration/crystallization is carried out. Alternatively, the crude material can be carried through the next step with no complications, which slightly enhances the overall yield of TMSdiazomethane from methanol by eliminating loss from crystallization. Use of the crude material should only be performed if no methylamine hydrochloride (δ 2.61 in CD
3OD) is detected in the
1H NMR spectrum of the crude material, since methylamine hydrochloride will form diazomethane in the next step.
49.
Isopropanol (Chromasolv plus, 99.9%) from Sigma-Aldrich was used.
50. Characterization data for trimethylsilyl[
13C]methylamine hydro-chloride (
4): mp 239-242 °C (
iPrOH:MeO
t Bu, 1:3);
1H NMR
pdf(400 MHz, CD
3OD) δ : 0.22 (d,
J = 2.5 Hz, 9H), 2.39 (d,
J = 131 Hz, 2H).
13C {
1H} NMR
pdf(101 MHz, CD
3OD) δ : -2.8 (d,
J = 4.5 Hz), 29.5. IR (ATR) 3200-2800, 2951, 1603, 1503, 1412, 1245 cm
-1; HRMS ESI-MS
m/z calcd for
13C
1C
3H
14NSi [M-Cl]
+: 105.09236, found: 105.09180.
51. The weight percent (wt%) purity was determined to be 99.4 wt% by quantitative
1H NMR (Q NMR)
pdf using dimethylsulfone purchased from Sigma Aldrich as an internal standard (99.96 wt%).
52. Characterization data for
2,2-diethyl-1,3-propanedinitrite (
5): bp 20 °C (3.5 mmHg);
1H NMR
pdf(400 MHz, CDCl
3) δ : 0.87 (t,
J = 7.5 Hz, 6H), 1.38 (q,
J = 7.5 Hz, 4H), 4.57 (s, 4H);
13C {
1H} NMR
pdf(101 MHz, CDCl
3) δ : 7.2, 23.3, 40.9, 69.7.
53. The submitters used a 24 cm tall, B24 Vigreux column (16 cm of effective column, actual height 24 cm) fitted with a condenser and collection flask. The Vigreux column should have deep indents/fingers for efficient separation (Figure 6A-B). The checkers used a slightly different Vigreux column with no deep indents, see photos.
54.
2-Methyltetrahydrofuran (anhydrous, inhibitor free, >99%) was purchased from Sigma Aldrich and used as received.
55.
3-Nitrophenol (99%) was purchased from Sigma Aldrich and used as received.
56. The checker used a digitally controlled (vacuum control V-850) vacuum pump (Büchi V700). The submitters used a vacuubrand MD 4 NT VARIO diaphragm pump with a CVC 3000 vacuum controller. The vacuum pump exhaust should be vented into a working fume cupboard.
57. The submitters added additional 2-MeTHF (10 mL) to the crude reaction mixture and performed a second distillation prior to washing with sat. aq.
NaCl solution.
58.
Magnesium sulfate (anhydrous, 99%) was purchased from Fisher Scientific and used as received.
59.
Trimethylsilyldiazo[13C]methane, relevant resonances in crude solution, both
1H and
13C NMR spectra are referenced to tetramethylsilane at 0.0 ppm:
1H NMR
pdf(400 MHz, 2-MeTHF/Et
2O) δ : 0.14 (d,
J = 2.8 Hz, 9H), 2.71 (d,
J = 171.6 Hz, 1H);
13C {
1H} NMR
pdf(101 MHz, 2-MeTHF/Et
2O) δ : -1.0 (d,
J = 5.1 Hz), 21.2; HRMS ESI-MS
m/z calcd for C
313C
1H
10N
2Si [M]
+ 115.16413, found: 115.06501. Slight variation in the reported chemical shifts is observed as a result of different ratios of Et
2O:2-MeTHF. CHCl
3 may be used as an alternative reference at 7.87 ppm in the
1H NMR spectrum and 79.1 ppm in the
13C NMR spectrum.
60. Molecular sieves (3Å, beads 8-12 mesh) were purchased by the checkers from Aldrich and activated before use. Molecular sieves (3Å, general purpose grade) were purchased by the submitters from Fisher Scientific and stored in an oven at 220 °C for a minimum of 5 days before use.
61. To determine the concentration of trimethylsilyldiazo[
13 C]methane, bibenzyl (42.3 mg) was weighed in an amber vial, and then 0.7 mL of the trimethylsilyldiazomethane solution was added and swirled to dissolve the
bibenzyl. CDCl
3 (Sigma-Aldrich, 99.8 atom% D) was added and
1H NMR spectrum was acquired. The concentration of TMSdiazomethane was then calculated using the following calculation; C=(4*m*b)/(M*V*a) where M = molecular weight of
bibenzyl, V = volume of
trimethylsilyldiazo[13C]methane solution, m = mass of
bibenzyl, a = integral value of the methylene protons (δ 2.89, (s)) of
bibenzyl and b = integral value of the methine proton (δ 2.71 (d)) of
trimethylsilyldiazo[13C]methane.
62. No attempts were made to continue the distillation and improve the yield.
63. Thick latex balloons (0.015 inch (15 mil)) rated for 12 L gas volume were purchased from Sigma Aldrich.
64. The submitters used two 0.015 inch (15 mil) thick latex balloons attached to a 5 mL disposable syringe barrel with electrical tape and a small metal hose clamp (Figure 8B). A needle (40 mm, 20 gauge) is attached and used to pierce the rubber septum.
65. Glass-backed TLC plates (Al
2O
3) were purchased from Sigma Aldrich.
66. Using petroleum ether:Et
2O (19:1) as the eluent, the reaction is deemed complete when only diphenylmethane (R
f = 0.9) and a baseline spot are visible. The spots can be viewed by fluorescence quenching on suitable TLC plates at 254 nm or by I
2 staining. (Figure 8C-D).
67. The time required for the hydrogenation reaction varies with scale. When the reaction is performed on smaller scales (ca. 30 mmol), the reaction was complete overnight (16 h). On full scale the reaction will theoretically consume 7.8 L of H
2 gas. Replacing the balloons to ensure an excess of H
2 is essential.
3. Discussion
Appendix
Chemical Abstracts Nomenclature (Registry Number)
[13C]Methanol: Methanol-13C; (14742-26-8)
p-Toluenesulfonyl chloride: Benzenesulfonyl chloride, 4-methyl-; (98-59-9)
Tetrahydrofuran: Furan, tetrahydro-; (109-99-9)
Acetic acid: Acetic acid; (64-19-7)
Sodium carbonate: Carbonic acid disodium salt; (497-19-8)
Sodium sulfate: Sulfuric acid disodium salt; (7757-82-6)
n-Butyllithium: Lithium, butyl-; (109-72-8)
Diphenylacetic acid: Benzeneacetic acid, α-phenyl-; (117-34-0)
Benzophenone imine: (1013-88-3)
Diisopropylamine: 2-Propanamine, N-(1-methylethyl)-; (108-18-9)
Chlorotrimethylsilane: Silane, chlorotrimethyl-; (75-77-4)
Methyl tert-butyl ether: Propane, 2-methoxy-2-methyl-; (1634-04-4)
2 M HCl in diethyl ether: Hydrochloric acid; (7647-01-0)
Dimethylsulfone: Methane, sulfonylbis-; (67-71-0)
Isopropanol: 2-Propanol; (67-63-0)
2-Methyltetrahydrofuran: Furan, tetrahydro-2-methyl-; (96-47-9)
3-Nitrophenol: Phenol, 3-nitro-; (554-84-7)
Sodium nitrite: Nitrous acid, sodium salt; (7632-00-0)
2,2-Diethyl-1,3-propanediol: (115-76-4)
Hydrochloric acid: Hydrochloric acid; (7647-01-0)
Magnesium sulfate: Sulfuric acid magnesium salt (1:1); (7487-88-9)
Bibenzyl: Benzene, 1,1'-(1,2-ethanediyl)bis-; (103-29-7)
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