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KlementineJBS / USYD_PhD_ELN

This repository forms the electronic laboratory notebook (ELN)for Klementine Burrell-Sander's PhD's
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KBS49-2 - Mitsunobu reaction with KBS28 and KBS45 #184

Closed KlementineJBS closed 6 months ago

KlementineJBS commented 7 months ago

Link to HIRAC and master page #174.

HIRAC KBS48 Mitsunobu reaction on linear amines.docx

Reaction scheme

KBS48 - Mitsunobu on linear amines

Outcome

KlementineJBS commented 7 months ago

19.02.24

  1. Added SM amine KBS45 (202 mg, 0.393 mmol), PPh3 (364.3 mg, 1.389 mmol, 3.5 equiv.) and SM KBS28 (228.8 mg, 1.016 mmol, 2.6 equiv.) to a dry flask
  2. Evacuted + backfilled with N2 x 5
  3. Added solvent (4 mL dry THF, 4 mL dry toluene)
  4. Cooled to 0 C
  5. Added DIAD (0.27 mL, 1.362 mmol, 3.5 equiv.)
  6. Left stirring from 4 pm
KlementineJBS commented 7 months ago

20.02.24

TLC at ~ 1.30 pm. Amine appears to be consumed but also didn't show up well in SM so could be due to TLC technique. Decided to run mass spec to check.

Eluent is 0.5:4.5:95 NH4OH:MeOH:DCM

KlementineJBS commented 7 months ago

LRMS of RM

KBS49-2 RM.d.zip KBS49-2 RM.pdf

Evidence of SM (513.11- [M-H]-), mono product (720.25- [M-H]-) and lots of PPh3O adducts (579+, 856(+2), 1133(+3). The same mass that was taken as evidence of bis product in #183, 951.31+, here shows up as 951.27 but with a 3+ charge - this suggests it is not in fact the bis product.

Took another spectrum ~5 hours later

KBS49-2 RM later 20-02-24.pdf KBS49-2 RM later 20-02-24.d.zip

KlementineJBS commented 7 months ago

20.02.24

Confused by this TLC as had thought that top spot of left plate was bis product, but this seems to have disappeared/reverted to mono in the later TLC (right), taken ~5.30 pm. Decided to do MS to check.

LRMS

KBS49-2 RM later 20-02-24.pdf KBS49-2 RM later 20-02-24.d.zip

Same as previously except new peak at 963.35- could represent [M+Cl]- for the bis compound, and 743.24+ is probably [M+Na]+ for mono compound.

KlementineJBS commented 7 months ago

21.02.24

Final TLC was still confusing.

Worked up anyway.

  1. Evaporated solvent under reduced pressure
  2. Triturated with ice cold diethyl ether (5 x 3 mL)
  3. Evaporated solvent again

vial weight: 15.7422 mass: 628.8 mg (0.677 mmol, well over 100%)

KlementineJBS commented 7 months ago

LRMS of crude product

Evidence of bis product (951+), as well as SM (513-), mono (720-) and lots of PPh3O.

KBS49-2 cr.d.zip KBS49-2 cr.pdf

KlementineJBS commented 7 months ago

H NMR

Seems to not have gone as cleanly as #183 and has obvious evidence of mono product, but seems that majority is still bis product. Will column soon.

nmr300_20240221_KBS49-2 cr_1.zip KBS49-2 cr.pdf

KlementineJBS commented 7 months ago

Column

Pooled fractions 3-6. F1-2 assumed to be DIAD - positive result with vanillin.

nmr300_20240223_KBS49-2 F3-6_1.zip KBS49-2 F3-6.pdf

Again pretty clean except for DIAD!

KlementineJBS commented 7 months ago

LRMS

KBS49-2 F3-6.pdf KBS49-2 F3-6.d.zip

KlementineJBS commented 7 months ago

Some relevant TLC plates

KlementineJBS commented 7 months ago

Column conditions

Advice from the internet suggested using DCM/acetone to remove DIAD. 5% acetone in DCM seems to offer the best separation, assuming that product is the white spot below DIAD. (Stained with vanillin)

KlementineJBS commented 7 months ago

Column b

image
Fractions Spots Vial tare (g) Mass (mg) NMR evidence LRMS evidence
1 A 15.8859 Fairly large amount of mono (?), no DIAD SM at 513.09-
2-6 ABC 15.9178 280.5 almost no DIAD, mix of bis and mono SM at 513.10-, mono at 720.25- and 744.11+and bis at 963.32- and 951.25+, also 313.16+, 603.15+
7-11 BC 15.9576 33.9 Bis, small amount of DIAD and mono 313.11+, didn't dissolve well
12-20 CD 15.7448 20.0 Bis, larger amount of DIAD, small amount of mono bis at 951.16+ and 963.27- but also 227.12+ (likely DIAD hydrazine), 313.12+, 603.20+, 773.32+
21-22 unclear
28-35 E 16.1142 12.4 tiny amount of product, mostly DIAD
36-53 E 15.8146 20.5 unclear, maybe just DIAD?

Seems that the first three spots ABC are mono (A) and bis (C) with some DIAD SM remaining (B). Hydrazine appears to be D/E.

Unreacted DIAD should be easier to remove than the hydrazine but this solvent system doesn't work for it.

KlementineJBS commented 6 months ago

H NMR

KBS49-2b fractions.pdf

nmr300_20240305_KBS49-2b F28-35_1.zip nmr300_20240305_KBS49-2b F7-11_1.zip nmr300_20240305_KBS49-2b F12-20_1.zip nmr300_20240304_KBS49-2b F1_1.zip nmr300_20240304_KBS49-2b F36-53_1.zip

KlementineJBS commented 6 months ago

LRMS

KBS49-2b F1.pdf KBS49-2b F2-6.pdf KBS49-2b F7-11.pdf KBS49-2b F12-20.pdf

KBS49-2b Fractions.d.zip

KlementineJBS commented 6 months ago

Yet another column

Considered some more column eluents. Ended up selecting 2.5% MeCN in DCM.

image

Ran column on F2-6 from previous attempt and got good separation of spots.

image image

Results

Fractions Vial tare (g) Mass (mg) substance
2-13 15.9051 19.1 unsure - DIAD adduct of bis product?
14-15 15.9252 3.2 mono, presumably SM
16-60 16.0097 mono, some DIAD still
61-74 15.7864 3.2 mono and bis
75-120 16.1755 - bis
KlementineJBS commented 6 months ago

LRMS

Identity of pure mono and bis fractions was confirmed by MS analysis.

bis product 951.35+ [M+Na]+ 963.25- [M+Cl]- with typical Cl isotope pattern

mono product 744.14+ [M+Na]+ 720.20- [M-H]- Some unknowns remain: 603.18+, 313.16+

KBS49-2c F16-60.pdf KBS49-2c F75-120.pdf KBS49-2c F75-120.d.zip

KlementineJBS commented 6 months ago

H NMR

KBS49-2c fractions.pdf

nmr300_20240312_KBS49-2c F16-60_1.zip nmr300_20240312_KBS49-2c bis_1.zip nmr300_20240312_KBS49-2c F14-15_1.zip nmr300_20240312_KBS49-2c F61-74_1.zip nmr300_20240311_KBS49-2c F75-120_1.zip nmr300_20240311_KBS49-2c F2-13_1.zip