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was dissolved in EtOAc (250 mL), extracted with 1 M HCl (3 × 75 mL),
and extracted from the combined aqueous layers with CH2Cl2
(3 × 75 mL). The combined CH2Cl2 layers were washed with 5%
Na2CO3 (75 mL) and concentrated. This residue was dissolved in
EtOAc (150 mL), washed with sat. NH4Cl (50 mL), 50% sat. NH4Cl
(2 × 50 mL), and a combination of 5% Na2CO3 and 1 M NaBF4
(2 × 25 mL), dried over Na2SO4, and concentrated. The resulting pale
yellow solid was recrystallized from ∼10:1 EtOAc/hexanes (125 mL)
for 6 days at −20 °C to provide a white solid (5.67 g, 79%). 1H NMR
(500 MHz, CDCl3) δ 4.52 (t, J = 5.6 Hz, 1H), 3.89 (hept, J = 6.7 Hz,
8H), 3.31 (dt, J = 7.4, 5.8 Hz, 2H), 1.59 (m, 2H), 1.39−1.18 (over-
lapping signals, 50H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 161.0, 121.9, 120.4, 50.3, 42.9, 32.1, 22.1, 20.3, 14.0. HRMS
(ESI+) for C35H65N7 [MH]+ m/z calcd 584.5380, found 584.5374.
Synthesis of GC2 base 8·HBF4. Compound 7.16c (1.17 g, 7.60
mmol, 1.00 equiv) in CH2Cl2 (8 mL) was added to a solution of 1
(7.68 g, 30.6 mmol, 4.02 equiv) in CH2Cl2 (200 mL) at 0 °C. After
stirring for 42 h, the CH2Cl2 was evaporated, the residue was
suspended in EtOAc (200 mL), washed with 50% sat. NH4Cl (2 ×
75 mL) and a combination of 5% Na2CO3 and 1 M NaBF4 (2 ×
25 mL), dried over Na2SO4, and concentrated. This solid was recrystallized
from ∼2:1 EtOAc/hexanes (50 mL) for 2 days at −20 °C to provide a
whose pKBH+ values discussed herein are literature values, except the
PC3 base 12 which was estimated from Figure 3. See the SI for complete
details.
Preparation of Single Crystals for X-ray Diffraction. In a
2 dram vial, higher-order superbase salts were dissolved in hot EtOAc,
cooled to rt, and then allowed to stand. In some cases, the vial was also
placed in a sealed jar containing a layer of hexanes to slowly diffuse
these vapors into the EtOAc solution.
C3 base 2·HBF4: salt (150 mg) in EtOAc (3 mL), standing with
hexanes diffusion for 3 days.
CG2 base 4·HBF4: salt (100 mg) in EtOAc (3 mL), seeded with a
few grains of the salt, then standing alone for 1 day and then with
hexanes diffusion for 5 days.
GC2 base 6·HBF4: salt (150 mg) in EtOAc (3 mL), standing with
hexanes diffusion for 2 days.
PC1 base 14·HBF4: salt (150 mg) in EtOAc (5 mL), standing alone
for 3 days and then with hexanes diffusion for 1 day.
GP2 base 10·HBF4: salt (100 mg) in EtOAc (5 mL), standing alone
for 2 days.
Conjugate Additions of α-Aryl Esters and Nitriles. KOt-Bu
(1 M in t-BuOH or THF, 25 μL, 0.025 mmol, 0.025 equiv) was added
to 8·HBF4 (20.3 mg, 0.0302 mmol, 0.030 equiv) in THF (3 mL),
followed by the α-aryl ester or nitrile and Michael acceptor (1 mmol
scale, see SI for details). After stirring for 8−12 h, acetic acid was
added (2 drops), and the reaction was concentrated. The residue was
purified by chromatography (EtOAc/hexanes) on silica gel (40 mL) to
afford the desired adducts. Experiments were also performed using
isolated free bases 8 or P4-tBu from a glovebox.
1
white solid (3.44 g, 67%). H NMR (500 MHz, CDCl3) δ 4.09 (s, 1H),
3.87 (hept, J = 6.8 Hz, 8H), 1.43 (s, 9H), 1.29 (d, J = 6.8 Hz, 48H). 13C
NMR (126 MHz, CDCl3) δ 159.4, 121.5, 120.4, 51.9, 50.3, 29.3, 22.1.
HRMS (ESI+) for C35H65N7 [MH]+ m/z calcd 584.5380, found 584.5374.
Synthesis of PC1 Base 14·HBF4 Compound 13.19 (1.05 g,
5.04 mmol, 1.00 equiv) in THF (5 mL) was added dropwise to
a solution of 1 (2.82 g, 11.2 mmol, 2.23 equiv) in THF (70 mL) at
−78 °C. After 4 h, the reaction was warmed to 0 °C, and after 2 h,
piperidine (2.5 mL, 25 mmol, 5.0 equiv) was added. After 24 h of
warming to rt, the reaction was concentrated, and the residue was
suspended in EtOAc (150 mL), washed with sat. NH4Cl (2 × 75 mL),
50% sat. NH4Cl (75 mL), and a combination of 0.5 M Na2CO3 and
1 M NaBF4 (2 × 20 mL), dried over Na2SO4, and concentrated. The
resulting yellow solid (3.21 g) was recrystallized from ∼2:1 EtOAc/
hexanes (100 mL) while diffusing in further hexanes at −20 °C to
provide the phosphazene·HBF4 as a white solid (2.71 g, 88%). 1H NMR
(500 MHz, CDCl3) δ 3.92 (hept, J = 6.9 Hz, 4H), 3.28 (d, J = 12.1 Hz,
1H), 3.19 (m, 4H), 3.08 (m, 4H), 1.63−1.52 (m, 12H), 1.33 (d, J =
7.0 Hz, 24H), 1.29 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 119.4 (d,
JPC = 22.1 Hz), 118.5, 52.1, 49.7, 46.2, 31.4 (d, JPC = 3.9 Hz), 26.1 (d,
JPC = 5.3 Hz), 24.4, 22.0. 31P NMR (121 MHz, CDCl3) δ 16.18. HRMS
(ESI+) for C29H57N6P [MH]+ m/z calcd 521.4461, found 521.4469.
Liberation of Higher-Order Superbases. In a glovebox, KOt-Bu
(1 M in THF, 1.0 equiv) was added to the superbase conjugate acid
salt in THF (∼0.2 M) at room temperature. After 5−10 min, the solu-
tion was filtered (0.2 μm PTFE), washed with THF, concentrated,
redissolved in PhMe, filtered again, and concentrated.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data, pKBH+ measure-
ments, and crystallographic data (CIF). The Supporting
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by NIHGMS (R01 GM102611).
E.D.N. is grateful for the Arun Guthikonda Memorial Graduate
Fellowship. We thank Serge Ruccolo, Michelle Neary, and the
Parkin group for X-ray structure determination, and the National
Science Foundation (CHE-0619638) is thanked for acquisition
of an X-ray diffractometer. We also thank the Owen group for
the use of their glovebox.
pKBH+ Measurements. Stock solutions of the HX salt of the
“substrate” superbase being studied (0.0667 M, 0.60 mL, 0.040 mmol)
and a reference free base (0.200 M, 0.20 mL, 0.040 mmol) were mixed
in NMR tubes under inert atmosphere. CD3CN was employed for all
experiments, which were performed using a dual manifold, except for
the GC2 (6) and GP2 (10) bases, which employed d8-THF and were
performed in a glovebox. The mixture was analyzed by 1H NMR
spectroscopy (as well as by 13C NMR for measurements in d8-THF).
The extents of protonation of both the substrate superbase and the
reference base were determined by comparison to the spectra of the
HX salt and the free base of each component. These data were used to
calculate the relative basicities of the substrate superbase and the
reference base, and this value was compared to the known pKBH+
value of the reference base to obtain the pKBH+ value of the substrate.
Measurements were performed in triplicate. Corrections were made
for the observed relative NMR integrations and to convert THF data
to the acetonitrile scale.
REFERENCES
(1) Caubere, P. Chem. Rev. 1993, 93, 2317.
(2) Superbases for Organic Synthesis: Guanidines, Amidines, Phospha-
zenes and Related Organocatalysts; Ishikawa, T., Ed.; John Wiley &
Sons, Ltd: Chichester, UK, 2009.
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́
(3) Recent reviews: (a) Palomo, C.; Oiarbide, M.; Lopez, R. Chem.
The reference bases used were DBU (pKBH+ = 24.34, MeCN)24 for
G1 (16); P1-tBu(pyrr)3 (pKBH+ = 28.35, MeCN)19 for C1 (17), P1
(4) Seminal publications: (a) Chinchilla, R.; Naj
́ ́
era, C.; Sanchez-
(18), G3 (11), CG2 (4), C3 (2), and PC1 (14); and P2-Et (pKBH+
=
́
32.94, MeCN)6c for GC2 (6), and GP2 (10). The remaining superbases
G
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX