Accelerated syntheses of amine-bis(phenol) ligands in polyethylene glycol or "on water" under microwave irradiation

Article abstract of DOI:10.1139/V08-043

Pure amine-bis(phenol) ligands are readily accessible in high yield, often >90%, when the Mannich condensation reactions are performed "on water" or in poly(ethyleneglycol) (PEG). Microwave-assisted synthesis dramatically reduces the time and energy required to prepare these molecules, typically from 24 h to 5 min. The approach seems to be widely applicable (7 amines and 5 phenols were tested to yield a diverse set of bis(phenol) ligands). Significant improvements in yield were observed for ligands derived from di-tert-amyl and di-tert-butyl phenols, possibly resulting from a hydrophobic effect. Single crystal X-ray diffraction data for the ligand derived from p-cresol and N,N-dimethylethylenediamine is reported.

Full text of DOI:10.1139/V08-043

435
Accelerated syntheses of amine-bis(phenol)
ligands in polyethylene glycol or “on water” under
microwave irradiation
Francesca M. Kerton, Stacey Holloway, Angela Power, R. Graeme Soper,
Kristina Sheridan, Jason M. Lynam, Adrian C. Whitwood, and Charlotte E. Willans
Abstract: Pure amine-bis(phenol) ligands are readily accessible in high yield, often >90%, when the Mannich conden-
sation reactions are performed “on water” or in poly(ethyleneglycol) (PEG). Microwave-assisted synthesis dramatically
reduces the time and energy required to prepare these molecules, typically from 24 h to 5 min. The approach seems to
be widely applicable (7 amines and 5 phenols were tested to yield a diverse set of bis(phenol) ligands). Significant im-
provements in yield were observed for ligands derived from di-tert-amyl and di-tert-butyl phenols, possibly resulting
from a hydrophobic effect. Single crystal X-ray diffraction data for the ligand derived from p-cresol and N,N′-
dimethylethylenediamine is reported.
Key words: amine-phenol, Mannich condensation, on water, microwave, ligand, high-throughput.
Résumé : Les ligands amine-bis(phénol) purs sont facilement accessibles avec des rendements élevés, souvent supé-
rieurs à 90%, lorsqu’on effectue des réactions de condensation de Mannich en présence d’eau ou de poly(éthylènegly-
col) (PEG). Les synthèses effectuées à l’aide de microondes réduisent sensiblement le temps et l’énergie requis pour
préparer ces molécules, passant généralement de 24 heures à 5 min. Il semble que cette approche peut être applicable
d’une façon générale; on a en effet testé sept amines et cinq phénols qui ont conduit à divers types de ligands bis(phé-
nol). On a observé des améliorations sensibles dans les rendements obtenus avec les ligands dérivés des di-tert-amyl- et
di-tert-butylphénols qui résultent peut-être d’un effet hydrophobe. On a obtenu des données de diffractions des rayons
X par un cristal unique pour des ligands dérivés du p-crésol et de la N,N′-diméthyléthylènediamine.
Mots-clés : amine-phénol, condensation de Mannich, en présence d’eau, microonde, ligand, grand débit.
[Traduit par la Rédaction] Kerton et al. 443
Fig. 1. Chelating amine-bis(phenol) ligands.
Introduction
Over the last 20 years, researchers have been exploring a
wide range of ligand systems for use in combination with
metals as new homogeneous catalysts. N-heterocyclic
carbenes have emerged as versatile alternatives to phosphine
ligands in late-transition metal-catalysed reactions (1–3).
Anionic ligands containing “hard” nitrogen and oxygen do-
nor atoms form a diverse set of ligands that are used as alter-
natives to cyclopentadienyl ligands, particularly in early
transition metal and lanthanide based catalysts (4–9). Of
these ligands, amine-bis(phenol) molecules have emerged as
versatile, modular, and easily accessible materials (Fig. 1).
Received 30 October 2007. Accepted 29 February 2008.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 9 April 2008.
Primarily, these ligands in combination with metals from
throughout the periodic table are active catalysts for alkene
polymerization (10–17) and initiators in the ring-opening
polymerization of lactones (18–30).
Liquid polymers are emerging as a useful class of nonvol-
atile solvents and possess valuable, facile separation charac-
teristics. The two most widely used polymers in this area are
PEG (polyethylene glycol) and PPG (polypropylene glycol)
(31, 32). They have a very low toxicity ranking and have
been approved by the US FDA for internal consumption
F.M. Kerton,1 S. Holloway, A. Power, R.G. Soper, K.
Sheridan. Green Chemistry and Catalysis Group, Department
of Chemistry, Memorial University of Newfoundland,
St. John’s, NL A1B 3X7, Canada.
J.M. Lynam, A.C. Whitwood, and C.E. Willans.
Department of Chemistry, University of York, Heslington,
York YO10 5DD, UK.
1Corresponding author (e-mail: fkerton@mun.ca).
Can. J. Chem. 86: 435–443 (2008)
doi:10.1139/V08-043
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Can. J. Chem. Vol. 86, 2008
Scheme 1. Synthetic route to modular amine-bis(phenol) ligands.
(31). The high stability and low toxicity of PEG and PPG al-
low these molecules to be used in a large number of prod-
ucts and industries. PEGs and PPGs are very similar in
structure to glymes, which are used as solvents because of
their high chemical and thermal stability, broad pH range,
and ability to dissolve polar compounds, such as water and
acids, as well as nonpolar compounds, such as hydrocar-
bons. The polarity of PEG can be compared with the com-
monly used laboratory solvents CH2Cl2 and MeCN, whereas
PPG is slightly less polar (32). In terms of laboratory safety,
whereas glymes readily form explosive peroxides, PEGs and
PPGS do not. The biodegradability of liquid polymers has
recently been summarized (32); for example, PEG 400–1500
is >95% biodegraded in 14 days. This makes PEGs and
PPGs much safer to use and dispose of than their corre-
sponding class of volatile solvents — the glymes and many
other common laboratory solvents.
Recently, cleaner, more benign routes to bis-imine Schiff
base ligands have been reported (33). These reactions
yielded high-purity ligand under neat reaction conditions or
by using polypropylene glycol (PPG) solvent. Inspired by
this research, we sought to reduce the amount of solvent
used in the preparation of our chosen ligand set and also the
time involved. We report herein the rapid, high-yielding syn-
thesis of amine-bis(phenol) ligands on water under micro-
wave irradiation and our journey en route to these results via
reactions in PEG solvents.
Table 1. Yields of amine-bis(phenol)s from reactions using PEG
and PPG solvents.
Entry
Phenol
Solventa
Yield (%)b
1
2
3
4
5
6
7
8
t-Bu, t-Bu
t-Bu, t-Bu
t-Bu, t-Bu
t-Bu, t-Bu
t-Bu, t-Bu
t-Bu, t-Bu
t-Am, t-Am
t-Am, t-Am
t-Am, t-Am
t-Am, t-Am
t-Am, t-Am
t-Am, t-Am
t-Am, t-Am
t-Am, t-Am
PPG 400 (dilute)
PPG 400
PEG 400(dilute)
PEG 400
PPG 1000 (dilute)
PPG 1000
PPG 400 (dilute)
PPG 400
PEG 400 (dilute)
PEG 400
PPG 1000 (dilute)
PPG 1000
Ethanol
Ethanol
38
73
48
81
40
73
52
74
43
96
31
76
72
79
Results and discussion
In following the work of van den Ancker and co-workers
(33), the first modified procedure we attempted (Scheme 1)
was the synthesis of amine-bis(phenol)s in PEG and PPG.
The phenol reagents dissolved in the warm polymers to form
solutions, however the tert-amyl and tert-butyl substituted
phenols were insoluble at room temperature. Vials were
loaded with phenol, polymer, solvent, aqueous formalde-
hyde, and finally the amine was added to the stirred mixture.
The reaction of primary amines with formaldehyde and
paraformaldehye is exothermic, and therefore care should be
taken when adding the amine. The reaction mixtures imme-
diately warmed to around 40 °C and were then heated to
75 °C overnight. Three polymer solvents were studied in this
first series of reactions: PEG 400, PPG 400, and PPG 1000.
Two concentrations were tested: 1 mmol amine per gram
polymer solvent and 2 mmol amine per gram solvent. The
amine used was N,N-dimethylethylenediamine, the phenols
were di-tert-butyl phenol and di-tert-amyl phenol.
Control reactions using ethanol as the solvent were also
performed and gave similar yields of products for the same
reaction temperatures and times. In this series of reactions
(Table 1), yields were similar for all reactions irrespective of
the substituted phenol used, but yields were lower at the
more dilute concentrations. PEG 400 gave slightly increased
yields compared with the other solvents and was therefore
used in subsequent experiments. Crystals of the ligand were
sometimes obtained upon cooling the reaction mixtures con-
taining PEG and PPG. However, larger crystals of the
amine-bis(phenol)s were more readily obtained from satu-
rated ethanol or methanol solutions. As in the work of van
9
10
11
12
13
14
aAll reactions were heated to 75 °C, 18 h. Reactions in polymers la-
belled dilute were performed using 1 mmol amine per gram of polymer;
otherwise 2 mmol amine per gram of polymer was used. Reactions in eth-
anol were performed by starting with a saturated solution of the phenol.
bIsolated yields, average of two identical reactions, compounds pure by
1H NMR spectroscopy.
den Ancker (33), the polymer solvent could be re-used in
subsequent experiments.
Over the past decade, tremendous advances in organic
synthesis (e.g., rate accelerations, enhanced selectivities)
have been achieved through the use of microwave irradiation
(34–36). A wide variety of microwave-assisted condensation
reactions have been studied, and therefore we attempted
amine-bis(phenol) syntheses in a household microwave
oven. Although there are concerns about the safety and
reproducibility of results obtained using these ovens, as long
as precautions are taken with safety and interpretation of the
data, these ovens act as a good entry point into microwave
chemistry (37–39). PEG 400 was used as the solvent in these
initial studies. Vials containing the reaction mixtures were
prepared as in the conventionally heated experiments. Each
vial was heated individually in the microwave at the desired
© 2008 NRC Canada

Kerton et al.
437
Table 2. Yields of amine-bis(phenol)s from reactions under microwave irradiation.
aPanasonic household microwave oven operated at constant power of 1200 W for 10 × 60 s, reaction scale of 2 g PEG
400, and 0.7 mL aq. CH2O. Biotage stands for a Biotage Initiator operated at constant temperature mode for 5 min at the
indicated temperature, reaction scale of 3 mL aq. CH2O.
1
bIsolated yields, average of two identical reactions, compounds pure by H NMR spectroscopy.
power and for varying lengths of time. Each reaction was
then triturated using ethanol, cooled to 0 °C, and the crystal-
line precipitate collected by filtration. Initial experiments
were performed using 60 s microwave pulses at low power
settings, 50% power (600 W) or 10% power (120 W). How-
ever, as expected, the yields increased with increased reac-
tion time and microwave power setting. Therefore, after
preliminary experiments, all amine-bis(phenol) syntheses
performed in the household microwave were conducted us-
ing ten 60 s full power (1200 W) pulses (Table 2). Reaction
temperatures were monitored between pulses and were be-
tween 80 and 100 °C. Some reactions were also performed
using catalytic amounts of aqueous acid, but this did not in-
crease the yield or rate of reactions.
To confirm the results obtained using a household micro-
wave, selected reactions were repeated using a research
grade instrument (Biotage Initiator System, 20 mL reaction
volume sealed vessels) (Table 2). In addition to reactions in
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Can. J. Chem. Vol. 86, 2008
Table 3. Yields of amine-bis(phenol)s using water as the reaction medium.
Note: Isolated yields, values in parentheses from microwave heated reactions using a Biotage Initiator system,
1
compounds dried in a vacuum desiccator to constant mass and pure by H NMR spectroscopy.
PEG 400, reactions were performed using ethanol and water.
Yields using ethanol (Table 2, entries 15–18) were compara-
ble with those using PEG 400, but interestingly, excellent
yields were obtained using water (Table 2, entries 19 and
20). These reactions can be reproduced using conventional
heating, however significantly longer reaction times are
needed.
A wide range of reactions using water as the reaction me-
dium have been studied because of their green potential (40–
42). These include Mannich-type reactions using surfactants
to facilitate the acid-catalyzed process (43). Therefore, we
decided to prepare a wide range of amine-bis(phenol) lig-
ands in water. Recently, it has been discovered that in some
cases when reactants and products are insoluble in water, the
reactions occur in a suspension or “on water” (44, 45). Al-
though, we did not see the rate enhancements observed by
Sharpless and co-workers (44), as can be seen in Table 3 the
yields of these Mannich condensation reactions improve
with an increase in hydrophobicity of the phenol. For exam-
ple, yields using di-tert-butyl and di-tert-amyl phenol are al-
ways significantly higher that those using para-cresol or
dimethyl phenol as the reagent (Table 3). We tentatively pro-
pose that the preferred reaction mechanism for the ligand
syntheses is via formation of the iminium ion intermediates
from the water-soluble amines and formaldehyde in homo-
geneous aqueous solution. This is followed by step-wise re-
actions of these species with two equivalents of phenol via a
heterogenous process on the surface of the suspended drop-
lets of liquid phenol. This prevents any alternative reaction
pathways occuring, such as reaction of the amine directly
with the phenol in homogeneous solution, thus increasing
the yields when hydrophobic phenols are used. As phenols
can be regarded as enols, when the phenol is water-soluble,
some of the amine reagent can react directly with the keto
tautomer of the phenol. This reduces the amount of amine
available for the desired reaction with formaldehyde and this
decreases the yield of amine-bis(phenol) when less sterically
demanding reagents such as p-cresol are used.
We have also performed this class of reaction on a large
scale (50 mL aqueous formaldehyde) using a Morton flask
equipped with a condenser, a mechanical stirrer, and a heat-
ing mantle. Reactions were performed using 2,4-di-tert-butyl
phenol
or
2,4-di-tert-amyl
phenol,
and
N,N-
dimethylethylenediamine, and yields were over 90%. How-
ever, care should be taken given the large amount of precipi-
tate that forms, which can affect the stirring mechanism.
© 2008 NRC Canada

Kerton et al.
439
Fig. 2. Molecular structure of 1. H atoms omitted for clarity.
During the course of this research, crystals of one ligand
suitable for single crystal X-ray diffraction studies were iso-
lated2. The molecular structure of 1, Fig. 2, is significantly
different from the previously reported more sterically con-
gested analogue derived from di-tert-amyl phenol, although
important bond lengths and hydrogen-bond distances are
similar (29). The structure of 1 (Table 4) exhibits a twist
along the backbone of the ligand, resulting in the phenol OH
groups residing on opposite sides of the molecule in the
solid state. In contrast, the di-tert-amyl derived ligand con-
tains both OH groups on the same side of the molecule (29).
The differences in the solid-state molecular structures of
these two molecules are presumably due to packing con-
straints in the solid state, as no significant differences in
their solution state structures are observed by 1H NMR spec-
troscopy.
Thermal ellipsoids are drawn at the 20% probability level. Se-
lected bond lengths (Å) and angles (°): C1–O1 1.3686(14), C7–
N1 1.4758(14), C8–N1 1.4693(14), C9–N1 1.4687(15), C8–
C8_2 1.520(2), O1–H1 0.91(2), C7-N1-C8 110.75(9), C7-N1-
C9 110.79(9), C8-N1-C9 111.28(9).
Table 4. Crystallographic data for compound 1.
Empirical formula
Formula weight
Temperature (K)
Crystal system
a (Å)
C20H28N2O2
328.44
100(2)
Monoclinic
5.5722(8)
Conclusions
In summary, we have reported the synthesis of related
amine-bis(phenol) ligands in ethanol, PEG, PPG, or water as
the solvent. Yields for these compounds are improved com-
pared with conventional routes and reaction times are dra-
matically reduced when microwave heating and water are
used. Therefore, microwave-assisted synthesis could aid in
the synthesis of libraries of these ligands for use in high-
throughput catalytic studies, and this approach could poten-
tially be extended to other related ligand syntheses (46–50).
Also, even in the absence of a microwave synthesizer, the
preferred method of synthesis for the di-tert-butyl and di-
tert-amyl derived ligands, and perhaps other sterically de-
manding analogues, should be to use water as the reaction
medium. During the initial submission period for this article,
a communication regarding the syntheses of related amine-
phenol ligands using water as the reaction medium has been
accepted for publication (51). Therein, data on the relative
solubilities of alkyl-substituted phenols is reported. How-
ever, further studies are ongoing into the reasons for the in-
creased yields of these ligands when hydrophobic phenol
reagents are used during their preparation in aqueous media.
b (Å)
c (Å)
β (°)
Space group
Volume (Å3)
Z
12.6340(19)
12.7270(19)
92.380(3)
P21/n
895.2(2)
2
Densitycalc (g/cm3)
Absorption coefficient (mm–1)
θ Range for data collected (°)
Index ranges
1.218
0.079
2.27 to 28.33
–7 ≤ h ≤ 7, –16 ≤ k ≤ 16,
–16 ≤ l ≤ 16
9049
Reflections collected
Independent reflections (Rint)
Max. and min. transmission
Data, restraints, parameters
Goodness-of-fit on F2
2224 (0.0300)
1.000 and 0.848
2224, 0, 115
1.061
Final R indices [I > 2σ(I)]
R1 = 0.0475, wR2 = 0.1300
0.444 and –0.192
Largest diff. peak and hole (eÅ–3)
therein. EI Mass spectra were recorded on a Fisons Instru-
ments VG Analytical Autospec mass spectrometer, and
MALDI-TOF spectra (anthracene matrix) were obtained on
an Applied Biosystems DE-RP instrument. Selected data are
presented in Table 5. Elemental analyses were performed on
several samples to provide additional confirmation of their
synthesis at Elemental Microanalysis Ltd., Devon, UK and
at Canadian Microanalytical Service Ltd., Delta, B.C., Can-
ada. For example, for Me2NCH2CH2N[CH2-3,5-Bu2-
C6H2OH–2]2 found: C 77.32, H 10.94, N 5.41. C34H56N2O2
requires: 77.81, H 10.76, N 5.34. However, not all samples
were analysed in this way as full characterisation data was
obtained on these ligands during their original preparation
by Kol and co-workers (10–14). Diffraction data were col-
Experimental
General procedures and instrumentation
Amines, phenols, and aqueous formaldehye were pur-
chased from Sigma-Aldrich and Alfa Aesar. Ethanol was
purchased from Fisher Scientific. PEG 400, PPG 400, and
PPG 1000 were purchased from Alfa Aesar. Microwave
heating was achieved using either an unmodified house-
hold MW oven (Panasonic NN-S740WA-1200W) or a re-
search grade microwave reactor (Biotage Initiator 2.0). NMR
spectra were recorded on a Jeol EX 270, a Tecmag
APOLLO 300, or a Bruker Avance 500 instrument (Table 5).
1H NMR spectra were referenced to residual protons in the
deuterated solvent and 13C NMR spectra to the 13C atoms
2 Supplementary data for this article are available on the journal Web site (canjchem.nrc.ca) or may be purchased from the Depository of Un-
published Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 3742. For more in-
formation on obtaining material refer to cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 658822 contains the crystallographic data for
this manuscript. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (Or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2008 NRC Canada

440
Can. J. Chem. Vol. 86, 2008
Table 5. Selected NMR and mass spectrometric data of amine-bis(phenol) ligands.
Amine and phenol
2,4-dimethyl phenol
Spectroscopic data (1H NMR, 13C{1H} NMR, mass spectra)
4
4
1H δ: 10.69 (br, 2H, OH), 6.87 (d, JHH = 1.1 Hz, 2H ArH), 6.62 (d, JHH = 1.1 Hz, 2H ArH),
3.63 (s, 4H, ArCH2), 2.65 (s, 4H, NC2H4N), 2.26 (s, 6H, NCH3), 2.21 (s, 6H, ArCH3), 2.20
(s, 6H, ArCH3). 13C{1H} δ: 153.3 (C), 130.5 (CH), 127.5 (C), 126.5 (CH), 124.6 (C), 120.5
(C), 61.7 (CH2), 54.0 (CH2), 20.4 (CH3), 15.6 (CH3). m/z: 357 (100%) [MH]+, 223 (7%)
[MH-C9H10O]+, 178 (26%) [C11H16ON]+, 135 (7%) [C9H11O]+.
1H δ: 9.48 (br, 2H, OH), 6.88 (d, JHH = 1.9 Hz, 2H ArH), 6.68 (d, JHH = 1.9 Hz, 2H ArH), 3.57
(s, 4H, ArCH2), 2.54 (s, 4H, NC2H4N), 2.34 (s, 6H, N(CH3)2), 2.20 (s, 12H, ArCH3). 13C{1H} δ:
152.5 (C), 131.1 (CH), 128.2 (CH), 127.2 (C), 125.3 (C), 121.4 (C), 55.9 (CH2), 48.9 (CH2), 44.7
(CH2), 20.3 (CH3), 16.1 (CH3). m/z: 357 (100%) [MH]+, 298 (30%) [MH-C3H9N]+, 223 (7%)
[MH-C9H10O]+, 164 (7%) [C10H14NO]+, 135 (16%) [C9H11O]+, 58 (17%) [C3H8N]+.
4
4
2,4-dimethyl phenol
1H δ: 9.06 (br, 2H, OH), 6.93 (d, JHH = 2.0 Hz, 2H, ArH), 6.83 (d, JHH = 2.0 Hz, 2H, ArH),
6.78 (s, 2H, ArH), 3.57 (s, 4H, ArCH2), 2.57 (br, 4H, NC2H4N), 2.28 (s, 6H, N(CH3)2), 2.22
(s, 6H, ArCH3). 13C{1H} δ: 154.7 (C), 130.8 (CH), 129.9 (CH), 128.1 (CH), 122.2 (C), 116.6
(C), 55.3 (CH2), 48.7 (CH2), 44.4 (CH2), 19.9 (CH3), 19.9 (CH3). m/z: 329 (65%) [MH]+,
270 (29%) [MH-C3H9N]+, 221 (79%) [MH-C7H8O]+, 209 (26%) [MH-C8H8O]+, 121 (12%)
[C8H9O]+, 58 (100%) [C3H8N]+.
3
3
p-cresol
3
4
3
1H δ: 9.50 (br, OH), 8.63 (dd, JHH = 5.1 Hz, JHH = 1.7 Hz, 1H, pyridine CH), 7.68 (dt, JHH = 7.7
p-cresol
4
3
3
Hz, JHH = 1.7 Hz, 1H, pyridine CH), 7.25 (dd, JHH = 7.7 Hz, JHH = 5.1 Hz, 1H, pyridine CH),
7.11 (d, JHH = 7.7 Hz, 1H, pyridine CH), 6.95 (d, JHH = 2.0 Hz, 2H, ArCH), 6.84 (d, JHH
3
3
3
=
2.0 Hz, 2H, ArCH), 6.78 (s, 1H, ArCH), 6.76 (s, 1H, ArCH), 3.86 (s, 2H, NCH2), 3.75 (s, 4H,
ArCH2), 2.21 (s, 6H, ArCH3). 13C{1H} δ: 156.4 (C), 155.2 (C), 148.5 (CH), 137.9 (CH), 131.1
(CH), 130.1 (CH), 128.4 (CH), 123.7 (CH), 122.9 (CH), 121.4 (C), 116.9 (C), 58.2 (CH2), 55.6
(CH2), 20.1 (CH3). m/z: 349 (20%) [MH]+, 256 (10%), [MH-C6H7N]+, 241 (100%) [MH-
C7H8O]+, 121 (57%) [C8H9O]+, 108 (38%) [C7H8O]+, 93 (100%) [C6H7N]+.
1H δ: 9.95 (br, OH), 6.96 (d, JHH = 1.7 Hz, 2H, ArH), 6.75 (d, JHH = 1.7 Hz, 2H, ArH), 6.72
(s, 2H, ArH), 3.63 (s, 4H, ArCH2), 2.63 (s, 4H, NC2H4N), 2.25 (s, 6H, NCH3), 2.22 (s, 6H,
ArCH3). 13C{1H} δ: 155.6 (C), 129.4 (CH), 129.3 (CH), 128.3 (C), 121.4 (C), 116.0 (CH),
61.6 (CH2), 53.8 (CH2), 41.4 (CH3), 20.1 (CH3). m/z: 329 (100%) [MH]+, 209 (5%) [MH-
C8H8O]+, 164 (19%) [C10H14NO]+, 121 (6%) [C8H9O]+.
3
3
p-cresol (1)
1H δ: 9.62 (br, 2H, OH), 7.07 (d, JHH = 2.4 Hz, 2H, ArH), 6.83 (d, JHH = 2.4 Hz, 2H, ArH),
3.59 (s, 4H, ArCH2), 2.54 (s, 4H, NC2H4N), 2.28 (s, 6H, N(CH3)2), 1.88 (m, 4H, CH2), 1.56
(m, 4H, CH2), 1.33 (s, 12H, CH3), 1.23 (s, 12H, CH3), 0.62 (m, 12H, CH3). 13C{1H} δ:
153.5 (C), 138.5 (C), 134.4 (C), 125.8 (CH), 121.7 (C), 56.4 (CH2), 55.7 (CH2), 48.7 (CH2),
44.5 (CH), 38.3 (C), 36.9 (CH2), 32.4 (CH2), 28.3 (CH3), 27.4 (CH3), 9.23 (CH3), 8.86
(CH3). m/z 581 (100%) [MH]+, 522 (32%) [MH-C3H9N]+, 347 (14%) [MH-C16H26O]+, 247
(5%) [C17H27O]+, 72 (6%) [C5H12]+, 58 (16%) [C3H8N]+. Found: 78.15, H 11.36, N 4.92.
C38H64N2O2 requires: C 78.57, H 11.10, N 4.82.
4
4
2,4-di-tert-amyl phenol
3
4
1H δ: 10.39 (br, 2H, OH), 8.67 (dd, JHH = 5.0 Hz, JHH = 1.7 Hz, 1H, pyridine CH), 7.67 (dt,
3JHH = 7.4 Hz, JHH = 1.8 Hz, 1H, pyridine CH), 7.26 (dd, JHH = 7.4 Hz, JHH = 5.0 Hz,
1H, pyridine CH), 7.13 (d, JHH = 7.4 Hz, 1H, pyridine CH), 7.07 (d, JHH = 2.4 Hz, 2H,
ArH), 6.85 (d, JHH = 2.4 Hz, 2H, ArH), 6.57 (s, 1H, ArH), 6.55 (s, 1H, ArH), 3.78 (s, 2H,
2,4-di-tert-amyl phenol
4
3
3
3
3
3
NCH2), 3.46 (s, 4H, ArCH2), 1.85 (m, 4H, CH2), 1.55 (m, 4H, CH2), 1.32 (s, 12H, CH3),
1.22 (s, 12H, CH3), 0.64 (m, 12H, CH3). 13C{1H} δ: 153.9 (C), 152.1 (CH), 148.5 (C), 141.2
(C), 139.1 (C), 137.6 (CH), 137.6 (CH), 126.0 (CH), 126.0 (CH), 124.3 (CH), 122.7 (CH),
121.4 (C), 115.9 (CH), 56.4 (CH2), 50.7 (CH2), 38.4 (C), 37.0 (CH2), 32.6 (C), 28.3 (CH3),
27.3 (CH3), 8.84 (CH3). m/z: 601 (15%) [MH]+, 508 (10%) [MH-C6H7N]+, 367 (24%) [MH-
C16H26O]+, 205 (100%) [C14H21O]+, 93 (17%) [C6H7N]+.
1H δ: 10.60 (br, 2H, OH), 7.06 (d, JHH = 2.0 Hz, 2H, ArH), 6.73 (d, JHH = 2.0 Hz, 2H, ArH),
3.64 (s, 4H, ArCH2), 2.60 (s, 4H, NC2H4N), 2.21 (s, 6H, NCH3), 1.86 (m, 4H, CH2), 1.55 (m,
4H, CH2), 1.34 (s, 12H, CH3), 1.22 (s, 12H, CH3), 0.61 (m, 12H, CH3). 13C{1H} δ: 154.2 (C),
138.8 (C), 134.0 (C), 125.3 (CH), 124.2 (CH), 120.9 (C), 62.5 (CH2), 53.4 (CH2), 41.2 (CH3),
38.3 (C), 36.9 (CH2), 32.5 (CH2), 28.2 (CH3), 27.2 (CH3), 9.18 (CH3), 8.74 (CH3). m/z: 581
(100%) [MH]+, 347 (18%) [MH-C16H26O]+, 290 (40%) [C19H32NO]+, 247 (11%) [C17H27O]+.
4
4
2,4-di-tert-amyl phenol
© 2008 NRC Canada

Kerton et al.
441
Table 5 (concluded).
Amine and phenol
Spectroscopic data (1H NMR, 13C{1H} NMR, mass spectra)
1H δ: 10.57 (br, 2H, OH), 7.08 (d, JHH = 2.3 Hz, 2H, ArH), 6.75 (d, JHH = 2.3 Hz, 2H, ArH),
3.85 (s, 4H, ArCH2), 3.15 (br, 2H, NH), 2.92 (s, 4H, NC2H4N), 1.84 (m, 4H, CH2), 1.56 (m,
4H, CH2), 1.35 (s, 12H, CH3), 1.23 (s, 12H, CH3), 0.64 (m, 12H, CH3). 13C{1H} δ: 154.2
(C), 139.2 (C), 134.2 (C), 126.3 (CH), 124.2 (CH), 120.9 (C), 59.0 (CH2), 51.3 (CH2), 38.1
(C), 37.0 (CH2), 33.0 (CH2), 28.3 (CH3), 27.3 (CH3), 9.10 (CH3), 8.76 (CH3). m/z: 319
(18%) [M-C16H25O]+, 234 (16%) [C16H26O]+, 219 (6%) [C15H23O]+, 205 (100%) [C14H21O]+.
4
4
2,4-di-tert-amyl phenol
1H δ: 8.87 (br, 2H, OH), 7.20 (d, JHH = 2.0 Hz, 2H, ArH), 6.88 (d, JHH = 2.0 Hz, 2H, ArH),
4.27 (m, 1H, CHO), 3.89 (m, 2H, CH2O), 3.77 (m, 4H, ArCH2NCH2Ar), 2.61(m, 4H,
CH2CH2), 2.51(m, 2H, NCH2Furf), 1.40 (s, 18H, C(CH3)3), 1.27 (s, 18H, C(CH3)3). 13C{1H}
δ: 153.02 (C), 140.63 (C), 136.05 (C), 124.95 (CH), 123.38 (CH), 121.43 (C), 77.54 (CH),
68.28 (CH2), 57.52 (CH2), 55.93 (CH2), 34.99 (CMe3), 34.10 (CMe3), 31.67 (CH3), 29.60
(CH3), 29.60 (CH2), 25.21 (CH2). m/z: 537 (100%) [M]+, 466 (47%) [M-THF]+, 410 (9%)
[M-THF-Bu]+, 332 (17%) [C21H34NO2]+, 205 (100%) [C14H21O]+.
4
4
2,4-di-tert-butyl phenol
4
4
1H NMR δ: 8.39 (br, 2H, OH), 7.20 (d, JHH = 1.9 Hz, 2H, ArH), 6.87 (d, JHH = 1.9 Hz, 2H,
2,4-di-tert-butyl phenol
3
ArH), 3.73 (s, 4H, ArCH2), 3.55 (t, JHH = 5.0 Hz, NCH2), 3.46 (s, 3H, OCH3), 2.73 (t,
3JHH = 5.0 Hz, 2H, CH2O), 1.37 (s, 18H, C(CH3)3), 1.27 (s, 18H, C(CH3)3). 13C{1H} δ:
152.8(C), 140.7(C), 136.0(C), 124.9(CH), 123.4(CH), 121.6(C), 71.4 (ArCH2), 58.0 (OCH3),
51.3 (CH2), 35.0 (C(CH3)3), 34.1 (C(CH3)3), 31.6 (C(CH3)3), 30.1 (C(CH3)3). m/z: 512 (3%)
[M]+, 454 (81%) [M-Bu]+, 306 (50%) [C19H32NO2]+, 205 (100%) [C14H21O]+.
4
4
1H NMR δ: 8.35 (s, 2H, OH), 6.85 (d, JHH = 1.8 Hz, 2H, ArH), 6.67 (d, JHH = 1.8 Hz, 2H,
2,4-di-methyl phenol
3
ArH), 3.72 (s, 4H, ArCH2N), 3.58 (t, JHH = 5.0 Hz, 2H, CH2O), 3.47 (s, 3H, OCH3), 2.70
(t, JHH = 5.0 Hz, 2H, NCH2), 2.20 (s, 12H, ArCH3). 13C{1H} δ: 152.84 (C), 131.37 (C),
3
121.24 (C), 127.68 (CH), 127.36 (CH), 125.15 (C), 70.89 (NCH2CH2O), 58.17 (OCH3),
57.04 (NCH2CH2O), 50.77 (CH2Ar), 20.24 (CH3), 16.03 (CH3). m/z: 343 (21%) [M]+, 320
(100%) [M-Me-H2O]+, 222 (9%) [C13H20NO2]+, 208 (87%) [C12H18NO2]+.
lected at 100 K on a Bruker Smart Apex diffractometer with
Mo Kα radiation (λ = 0.710 73 Å) using a SMART CCD
camera. Diffractometer control, data collection, and initial
unit cell determination was performed using SMART (52).
Frame integration and unit cell refinement software was car-
ried out with SAINT+ (53). Absorption corrections were ap-
plied by SADABS (54). Structures were solved by direct
methods (SHELXS-97) and refined by full-matrix least-
squares based on |F|2 using SHELXL-97 (55, 56).
60 s pulses. The temperature of the reaction mixture in the
vial was measured between pulses and temperatures were
maintained below 100 °C. Caution: occasionally the reaction
mixtures would become very hot and spill out of the con-
tainer; reactions in a household microwave oven should not
be left unattended and safety precautions should be taken.
After heating, the vial was cooled in an ice bath and filtered.
If required, the solid was washed with a minimum amount
of ethanol and dried under vacuum.
Biotage initiator
General procedure for amine-(bis)phenol ligand
A 10–20 mL Biotage reaction tube was loaded with PEG
400 (8.0 g), 37% aq. formaldehyde (3.0 mL), substituted
phenol (37 mmol), and amine (18 mmol). The tube was
sealed with a lid containing a septum and placed in the reac-
tion cavity. The mixture was stirred and heated to the desired
temperature for 5 min. During this time, the pressure in the
tube was monitored by a pressure sensor on the lid of the
tube. The reaction tube was rapidly cooled under a nitrogen
flow, and once the pressure in the tube had reduced to near
atmospheric the septum was removed. The contents of the
tube were filtered, washed with a minimum amount of etha-
nol, and dried under vacuum.
synthesis in PEG under conventional heating
A capped 10–20 mL vial was loaded with PEG 400
(2.0 g), 37% aq. formaldehyde (0.70 mL), and phenol
(8.0 mmol). The mixture was stirred and N,N-
dimethylethylenediamine (0.35 g, 4.0 mmol) was added
dropwise. Vials were stirred in a heated block (Chemglass
OptiChem) at 75 °C for 18 h. The vial was cooled in an ice
bath and filtered. If required, the solid was washed with a
minimum amount of ethanol and dried under vacuum to
yield the amine-bis(phenol) as a colourless, crystalline solid.
General procedure for amine-(bis)phenol ligand
synthesis in PEG under microwave heating
General procedure for amine-(bis)phenol ligand
synthesis in ethanol under conventional heating
Household microwave oven
A loosely capped 10–20 mL vial was loaded with PEG
400 (2.0 g), 37% aq. formaldehyde (0.70 mL), and phenol
(8.0 mmol). Substituted amine (4.0 mmol) was added
dropwise. Vials were heated on full power (1200 W) for ten
Phenol (0.123 mol) was weighed into a 100 mL beaker
and ethanol (around 30 mL) added to give a saturated solu-
tion. The phenol solution was transferred to a 200 mL
round-bottomed flask and 37% aq. formaldehyde (10 mL)
© 2008 NRC Canada

442
Can. J. Chem. Vol. 86, 2008
12. E.Y. Tshuva, I. Goldberg, M. Kol, and Z. Goldschmidt. Inorg.
Chem. Commun. 3, 611 (2000).
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was added. The flask was equipped with a condenser and the
amine (0.06 mol) was added. The reaction mixture was
stirred and heated at 70 °C for 18 h. The reaction mixture
was cooled in an ice bath, filtered, and the residue washed
with cold ethanol (2 × 20 mL). The solid was dried under
vacuum.
General procedure for amine-(bis)phenol ligand
synthesis in ethanol or water under microwave heating
A 10–20 mL Biotage reaction tube was loaded with water
or ethanol (5.0 mL), 37% aq. formaldehyde (3.0 mL), substi-
tuted phenol (37 mmol), and amine (18 mmol). The tube
was sealed with a lid containing a septum and placed in the
microwave reaction cavity. The mixture was stirred and
heated to the desired temperature for 5 min. During this
time, the pressure in the tube was monitored by a pressure
sensor on the lid of the tube. The reaction tube was rapidly
cooled under a nitrogen flow, and once the pressure in the
tube had reduced to near atmospheric the septum was re-
moved. The contents of the tube were filtered, washed with a
minimum amount of ethanol, and dried under vacuum.
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General procedure for amine-(bis)phenol ligand
synthesis in water under conventional heating
Phenol (0.123 mol) was weighed directly into a 200 mL
round-bottomed flask, water (80 mL) and 37% aq. formalde-
hyde (10 mL) were added. The flask was equipped with a
condenser and the amine (0.06 mol) was added. The reaction
mixture was stirred and heated at 100 °C for 18 h. Upon
cooling to room temperature, the product formed a separate
phase as either a solid or an oil that could be easily isolated.
The product was dried under vacuum, or if significant quan-
tities of water were still present, it was dissolved in an or-
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31. J. Chen, S.K. Spear, J.G. Huddleston, and R.D. Rogers. Green
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Acknowledgements
We thank Memorial University of Newfoundland, Natural
Sciences and Engineering Research Council of Canada
(NSERC) (Discovery Grant and Research Tools and Instru-
ment Grant, FMK), WISE-NL Student Summer Employment
program (SH), and the EPSRC (Studentship, CEW) for gen-
erous funding. We are also grateful to Biotage for access to
an Initiator microwave system on a free trial basis.
34. S.M. Nikles, M. Piao, A.M. Lane, and D.E. Nikles. Green
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35. M. Nüchter, B. Ondruschka, W. Bonrath, and A. Gum. Green
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38. V.V. Namboodiri and R.S. Varma. Green Chem. 3, 146 (2001).
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