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Synthetic Possibilities for Hemilabile Ligands: A Case Study of Decacyclo[10.8.15,8.02,11.04,9.013,20.015,18]-heneicosane-3,10,14,19-tetraone

Authors:
RESEARCH ARTICLE Johan H. L. Jordaan, Frans J. Smit, Hermanus C. M. Vosloo, Agatha M. Viljoen 163
S. Afr. J. Chem., 2023, 77, 163–170
https://journals.co.za/content/journal/chem/
*To whom correspondence should be addressed
Email:
johan.jordaan@nwu.ac.za
or
frans.smit@nwu.ac.za
ISSN 1996-840X Online / South African Chemical Institute / http://saci.co.za/journal
© The Author(s) Published under a Creative Commons Attribution 4.0 International Licence (CC BY 4.0)
https://doi.org/10.17159/0379-4350/2023/v77a21
Synthetic Possibilities for Hemilabile Ligands: A Case Study of
Decacyclo[10.8.15,8.02,11.04,9.013,20.015,18]-heneicosane-3,10,14,19-tetraone
Johan H. L. Jordaan* , Frans J. Smit* , Hermanus C. M. Vosloo , Agatha M. Viljoen
Research Focus Area for Chemical Resource Beneciation: Catalysis and Synthesis Research Group, North-West University, Potchefstroom, South Africa
ABSTRACT
As proof of the synthetic possibilities for hemilabile ligands the chemistry of decacyclo[10.8.15,8.02,11.04,9.013,20.015,18]heneicosane-3,10,14,19-
tetraone (5) was investigated. Reacting 5 with ethylene glycol under acid conditions gave the expected di-acetal protected ketone (6) as four
possible isomers. Reduction of these isomers to produce the dialcohol ketal (7) was only possible with LiAlH4, aer NaBH4, Luches, and
Meerwein-Ponndorf-Verley reduction methods were unsuccessful. Deprotection of 7 to the hydroxyl ketone (8) derivative was not possible
under reux with a 25% HCl solution. To evaluate the reactivity of 5, and investigate alternative synthetic routes to Grubbs pre-catalysis,
5 was treated with the reducing agents i) NaBH4, ii) glacial AcOH, Zn and iii) 80% AcOH/H2O/Zn mixture, which resulted in various
reduction products. e AcOH/H2O/Zn reduction resulted in various products and a further investigation into the mechanism is given
within this report.
KEYWORDS
Pentacycloundecane, Grubbs pre-catalyst, Cyclo-addition, Hemilabile ligands
Received 19 April 2023, revised 4 August 2023, accepted 27 September 2023
INTRODUCTION
As part of a program that is concerned with the design and synthesis
of novel Grubbs-type pre-catalysts, containing the hemilabile
pyridinyl alcholato ligand for the metathesis of 1-alkene derivates,
these ligands convey increased thermal stability of the pre-catalysts
and decreased the extent of side reactions.1-7 Incorporation of an
alicyclic moiety in the hemilable ligands may further improve the
thermal stability of these Grubbs-type pre-catalysts.8 Filipescu9 and
Kusher10 were able to synthesize the Diels-Alder adduct (2) from
the cyclo-addition of cyclopentadiene and 1,4-naphthoquinone
(1) by intramolecular photocyclization to produce the expected
hexacyclo[7.4.2.01,9.03,7.04,14.06,15]pentadeca-10,12-diene-2,8-dione
(3, Scheme 1). Besides this compound’s thermal stability,11 and thus
the potential to bestow additional stability to the Grubbs-type pre-
catalysts, it can also undergo further Diels-Alder reactions.12 Var ious
researchers have shown that 3 can react exclusively either from the
cyclobutane face or from the ketone face of the diene, depending
on the nature of dienophiles (Figure 1).12-16 In 1987 Coxon et al.12
showed that due to the steric bulk of the p-benzoquinone, it reacts
exclusively on the carbonyl face to produce the Diels-Alder adduct
(4). If 4 is then irradiated with UV it undergoes a cyclization reaction
to form the decacyclo-[10.8.15,8.02,11.04,9.013,20.015,18]heneicosane-
3,10,14,19-tetraone (5, Scheme 1).10, 17, 18
It was envisaged that cage compound 5, be used as a substrate for
the synthesis of bidentate or monodentate hemilabile ligands for
Grubbs-type pre-catalysts. However, before the hemilabile ligands are
to be synthesized, an understanding of the chemistry and reactions of
5 is required. is paper will present the synthesis, characterization,
and chemistry of derivatives of 5.
EXPERIMENTAL
e quantum-chemical calculations were carried out by density
functional theory (DFT) since it usually gives realistic geometries,
relative energies, and vibrational frequencies for transition metal
compounds. All calculations were performed with the DMol3
DFT code as implemented in Accelrys Materials Studio® 4.2 using
GGA/DNP/PW91 functional. e convergence criteria for these
optimisations consisted of threshold values of 2 x 10−5 Ha, 0.004 Ha/Å
and 0.005 Å for energy, gradient and displacement convergence,
respectively, while a self-consistent eld (SCF) density convergence
threshold value of 1x10−5 Ha was specied. e electron density,
Scheme 1: e reaction scheme for the synthesis of 5.
Figure 1: π-Facial selectivity of 3.12
RESEARCH ARTICLE Johan H. L. Jordaan, Frans J. Smit, Hermanus C. M. Vosloo, Agatha M. Viljoen 164
S. Afr. J. Chem., 2023, 77, 163–170
https://journals.co.za/content/journal/chem/
frontier orbitals and Fukui-function was also calculated. Two
computer systems were used for calculations, viz.
• HP Proliant CP4000 Linux Beowulf cluster, with 12 calculation
nodes consisting of 4 HP DL145, 2 x 2.8 GHz AMD Opteron 64
CPU, 2 GB RAM, running Redhat Enterprise Linux 4
• HP Compaq dx2200 MT Intel® Core™2 Duo T7300 CPU @
2.00 GHz, 3 GB RAM running Microso Windows XP Professional
with service pack 2.
Experimental data were recorded using the following instruments:
Infrared spectra (KBr discs) were recorded on a Bruker Tensor 27-IR
spectrometer; EI mass spectra were obtained at 70 eV on a Micromass
Autospec-TOF mass spectrometer and FAB mass spectra were obtained
on a VG 70-70E magnetic sector analyser with matrix of nitrobenzyl
alcohol (NBA). High-resolution MS spectra were obtained on a
Bruker Micro-QTof II with an APCI source. NMR data were collected
on a Varian Gemini-300 NMR spectrometer and a Bruker 600MHz
Avance Ultrashield Plus. Melting points were determined using a
Büchi Melting Point B-540 apparatus. Melting points are uncorrected.
Synthesis of 2:10
10 g (63.28 mmol) 1,4-naphthoquinone (1) was dissolved in 800
ml methanol, aer which 10 g of activated carbon was added and
stirred for 10 minutes on a hot plate. e solution was ltered to
yield a yellow solution of 1,4-naphthoquinone. To this solution 2.5 g
(6.86 mmol) cetyl trimethylammonium bromide (CTAB) was added,
followed by the addition of 25 ml (297.28 mmol) freshly distilled
cyclopentadiene. Aer 3 hours of stirring in the dark at room
temperature, the solution was concentrated to a small volume and
was poured into 500 ml water, upon which a white to light-peach
coloured precipitate formed. e precipitate was ltered and washed
with 10 ml cold water and 5 ml methanol under vacuum suction,
successively. e crystals were dried to yield 12.03 g (53.69 mmol,
85 %) as a white powder. Melting point: 101 °C. IR (KBr): νmax 3443,
2992, 1680, 1589 and 1270 cm-1. MS (EI): M+ m/z 224. NMR: data
were identical to the authentic samples.
Synthesis of hexacyclo[7.4.2.01,9.03,7.04,14.06,15]pentadeca-10,12-
diene-2,8-dione (3):10
6 g (26.78 mmol) of the Diels-Alder adduct 2 was dissolved in 300 ml
benzene and irradiated with a medium-pressure UV lamp for 2 hours
in Pyrex vessels. Aer 2 hours the benzene was removed by reduced
pressure which aorded an o-white solid, which was recrystallized
from n-heptane to yield white-light yellow crystals (5.2 g, 23.21 mmol,
87%). Melting point: 109 °C. IR (KBr): νmax 3443, 2984, 1745, 1089
and 704 cm-1. MS (EI): M+ m/z 224. 13C-NMR [CDCl3, 150 MHz]:
δC 210.33 (S, C=O), 124.67 (D, HC=CH), 119.73 (D, HC=CH),
54.538 (D), 51.57 (D), 50.10 (S), 44.16 (D), 38.91 (T, CH2) ppm. 1H
NMR [CDCl3, 600MHz]: δH 5.96-5.90 (m, HC=CH), 5.38-5.31 (m,
HC=CH), 3.31-3.0 (s), 2.98-2.93 (m), 2.77-2.76 (s), 1.98-1.93 (d) and
1.74-1.70 (d) ppm.
Synthesis of octacyclo[10.6.2.15,8.02,6.02,11.04,9.07,11.013,18]hene-
icosa-15,19-diene-3,10,14,17-tetraone (4):12
4.8 g (21.42 mmol) of 3 was dissolved in 350 ml benzene to which
2.32 g (21.48 mmol) para-benzoquinone was added and reuxed for
20 h aer which a yellow solid precipitated. e solid was ltered
and washed with 40 ml, 50% water/methanol solution to remove any
unreacted reactants. e yellow crystals were dried to yield 6.79 g
(20,45 mmol, 95 %) of 4. Mp: 265°C, Lit. Mp: 265 – 267 °C. IR (KBr):
νmax 2924, 1744, 1716, 1666, 1276 and 1062 cm-1. MS (EI): M+ m/z
332, HRMS (APCI): m/z calc. for C21H16O4 [M+]: 332.1043, found:
332.1056. 13C-NMR [CDCl3, 75 MHz]: δC 211.96 (S, C=O), 197.75
(S, C=O), 141.43 (D, HC=CH), 133.79 (D, HC=CH), 55.99 (D), 53.15
(S), 43.47 (D), 43.39 (D), 41.66 (D), 40.68 (T, CH2), 34.28 (D) ppm.
1H NMR [CDCl3, 300MHz]: δH 6.63 (s, HC=CH), 6.38-6.36 (m,
HC=CH), 3.57-3.56 (s), 3.47-3.44 (m), 2.89-2.87 (t), 2.74-2.73 (d),
2.64-2.63 (d), 1.97-1.93 (d, CH2), 1.84-1.80 (d, CH2) ppm.
Synthesis of decacyclo[10.8.15,8.02,11.04,9.013,20.015,18]hene-
icosane-3,10,14,19-tetraone (5):17
6 g (18.07 mmol) of 4 was dissolved in 600 ml chloroform and irradiated
with a medium-pressure UV lamp for 3 hours in a Pyrex vessel. Aer
3 h a white solid precipitated which was ltered and washed with
chloroform to remove any unreacted reagents (4.31 g, 12.98 mmol,
95 %). Mp: 371°C, Lit. Mp: >360°C. IR (KBr): νmax 2984, 1736, 1709,
1347, 1301, 1237, 1145 and 1095 cm-1. MS (EI): M+ m/z 332, HRMS
(APCI): m/z calc. for C21H16O4 [M+]: 332.1043, found: 332.1083.
13C-NMR [CDCl3, 75 MHz]: δC 210.50 (S, C=O), 209.22 (S, C=O),
55.12 (D), 46.77 (S), 45.53 (D), 43.99 (D), 43.93 (D), 40.92 (D), 40.74
(T, CH2), 33.12 (D), 31.81 (D) ppm. 1H NMR [CDCl3, 300MHz]: δH
3.38-3.34 (m), 3.15-3.13 (m), 3.14-2.96 (m), 2.86-2.84 (s), 2.80-2.79 (s),
2.23-2.20 (m), 2.08-2.07 (d, CH2), 1.96-1.92 (d, CH2) ppm.
Synthesis of oxa-ketal (6):19, 20
5 g (15.6 mmol) of 5, 1.9 g (1.7 ml, 30.63 mmol) ethylene glycol and 0.3
g (1.74 mmol) p-toluenesulfonic acid (PTSA) was added in a conical
ask equipped with a magnetic stirrer and a Dean-Stark apparatus and
reuxed in 300 ml toluene for 12 h. Aer this time, the toluene was
removed under reduced pressure and a brown solid precipitated. e
solid was washed with cold water and 10 ml cold methanol, to remove
the unreacted ethylene glycol and PTSA, which liberated light brown-
white crystals. e crystals were dried to yield 5.66 g (13.47 mmol, 89
%) of 6. Mp: 253 °C. IR (KBr): νmax 2970, 1743, 1332, 1111 and 942
cm-1. MS (EI): M+ m/z 420, HRMS (APCI): m/z calc. for C25H25O6
[M++H]: 421.1646, found: 421.1653. 13C-NMR [CDCl3, 150 MHz]: δC
214.04 (S, C=O), 213.94 (S, C=O), 213.41(S, C=O), 212.96 (S, C=O),
113.55 (S, O-C-O), 113.31 (S, O-C-O), 113.04 (S, O-C-O), 112.94 (S,
O-C-O), 65.81 (T, O-CH2), 65.65 (T, O-CH2), 65.43 (T, O-CH2), 65.31
(T, O-CH2), 65.26 (T, O-CH2), 65.24 (T, O-CH2), 64.56 (T, O-CH2),
64.27 (T, O-CH2), 54.23 (D), 54.11 (D), 51.18 (D), 46.84 (S), 46.74 (S),
44.49 (D), 44.44 (D), 44.19 (D), 43.86 (D), 43.41 (D), 43.36 (D), 42.88
(D), 42.64 (D), 42.55 (D), 42.45 (D), 42.38 (D), 42.20 (D), 41.86 (D),
39.03 (T, CH2 of bridge), 38.98 (D), 38.19 (D), 35.59 (D), 35.24 (D),
32.79 (D), 32.04 (D), 31.47 (D), 31.10 (D), 30.33 (D) ppm.
Synthesis of the hydroxyl-ketal (7):
Method 1:
2 g of the diketal (6) was dissolved in 100 ml ethanol. e solution
was cooled to 0 °C by means of an ice bath. 1.5 g sodium borohydride
(NaBH4) was added in small amounts so that the temperature did not
rise above 5 °C. Aer addition, the reaction was stirred for 2 h in the
ice bath, aer which it was quenched with the addition of a solution
of 50 ml water and 5 ml HCl. e resulting mixture was subjected
to rotary evaporation to remove the excess ethanol. Subsequently, the
solution was extracted three times with 50 ml CH2Cl2. e combined
organic layers were washed with a small amount of water and
successively with brine. e organic layer was dried with MgSO4 and
ltered, aer which the solvent was removed by rotary evaporation. IR
and MS analysis showed no trace of a hydroxyl group, but rather the
diketal (6) as the only compound present.
Method 2 (Luche reaction):21, 22
2 g of the diketal (6) was dissolved in a 0.4 M solution of CeCl3·7H2O
in ethanol. e solution was cooled to 0 °C in an ice bath. 1.5 g
sodium borohydride (NaB14) was added in small amounts so that
the temperature did not rise above 5 °C. Aer addition, the reaction
was stirred for 2 h in the ice bath, aer which it was quenched with
the addition of a solution of 50 ml water and 5 ml HCl. e resulting
RESEARCH ARTICLE Johan H. L. Jordaan, Frans J. Smit, Hermanus C. M. Vosloo, Agatha M. Viljoen 165
S. Afr. J. Chem., 2023, 77, 163–170
https://journals.co.za/content/journal/chem/
mixture was subjected to rotary evaporation to remove the excess
ethanol. Subsequently, the solution was extracted three times with
50 ml CH2Cl2. e combined organic layers were washed with a small
amount of water and successively with brine. e organic layer was
dried with MgSO4 and ltered, aer which the solvent was removed by
rotary evaporation. IR and MS analysis showed no trace of a hydroxyl
group, but rather the diketal (6) as the only compound present.
Method 3 (Meerwein-Ponndorf-Verley reduction):23
3 g of 6 and 5 g of isopropanol was added to 100 ml toluene to which
0.3 g Al(OiPr)3 was added. e reaction mixture was reuxed at 60 oC
for 96 h. e solution was cooled and extracted with 3x75 ml CH2Cl2
and the combined organic layers were washed with 100 ml water. e
organic layer was dried with MgSO4 and concentrated by means of
rotary evaporation. IR and MS analysis showed no trace of a hydroxyl
group, but rather the diketal (6) as the only compound present.
Method 4:20, 24
1.2 g (31.62 mmol) LiAlH4 was added over a period of 30 minutes
to a stirred solution of 4 g (9.52 mmol) of 7 in 100 ml dry THF.
Aer addition, the solution was reuxed for 30 minutes and le to
cool to room temperature. 200 ml H2O was added to decompose
the reaction mixture. is solution was extracted with 3 × 50 ml
dichloromethane, washed with water, dried over MgSO4 and the
solution was condensed in vacuo. e brown oil that formed was
dissolved in 2 ml dichloromethane and added to 20 ml petroleum
ether. e milky solution was poured into a clean beaker and le to
evaporate to yield 3.8 g (8.96 mmol, 94%) of 7 as a white powder. Mp:
223°C. IR (KBr): νmax 3427, 2966, 2890, 1468, 1454, 1320, 1282, 1269,
1150, 1102, 1068, 1027, 1003, 956 and 581 cm-1. MS (EI): M+ m/z 424,
HRMS (APCI): m/z calc. for C25H29O6 [M++H]: 425.1959, found:
425.1987. 13C-NMR [CDCl3, 150 MHz]: δC 115.70 (S, O-C-O), 115.69
(S, O-C-O), 115.12 (S, O-C-O), 115.07 (S, O-C-O), 75.67 (D), 73.79
(D), 65.76 (T, O-CH2-R), 65.60 (T, O-CH2-R), 65.08(T, O-CH2-R),
64.94 (T, O-CH2-R), 64.06 (T, O-CH2-R), 63.86 (T, O-CH2-R), 62.34
(T, O-CH2-R), 62.08(T, O-CH2-R), 47.70 (D), 47.63 (D), 47.46 (D),
47.29 (D), 44.58 (S), 43.89 (S), 43.71 (S), 43.63 (D), 43.47 (D), 43.16
(S), 41.89 (D), 41.83 (D), 41.26 (D), 41.07 (D), 40.96 (D), 40.57 (D),
40.37 (D), 39.80 (D), 39.61 (D), 39.31 (D), 38.25 (D), 38.22 (D), 38.00
(D), 36.93 (D), 35.57 (D), 35.49 (D), 34.89 (T, CH2 Bridge), 34.87 (T,
CH2 Bridge), 34.74 (D), 34.62 (D), 32.70 (D), 31.38 (D) ppm. 1H NMR
[CDCl3, 600MHz]: δH 6.13-6.00 (dd, OH); 5.07-5.01 (dd, OH).
Synthesis of hydroxy-ketone (8):25
1 g (2.36 mmol) of 7 was added to a stirring solution of a 24% HBr
solution. is was reuxed for 12 hours aer which the hot solution
was poured over ice water. e solution was extracted with 3 × 50
ml CH2Cl2, washed with water, and dried over MgSO4. e CH2Cl2
was concentrated on a rotary evaporator to yield a small amount of
clear oil. e oil was dissolved in 1 ml CH2Cl2 and poured into 20
ml petroleum ether. A white solid precipitated and was ltered o to
yield 116 mg (0.35 mmol, 14%) of 8. IR (KBr): νmax 3423, 2964, 2867,
1720, 1333, 1304, 1276, 1150, 1131, 1076, 1056, 1004 and 923 cm-1.
MS (EI): M+ m/z 336, HRMS (APCI): m/z calc. for C21H20O4 [M++H]:
336, found: 336. NMR data were inconclusive in the identication of
the product, due to solubility problems.
Reaction of 5 with Zn/AcOH/H2O:26
20 g (305.90 mmol) Zinc was activated with a small amount of
hydrochloric acid (HCl), aer which the Zn was washed with acetone
and subsequently with water. e activated Zn was added to a stirred
solution of 100 ml 80 % acetic acid/H2O (AcOH) and 1 g (3.01 mmol)
of 5. is solution was reuxed for 5 h, aer which it was subjected
to rotary evaporation until only a small amount of acetic acid was le
and a white solid precipitated. is solid was ltered o and water
was added to the mother liquor aer which 30 precipitated (96 mg).
e remaining ltrate was dissolved in water and extracted with 3 ×
50 ml CH2Cl2. e combined organic layers were washed with water
and dried over MgSO4. e CH2Cl2 was concentrated on a rotary
evaporator to yield 33 and 35 (558 mg) as a white solid. 30: Mp: 281°C,
IR (KBr): νmax 3400, 2961, 2874, 1741, 1355, 1296, 1226, 1196, 1134,
1071, 1013, 951, 908, 864, 643 and 499 cm-1. MS (FAB): [M]+ m/z 352.
13C-NMR [DMSO, 150 MHz]: δC 215.13 (S, C=O), 109.54 (S, O-C-O),
108.10 (S, O-C-O), 84.12 (S), 55.32 (D), 49.85 (D), 49.71 (D), 49.66
(D), 49.52 (D), 47.89 (D), 47.72 (D), 47.63 (S), 45.44 (D), 44.76 (D),
43.58 (D), 38.92 (D), 38.57 (D), 37.96 (D), 37.05 (D), 36.75 (D), 31.72
(D) ppm. 1H NMR [DMSO, 300MHz]: δH 6.55 (s), 5.12 (s), 3.35 (s),
2.54-1.46 (a series of multiples), 1.48-1.46 (d, CH2 – Bridge), 1.38-
1.36 (d, CH2 – Bridge) ppm. 31 and 32: Mp: 278°C IR (KBr): νmax
3307, 2969, 1740, 1332, 1273, 1228, 1156, 1066, 1013, 913, 850, 709
and 540 cm-1. MS (FAB): [M-H2O+H]+ m/z 337. 13C-NMR [DMSO,
150 MHz]: δC 215.10 (S, C=O), 215.04 (S, C=O), 116.06 (S, O-C-O),
114.69 (S, O-C-O), 84.25 (S), 84.20 (S), 77.71 (D), 76.36 (D), 55.31 (S),
55.25 (S), 49.88 (D), 49.86 (D), 49.70 (D), 49.66 (D), 48.11 (D), 47.93
(D), 47.91 (D), 47.78 (D), 47.70 (D), 47.66 (D), 45.50 (D), 45.42 (D),
45.25 (D), 45.08 (D), 44.74 (D), 44.70 (D), 42.77 (D), 41.45 (D), 40.73
(D), 40.04 (D), 38.74 (D), 38.67 (D), 38.56 (D), 38.53 (D), 38.03 (D),
37.53 (D), 37.48 (D), 37.03 (T, CH2 – Bridge), 37.01 (T, CH2 – Bridge),
35.52 (D), 32.54 (D), 30.33 (D) ppm. 1H NMR [DMSO, 300MHz]: δH
6.66 (s), 5.22 (s), 4.35-4.33 (t), 4.26-4.24 (t), 3.33 (s), 2.72 -2.71 (t),
2.67-2.66 (t), 2.61-2.56 (m), 2.52-2.40 (series of multiples), 2.36-2.34
(d), 2.26-2.22 (m), 2.14-1.88 (series of multiples), 1.75-1.72 (m), 1.48-
1.46 (d, CH2-Bridge), 1.38-1.36 (d, CH2-Bridge) ppm.
Synthesis of the transannulated hydrate (25):
1g of 5 was added to a stirred solution of glacial acidic acid and zinc.
Aer 24h of reux, a white solid precipitated. e solution was cooled,
ltered, and dried to yield 1.01 g of 25 as the exclusive product (96%).
IR (KBr): νmax 3412, 2984, 1736, 1709, 1348, 1302, 1237, 1201, 1146,
1096, 911 and 575 cm-1. MS (FAB): [M+H]+: m/z 351. 13C-NMR
[DMSO, 150 MHz]: δC 213.48 (S, C=O), 110.37 (S, O-C-O), 54.84
(D), 48.74 (S) 46.65 (D), 44.92 (D), 43.43 (D), 40.55 (T, CH2 – Bridge)
40.25 (D), 34.67 (D), 31.91 (D) ppm. 1H NMR [DMSO, 600MHz]:
δH 6.82, 3.34, 2.93, 2.88, 2.74, 2.63, 2.49, 2.39, 2.20, 1.95, 1.92(d, 11.07
Hz), 1.80 (d, 10.84 Hz) ppm.
RESULTS AND DISCUSSION
It was found that for compounds 2-5b, all analytical data were in
accordance with authentic samples. For 5, the melting point was higher
than that published by Pandey et al.,17 however it was in the same order
(374375 °C) as that published by Tolstikov et al.18 e melting point
of 371 °C was conrmed with thermogravimetric analysis (TGA).
e discrepancy in melting points between the two authors could be
ascribed to the limitation of the older apparatus used by Pandey. e
mono addition of ethylene glycol to pentacycloundecane compounds
was introduced by Eaton et al.19 in 1976. According to Eaton the steric
bulk of the cage compound together with the introduction of the rst
acetal group hinders the introduction of a second acetal group on
the adjacent carbonyl. Although this reaction is chemoselective it is
not regioselective, resulting in the formation of four dierent isomers
(Figure 2). It can be observed from Figure 2 that 6a and 6c as well as
6b and 6d will result in only two isomers detected by NMR analysis.
e 13C-NMR of 5 indicates that there are only two carbonyls present
and only eleven signals are registered instead of the twenty-one
carbons present, which designate that the adjacent carbonyls are
equivalent. us any one of the carbonyls on each side can therefore
form an acetal, but the formation of a second acetal on the same side
is prevented, due to steric hindrance, as indicated by Eaton et al.19
Contradictory to 5, the 13C-NMR of 6 shows almost double the
number of peaks, 44 versus the expected 50 carbons for the expected
RESEARCH ARTICLE Johan H. L. Jordaan, Frans J. Smit, Hermanus C. M. Vosloo, Agatha M. Viljoen 166
S. Afr. J. Chem., 2023, 77, 163–170
https://journals.co.za/content/journal/chem/
isomers. e discrepancy in the number of peaks is due to some carbons
having the same chemical shi (being degenerate) in both structures,
for example, the DEPT shows only one CH2 bridge carbon and only
two quaternary carbons, while there are two CH2 bridge carbons and
four quaternary carbons respectively.27 Furthermore, the 13C-NMR of
6 shows four dierent carbonyl groups at δC 214.04, 213.94, 213.41
and 212.96 ppm. Figure 3 illustrates the numeric numbering of 6a and
6b used in Tabl e 1 , which shows the calculated C-C-O bond angles
(Accelrys Materials Studio® 4.2 using GGA/DNP/PW91 functional).
From this table, it was observed that although the angles do not
dier signicantly, this could be responsible for the slight chemical
shi in the 13C-NMR. e distance between the oxygen of the acetal
transannular to the carbonyl oxygen was also measured.
e carbonyl oxygen (on C10) and the acetal oxygen (on C3)
distances are 3.26 Å and 3.23 Å for 6a and 6b, respectively, while the
carbonyl oxygen (on C19) and the acetal oxygen (on C14) distance
are 3.17 Å and 3.15 Å, respectively. e bond angles together with
the slight dierence in interatomic distances cause a minor change
in the electronic environment around the carbonyls which causes
the carbon atoms of 6a to be deshielded and shied downeld, while
the carbon atoms of 6b are more shielded and shied upeld. is
is commonly known as magnetic anisotropic systems and refers to
the electron distribution of molecules with high electron density. is
change in electron density aects the applied magnetic eld on the
dierent carbons and causes the observed chemical shi to change.28
is eect can be seen especially for the bridge CH2, where the two
protons are split into two very distinct doublets in the 1H-NMR.
Normally the carbonyl peak of C10 is downeld of the carbonyl peak
of C19, which means that the chemical shi at δC 214.04 ppm, can
be assigned to C10 in 6a, 213.94 ppm can be assigned to C10 in 6b,
likewise, 213.41 ppm can be assigned to C19 in 6a, and 212.96 ppm
can be assigned to C19 in 6b.
Since two distinguishable isomers are forming during the addition
of ethylene glycol to 5 and conventional separation techniques, such
as column chromatography, are unable to separate/purify these cage
compounds, all the following products will have two or more isomers.
us, for simplicity, the numeric value alone will imply all the isomers
of a specic compound, while the alphabetical letter together with the
numeric value will imply the specic isomer.
For the reduction of 6 to 7 the rst method employed was the
reduction of a carbonyl with NaBH4 (Scheme 2). Since the carbonyls
of 6 are sterically blocked on one side by the acetal group, only exo
hydride attack can occur, producing only the endo product. However,
this method was unable to reduce the carbonyls of 6 and only the
starting compound could be extracted in high yields.
Since NaBH4 alone were incapable of reducing the carbonyl groups
of 6, the Luche21, 22 reaction was attempted. e Luche reaction is a
selective reduction method for the reduction of enones or ketones
in the presence of aldehydes. e activity of the Luche reaction can
be explained by the Hard and So Acid and Base (HSAB) theory.
Carbonyl groups require hard nucleophiles for the addition of a
nucleophile to the carbonyl. e hardness of the borohydride is
increased by replacing the hydride groups with alkoxide groups. is
reaction is catalysed by cerium salts by increasing the electrophilicity
of the carbonyl groups.22us, a stronger reducing agent is produced
and the cerium facilitates the reduction by binding to the oxygen,
thereby weakening the carbonyl bond and making it more susceptible
to reduction. Even with the ketone being more susceptible to reduction
no reaction took place.
As a last option, LiAlH4 was used as a reducing agent.20, 24 It was
possible to reduce 6 to 7, with relative ease and high yields (94%). is
reaction was initially conducted with LiAlH4 dissolved in THF and the
ketone being added portion-wise, over a period of 2 hours. It was argued
that since the ketone is resistant to reduction this setup will result in a
higher concentration of H- (hydride) at any given time compared to
the concentration of the ketone. e resulting product was an orange-
brown oil that we were unable to crystalize, however, the IR showed a
distinctive OH stretching band at 3427 cm-1 and the disappearance of
the carbonyl peak at 1743 cm-1, however, the resultant reaction mixture
was highly contaminated, and we were unable to purify this any further.
e reaction was therefore repeated in the same manner as before,
except that LiAlH4 was added slowly to the stirred ketone (6) in THF
over a period of 2 hours which resulted in 7 as an o-white powder.
13C NMR conrmed the disappearance of the carbonyl peaks. As with
6, the number of signals attributed to the dierent inseparable isomers
made full elucidation problematic, however, the HRMS indicated that
the calculated and measured m/z were in accordance to compound 7
(calc. for C25H29O6 [M++H]: 425.1959, found: 425.1987).
As with 6, there are two distinguishable compounds giving rise to
eight dierent CH2-O-R carbon peaks between δC 65 and 62 ppm. e
DEPT indicate two CH2 bridge peaks that were degenerate in 6. In
comparison to 6, 7 has four dierent quaternary carbons, indicating
that the isomer eect is more prominent in 6 than in 7. is can be
explained by taking into consideration that the hydroxyl group is
spatially larger than the ketone group, which has an increased electronic
eect on the C3, C10, C14 and C19 of the two isomers.
e logical next step would then be the removal of the protecting
acetal group of 7 to produce the hydroxyl ketone 8. For the pentacyl-
coundecane system, this can normally be accomplished by stirring the
ketol 7 in a 10% HCl solution for 2 hours under reux. For 7 this proce-
dure was inadequate to remove the acetal group. Even when the solution
was reuxed for 6 days in a 25% HCl solution no reaction took place.
To test the reactivity of the 4 carbonyl groups of 5, it was subjected to
reduction with NaBH4. e expected product was a tetraol, 15 (Scheme
3), but the triol 16a and 16b, as the major products with 17 as a minor
product were obtained.
Figure 3: 6a and 6b showing the numeric numbering.
Table 1: Calculated bond angles of the carbonyl groups.
Selected bond angle 6a 6b
C9-C10-O 127.53 127.59
C11-C10-O 127.65 127.67
C20-C19-O 127.23 127.59
C18-C19-O 127.71 127.57
Figure 2: e four possible isomers that can form during the
addition of ethylene glycol to 5.
RESEARCH ARTICLE Johan H. L. Jordaan, Frans J. Smit, Hermanus C. M. Vosloo, Agatha M. Viljoen 167
S. Afr. J. Chem., 2023, 77, 163–170
https://journals.co.za/content/journal/chem/
Molecular modelling indicates that the LUMO of 5 (Figure 4) is
concentrated on the CH2-bridge side of the molecule and thus it is
expected to be reduced rst. It has been reported by Mehta et al.29
that for the pentacycloundecane system, the hemiacetal 18 is only
observed in equilibrium with the ketol 19 (Scheme 4). It should be
noted that the two carbonyl groups are equivalent and the reaction
occurs without regiospecicity, although it was pointed out by Sasaki
et al.30 that 18 did not cyclise to 19, even at 270 °C. Whether or not
this cyclization occurs, it is evident from the 13C-NMR that only 16a
and 16b are present, with 17 as the minor product, in this case.
Although physical evidence such as δC at 78.80 and 78.65 ppm are
indications of a transannular ether-bearing carbon with hydrogen
(instead of the normal hydroxyl group attached to this carbon).
DEPT135 indicates that there are ve quaternary carbons at δc 44.99,
44.51, 44.28, 43.90 and 43.80 ppm, four originating from 16a, 16b and
one for 17 (since 17 is symmetrical). From the reaction in Scheme 3,
it seems that all four ketones are active towards reduction. However,
due to the steric hindrance around the ketones in 6, conveyed by the
steric bulk of the acetal groups, they may be resistant to reduction.
In 1981 Mehta et al.26 showed that 20 can be directly synthesized
from 3 with the use of zinc and acetic acid. It was argued that this
reaction will allow the direct synthesis of 21, a hydroxyl ketone with
the correct functionality, akin to 8 (Scheme 5).
Initially, the reaction was carried out with the use of 99.9% acetic
acid. However, 13C-NMR elucidation indicated a symmetrical
product with the presence of only one carbonyl as well as a hydrate
(O-C-O) group at δC 213.47 and 110.37 ppm, respectively, which
correlates to the NMR data of 25. Scheme 6 shows a possible reaction
mechanism for the hydrate 25 formation as well as the formation
of the hydroxyl ketone (30). It was posited that for the reaction to
occur a hydrate must rst form and thus there is insucient water to
solvate the acetic acid to release a proton that initiates the hydroxyl
ketone formation (30). For this reason, the reaction stops at 25. is
is like the reduction of 5 with NaBH4 (Scheme 3), of which 25 is a
minor product that is reduced to 17 during the reaction. 13C-NMR of
25 showed only one carbonyl group, indicating that the transannular
Scheme 2: Reduction of 6 to 7 with reducing agents [RA]: a) NaBH4, b) NaBH4, CeCl3, c) iPrOH, Al(OiPr)3, d) LiAlH4, THF
Scheme 3: Reduction of 5.
Figure 4: e LUMO of 5.
Scheme 4: Transannular reaction of 18.
Scheme 5: Synthesis of the hydroxyl ketones 20 and 21.
RESEARCH ARTICLE Johan H. L. Jordaan, Frans J. Smit, Hermanus C. M. Vosloo, Agatha M. Viljoen 168
S. Afr. J. Chem., 2023, 77, 163–170
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hydrate formation is chemoselective and consequently forms only
one symmetrical product (an interesting observation from the
1H-NMR of this compound is the number of singlet peaks). is can
be ascribed to the fact that within some cage compounds, 1, 2 and
3 bond coupling can be observed which results in extremely small
coupling constants (J) which consequently results in the multiplet
(that should have formed) being displayed as singlets.28 Furthermore,
it depicts that when the rst hydrate forms on one side, the reaction
stops, and the addition of a second hydrate does not occur. It also
sheds some light on the mechanism of the reaction, i.e., non-
concerted manner.
Galin et al.31 showed that it is possible to hydrate 5 to form 31 by
reacting 5 in an aqueous acetone solution for three days (Figure 5). e
ndings of Galin are supportive of the proposed hydration mechanism
as shown in Scheme 6.
Repeating the reaction with an 80% acetic acid solution for 5 hours,
the 13C-NMR showed a mixture of products which included three
hydroxyl-bearing carbons at δC 84.12, 84.25 and 84.20 ppm, which
is consistent with a tertiary alcohol.28 e 13C-NMR also shows three
dierent carbonyl groups at δC 215.13, 215.10 and 215.04 ppm. e
spectrum also indicated that there still was a hydrate present together
with two geminal alcohol groups. ese products were separated by
means of their dierences in solubility. 13C-NMR of the product
removed by ltration and washed with water (30), indicated only
one carbonyl peak at δC 215.13 as well as the presence of a hydrate
(O-C-O) at δC 109.5 ppm.
e 13C-NMR of the other fraction isolated (33 and 35), signifying
that there were 42 resonance signals of which there were two
carbonyl peaks at δC 215.1 and 215.04, two O-C-O peaks at δC 116.06
and 114.69, two dierent tertiary hydroxyl bearing carbon atoms at
δC 84.25 and 84.20, two secondary hydroxyl bearing carbon atoms at
δC 77.71 and 76.36, as well as two quaternary carbons at δC 55.31 and
55.25 ppm. is indicated that there were two isomers of which the
degenerate peaks were split due to the isomer eect. Furthermore,
the product contained a geminal alcohol together with an additional
hydroxyl group. Scheme 7 shows the possible reaction mechanism
for the formation of 33 and 35.
From these results it seemed that the formation of 25 is
chemoselective and that only one hydrate is formed during the
reduction of 5 with Zn/AcOH, resulting in only one side forming a
hydroxyl ketone.
When the Zn/AcOH reduction reaction of 5 was carried out for
24 hours, instead of the original 5 hours with 80% AcOH, 33 and
35 are produced exclusively, conrming that 30 is a precursor for
these compounds. It seems that the Zn/AcOH reduction of 5 does
not form the double transannular hydroxy ketone 21, but rather
the reaction proceeds through the formation of 25 and subsequent
reduction of 25 to form 30, which reacts further with zinc in acetic
acid to produce 33 and 35.
Although these are interesting results as to the derivatization
of 5 showing the possibilities, it would be advantageous to be able
to synthesize the Schi-base (40) or the pyridinyl alcholato (38)
derivatives of 5 (Figure 6). For these can act as ligands for the Grubbs
catalysts. Attempts to derivatise 6 to 38 via 36 or 37 by means of
the Huang-Minlon reaction were unsuccessful. Similarly, were the
attempts to react 6 with hydroxyl amine to produce 39 unsuccessful.
In all these cases only the starting material 6 was recovered.
CONCLUSION
In the process of developing novel hemilabile ligands, it was
important to understand the chemical and physical properties of the
tetraone 5. It seems that 5 shows similar chemistry as 3 when reacted
with ethylene glycol to produce the corresponding acetal isomers
Scheme 6: Possible reaction mechanism of the hydrate (25) and hydroxyl ketone (30) formation.
Figure 5: Hydrate of 5.
RESEARCH ARTICLE Johan H. L. Jordaan, Frans J. Smit, Hermanus C. M. Vosloo, Agatha M. Viljoen 169
S. Afr. J. Chem., 2023, 77, 163–170
https://journals.co.za/content/journal/chem/
6a to 6d. Paradoxically, the isomers of 6 did not react with, Luches
or Meerwein-Ponndorf-Verley’s reagents to give the corresponding
hydroxyl acetal derivative 7, as it would have with 3. It seems that
stronger reducing agents were to be used to convert 6 to 7. From the
results obtained with the zinc/acetic acid reduction, it became clear
that the chemistry of 5 is dierent from that of 3. With two active
reducing sites present, the ketones on the CH2-bridge side were the
rst to undergo chemoselective hydration through a transannular
mechanism. Following the formation of 25 it is further hydrated to
form 30 and ultimately to 33 and 35. is is not surprising, since
the transannular distance between the carbonyl groups is shorter on
the CH2-bridge and the pi-orbitals show an overlap with molecular
modelling. What is interesting though is that the extent of hydration
can be controlled. erefore, the chemistry which applies to 3 is not
always applicable to that of 5. is was seen with the deprotection
of the ketone groups in 7. It was also found that some of these
compounds became less soluble and ultimately further reactions
were not possible. is presents a problem with the synthesis of
the possible ligands 38-40. With the knowledge gained from this
investigation, it should be possible to devise a synthetic strategy to
synthesise these ligands.
ACKNOWLEDGEMENTS
e authors would like to thank Prof Cornie van Sittert, for her
help with the molecular modelling. Andre Joubert, for collection of
NMR data. Prof. F.J.C. Martins for his assistance in the NMR data
assignment. e National Research Foundation, c*Change and the
North-West University for nancial support.
SUPPLEMENTARY MATERIAL
Supplementary information for this article is provided in the online
supplement.
ORCID IDS
Johan H. L. Jordaan: https://orcid.org/0000-0002-8134-6753
Frans J. Smit: https://orcid.org/0000-0003-1956-6584
Hermanus C. M. Vosloo: https://orcid.org/0000-0002-5879-323X
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