Increasing the antioxidant capability via the synergistic effect of coupling diphenylamine with sterically hindered phenol

Article abstract of DOI:10.1016/j.tet.2019.130759

A series of novel diphenylamine-phenol antioxidants were synthesised that combined the two antioxidant types into a single molecule. These antioxidants were then functionalised with alkyl chains to aid their solubility in hydrocarbon media. As part of a s

Full text of DOI:10.1016/j.tet.2019.130759

Journal Pre-proof
Increasing the antioxidant capability via the synergistic effect of coupling
diphenylamine with sterically hindered phenol
Clare L. Higgins, Sorin V. Filip, Ashfaq Afsar, Wayne Hayes
PII:
S0040-4020(19)31152-4
https://doi.org/10.1016/j.tet.2019.130759
TET 130759
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 August 2019
Revised Date: 24 October 2019
Accepted Date: 31 October 2019
Please cite this article as: Higgins CL, Filip SV, Afsar A, Hayes W, Increasing the antioxidant capability
via the synergistic effect of coupling diphenylamine with sterically hindered phenol, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.130759.
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Increasing the antioxidant capability via the synergistic effect of
coupling diphenylamine with a sterically hindered phenol
1
2
1
1*
Clare L. Higgins , Sorin Filip , Ashfaq Afsar and Wayne Hayes
1
2
*
Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK.
BP Formulated Products Technology, Research & Innovation, Pangbourne, UK.
Corresponding author. Tel.: +44 118 378 6491, Fax: +44 118 378 6331
Email address: w.c.hayes@reading.ac.uk (Wayne Hayes)
Graphical Abstract
1

Increasing the antioxidant capability via the synergistic effect of
coupling diphenylamine with sterically hindered phenol
1
2
1
1*
Clare L. Higgins , Sorin V. Filip , Ashfaq Afsar and Wayne Hayes
1
Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK.
BP Formulated Products Technology, Research & Innovation, Pangbourne, UK.
Corresponding author. Tel.: +44 118 378 6491, Fax: +44 118 378 6331
2
*
Email address: w.c.hayes@reading.ac.uk
Abstract: A series of novel diphenylamine-phenol antioxidants were synthesised that
combined the two antioxidant types into a single molecule. These antioxidants were then
functionalised with alkyl chains to aid their solubility in hydrocarbon media. As part of a
structure-activity study, diphenylamine derivatives were also generated bearing carboxylic
acid functionalities in either the ortho, meta or para position with respect to the secondary
amine. Methyl or ethyl spacers were also incorporated between the carboxylic acid and the
aromatic ring. The antioxidant ability of the diphenylamine-phenols was evaluated using
Differential Scanning Calorimetry (DSC) and compared to commercially available
antioxidants Irganox L135 and Irganox L57 both as individual components and when
blended together. The diphenylamine-phenol antioxidant with an ethyl spacer between the
diphenylamine and carboxylic acid in the meta position with respect to the secondary amine
functionality showed an impressive oxidation induction time of ca. 24 minutes in direct
comparison with the blend of Irganox L135 and Irganox L57 (ca. 16 minutes).
Keywords: Synergism, Dual functional antioxidants, Diphenylamines, Phenols, Oxidative
Stability Studies
1
.
Introduction
1

Oxidative degradation of hydrocarbon materials such as oils, fuels, biofuels, and polymers
is a common problem in several industrial processes. [1-4] In particular, when an
automotive lubricant or a lubricant for any mechanical system is being used, this oxidizes
more easily, depending on its type (paraffinic, naphthenic, or aromatic), to form harmful
species which can shorten its service life and ultimately damage the physical integrity of the
machinery. [5-6] Among several possibilities to reduce or prevent the speed of lubricant
oxidation, antioxidants are the key additives incorporated by chemical industries in their
lubricant formulations to protect oils from oxidative degradation and prolong service life. [7-
1
1] Phenols and diphenylamines constitute the bulk of radical trapping antioxidants that are
incorporated into lubricant formulations because of their high inherent reactivities toward
peroxyl radicals and the persistence of the resultant radicals toward both O and non-
2
radical species. [12-15] Phenols, especially sterically hindered phenols, are environmentally
friendly and have low toxicity which make them prevalent in automotive lubricating oils but
are restricted from high temperature applications because of their poor thermal stability and
liability to failure owing to photochromatic effect under severe conditions. [16-19] In
contrast, diphenylamines have better performance at elevated temperatures but the
antioxidant performance still needs to be improved. [20-22] Complying with these
limitations, there is an increasing demand to meet strict emission legislation whilst
enhancing fuel economy thus forcing the petrochemical industry to develop highly effective
antioxidants for used in fuels. [23] Therefore, in order to meet these demands upon the
properties of lubricating oils, improving via the synergistic means the performance of
commercial antioxidants using sulfur-, phosphorus- and heavy metal-free compounds is
desirable. [24] The term ‘synergism’ in this case refers to the cooperative action of two or
more additive species in such a way that the total antioxidant effect is greater than the sum
of the individual effects taken independently. [25] It is well-known, particularly in some
2

lubricant formulations that, sterically hindered phenols and diphenylamines, when added to
the oil simultaneously can remarkably enhance the antioxidant efficiency due to their
intermolecular synergistic effect. [26-29] These exciting results prompted us to design a
series of antioxidants that combines the sterically hindered phenol and diphenylamine
moieties into a single structure to form a bifunctional antioxidant. The benefits of this
approach are that increasing molecular weight of the antioxidant could also improve the
thermal stability at elevated temperatures and could reduce the amount of additives used in
formulations. [30] Although considerable efforts have been devoted to investigating and
improving the individual antioxidant capabilities of hindered phenols and diphenylamines
through structural variations [31-34], only a few examples have been reported that detail the
inclusion of both functional groups within the same compound. [35-36] Recently Liu et al.
[
37] designed a new type of antioxidant which combined the two antioxidant types into a
one molecule via Schiff base (Figure 1). These Schiff base antioxidants bridged phenolic
diphenylamine antioxidants (SPD1 and SPD2) exhibited better thermal stability and
antioxidant efficiency than the commonly used commercial antioxidants. Inspired by this
study, we report the design and synthesis of a series of novel mixed diphenylamine-phenol
antioxidants that combine the two traditional antioxidants into one molecule in addition to
alkyl chains to gain better solubility. To further investigate the structure-activity relationship,
diphenylamine derivatives that possess carboxylic acid functionalities in either ortho, meta
or para position with respect to the secondary amine and methyl or ethyl spacers were
incorporated between the carboxylic acid and the aromatic ring. Their antioxidant ability
was examined using pressurised differential scanning calorimetry (PDSC) and the
antioxidant performance compared to the current industry antioxidants Irganox L135 and
Irganox L57 (Figure 2) both as individual components and as a synergistic blend together.
2
.
Results and discussion
3

2
.1. Synthesis
The palladium catalysed Buchwald-Hartwig amination [38-40] was used to synthesise the
ester derivative 3 (see SI Scheme S1). [41-42] After base catalysed ester hydrolysis, the
acid derivative of diphenylamine 4 and 3-(3,5 di tert-butyl 4 hydroxyphenyl)propionic acid 7
were attached to the first generation hydroxyl linker 6. [30] Two different synthetic
procedures were targeted, both utilising N,N’ dicyclohexylcarbodiimide (DCC) mediated
coupling. The first approach, shown in Scheme 1, involved a statistical reaction whereby 4,
the hindered phenol 7 and 6 were reacted in a ratio of 1:1:1. The statistical reaction yielded
successfully the desired compound 8 in ca. 30%, however, the competing by-products 9
and 10, shown in Figure 3, were isolated in a yield of ca. 30% each, respectively. To
improve production of 8, an alternative synthetic methodology was utilised where a mono-
phenolic hydroxyl linker 5 was synthesised from the reaction of 7 with a single hydroxyl
functionality of 6. Subsequently, the reaction of 5 with diphenylamine 4 via DCC mediated
coupling (Scheme 2) afforded the desired mixed amine-phenol 8 with an improved yield of
ca. 70%. To investigate the structure-activity relationships of the novel mixed amine-phenol,
para-substituted derivatives of mixed amino-phenol 11 and bis(diphenylamine) 13 (see
Series 1, Table 1) were prepared by reacting 2-(4-(phenylamino)phenyl)acetic acid 12 with
5
and 6 following the above synthetic methodology (see SI Scheme S2). To further refine
the structure of the mixed amine-phenols, an additional alkyl chain was introduced in
Series 2 by employing 4-butylaniline 16 as the starting material. The most effective position
to link the diphenylamine to the hydroxyl linker was also investigated and ortho, meta and
para carboxylic acid substituted diphenylamines were synthesised via the Buchwald-
Hartwig amination [38-40] methodology previously described. The esters 14 (ortho), 17
(
meta) and 19 (para) were generated, followed by base hydrolysis to afford the carboxylic
acids 21-23 in good yields (>80%) as shown in Scheme 3. [43-46] Successful coupling of
4

4
-butylaniline 16 to methyl 3-bromobenzoate 18 and methyl 4-bromobenzoate 20 was
achieved to yield the meta and para diphenylamines 17 and 19, respectively (isolated yields
ca. 50%). However, the synthesis of 14, using methyl 2-bromobenzoate 15, proved to be
more challenging and a low yield of only ca. 25% was achieved. In an attempt to improve
the yield, K CO was used as a base for the Buchwald-Hartwig amination reaction and a
2
3
significant improvement in the isolated yield (53%) was observed. With the (ortho, meta and
para)-substituted diphenylamines derivatives 21-23 and mono-phenolic hydroxyl linker 5 in
hand, mixed amine-phenols 24-26 were prepared successfully employing the same
methodology described to generate Series 1. In addition, the bis(diphenylamines) 27-29
were also generated from the reaction of 21-23 with first generation diol linker 6 (see Series
2
, Table 2). To conclude the series, the inclusion of a methyl or ethyl spacer between the
carboxylic acid and aromatic ring was also investigated. The esters 30 (meta –CH CH -),
2
2
3
2 (para –CH -) and 34 (para –CH CH -) were generated first by coupling of 16 to 31, 33
2 2 2
and 35 respectively, followed by ester hydrolysis to yield the carboxylic acids 36-38 in a
yield of ca. 80% as shown in Scheme 4. The monophenol hydroxyl linker 5 was then
functionalised with the carboxylic acid diphenylamine derivatives (36-38) to prepare a series
of mixed amine-phenols (39-41) as shown in (see Series 3, Table 3). In addition, the
bis(diphenylamines) (42-44) were also generated by the reaction of carboxylic acid
diphenylamine derivatives with the first generation diol linker 6.
2
.2. Oxidative stability studies
To assess the antioxidant potential, 8, 9, 11 and 13 were blended into a synthetic lubricant
base oil - Durasyn 164 (a polyalphaolefin, hydrogenated hydrocarbon base oil composed of
dec-1-ene trimers typically used in lubricating oils). At this stage it was found that the
miscibility of the bis(diphenylamines) 9 and 13 in the lubricant base oil was poor and hence
oxidative stability analysis was not feasible. In comparison, the mixed amine-phenols
5

exhibited better solubility even though an extended heating period was required to ensure
full dissolution. Current commercial antioxidants Irganox L135 and Irganox L57 were used
as a comparison and samples were prepared by blending of 0.5% w/w of each antioxidant
in 50 mL of the lubricant base oil. The blends were analysed using (PDSC) to monitor the
heat effects associated with phase transitions and chemical reactions as a function of
temperature. Oxidation induction time (OIT) and oxidation onset temperature (OOT) were
utilised to study the effect of antioxidants on the stability of the oil sample. OIT analysis
revealed that the presence of 8 and 11 in the base oil had resulted in increase in the
stability of the sample as shown in Figure 4. The induction time was increased from <1
minute for the unblended base oil to ca. 10-13 minutes for the blended samples. In addition,
8
and 11 showed superior performance to both commercial antioxidants, Irganox L135 and
Irganox L57. However, the synergistic effect of having both functionalities on the same
compound did not outweigh the effect of blending both together as evident in the L135/L57
blend (ca. 16 minutes). The methylene spacer in the mixed amine-phenol 11 appeared to
have a positive effect on the antioxidant capabilities, revealing an induction time of ca. 3
minutes longer than 8. OOT analysis was also performed and the results for each oil blend
ᵒ
are shown in Figure 5 where again, a significant increase in temperature (ca. 251 C) was
observed for both 8 and 11 when incorporated into the blend compared to the base oil in
ᵒ
isolation (ca. 223 C). The above results revealed that these compounds did have
antioxidant capabilities but physical properties such as solubility was an issue. OIT analysis
of 24-26 bearing an additional alkyl chain for enhanced solubility were then carried out that
revealed a difference in the antioxidant capabilities of each compound (Figure 6)
demonstrating that there was clearly a favoured substitution position on the ring for
enhanced antioxidant properties. The mixed amine-phenol 24 (ca. 7 minutes) exhibited the
quickest OIT in comparison to 25 and 26 and this poor performance can be attributed to the
6

ortho substitution which allowed intramolecular hydrogen bonding between the aromatic
amine proton and the carbonyl oxygen from the ester moiety. In comparison, the mixed-
amine phenol 25, which was substituted in the meta position, revealed the best oxidation
induction time of 13 minutes. Interestingly, this result still was not greater than a simple 1:1
blend (0.25% w/w of each of Irganox L135 and Irganox L57) of Irganox L135 and Irganox
L57 (ca. 16 minutes), however, some improvement was observed from Series 1. A direct
comparison was made between the oxidation induction times from Series 1 and 2 to
determine the structural characteristics that were contributing to an increase in induction
time (Figure 7). Comparison of the meta substituted mixed amine-phenols 8 and 25 (from
Series 1 and 2, respectively) revealed that an increase in oxidation time was observed
upon addition of an alkyl chain. It was proposed that this increase was associated with an
improved solubility in the lubricant base oil and hence better diffusion within the medium
was achieved. Additionally, comparison of the para substituted mixed amine-phenols 11
and 26 revealed that incorporation of a methylene spacer between the aromatic ring and
the ester moiety had an even greater effect on the OIT than just the addition of a
solubilising group. This was believed to be a result of a change in the electronics of the
system and instead of the strongly electron-withdrawing ester moiety, the methyl spacer
provided some electron-donating capacity to the aromatic ring. Oxidation onset temperature
was also analysed and revealed the same trend of increasing oxidative stability from 24
(ortho) to 26 (para) to 25 (meta) (Figure 8). The ortho substituted mixed amine-phenol 24
ᵒ
revealed an oxidation onset temperature of ca. 243 C that was significantly less than that
ᵒ
observed for the Irganox L57 (ca. 249 C). The para and meta substituted mixed amine-
phenols (26 and 25, respectively), however, revealed the ability to perform in the higher
temperature region associated with diphenylamines. Oxidative stability analysis of the
bis(diphenylamines) proved more challenging as the solubility in the lubricant base oil
7

remained an issue even with the additional butyl chain. OIT analysis (Figure 9) revealed
very poor results for the series of bis(diphenylamines) whereby only 28 was able to stabilise
the base oil for more than 3 minutes. OOT analysis also revealed the same trend where 28
provided the best stabilisation out of the series, however, it was noted that none of the new
species were able to perform better than Irganox L57. The poor dispersion within the
lubricant oil significantly hindered the radical scavenging ability of this series of
bis(diphenylamines) and it was proposed that an additional branched alkyl unit would need
to be incorporated to disrupt the ordered structures and hence improve solubility. These
results did, however, give confirmation that there was a synergistic effect occurring in the
mixed amine-phenols where both induction time and onset temperature were significantly
increased through incorporation of a phenolic moiety. To conclude the series, (meta -
CH CH -), (para -CH -) and (para -CH CH -) substituted mixed amine-phenols with a butyl
2
2
2
2
2
chain were synthesised and their antioxidant capabilities were investigated. OIT analysis of
9-41 revealed a dramatic increase in the stabilisation capabilities of all three compounds
3
where the induction time for each exceeded that of the Irganox L135/57 1:1 blend as shown
in Figure 10. The highest induction time of ca. 24 minutes was revealed for the mixed
amine-phenol 39 possessing an ethyl spacer between the aromatic ring and the ester
moiety. Interestingly, Liu et al. have also reported [37] similar OIT results for their Schiff
base bridged phenolic diphenylamine antioxidants with a maximum value of ca. 25 minutes.
An increase of ca. 4 minutes was observed from 40 (ca. 23 minutes) to 41 (ca. 19 minutes)
where an additional methylene unit was introduced. This result indicated that stabilisation of
the secondary amine, through electron donation, was a significant factor in increasing the
antioxidant capabilities of these compounds. It was also proposed that the ethyl spacers
provided the ideal contact distance between the diphenylamine and the phenol, therefore
potentially increasing the ability of amine regeneration. A direct comparison of the meta
8

substituted compounds (8, 25 and 39) from the three series revealed the increase in
induction time associated with each of the structural developments (Figure 11). This
highlighted the significance of enhanced solubility through the inclusion of an alkyl chain
which increased the induction time by ca. 3 minutes (25). In addition, inclusion of electron
donating substituents as opposed to electron withdrawing substituents increased the
oxidation induction time by a further ca. 10 minutes (39). OOT analysis also revealed
excellent stability properties from the mixed amine-phenols where 39, 40 and 41 all
ᵒ
performed (ca. 254 C) in the same temperature region as the L135/57 blend (Figure 12).
The bis(diphenylamines) 42-44 also revealed similar solubility issues as seen in Series 2,
however, the OIT did not exceed that of the aromatic amine Irganox L57 hence reinforcing
further the excellent synergistic effects of combining both diphenylamines and sterically
hindered phenols within the same compound.
3
.
Conclusions
In summary, three series of mixed amine-phenols and bis(diphenylamines) were
synthesised successfully, blended into the lubricant base oil and analysed for their oxidative
stability properties, highlighting interesting structure-activity relationships. The mixed amine-
phenols were all soluble in the lubricant base oil at 0.5% w/w which was further improved
through the introduction of a butyl chain on the aniline ring. Even with the additional alkyl
chain, all of the bis(diphenylamines) derivatives revealed poor solubility and hence
oxidation induction times and oxidation onset temperatures were all lower than the current
diphenylamine antioxidant Irganox L57. Series 2 of the mixed amine-phenols revealed that
meta and para substitution provided the best oxidative stability properties. These properties
were further enhanced in Series 3 through the inclusion of methyl or ethyl spacers between
the diphenylamine and the ester moiety from the attachment to the mono-phenol linker. It
was observed that meta substitution with an ethyl spacer provided the longest oxidation
9

induction time of ca. 23 minutes, which was ca. 8 minutes longer than the current 1:1
synergistic blend of Irganox L135 and Irganox L57.
4
.
Experimental
4
.1. General procedure for purification, characterisation, thermal and oxidative analysis
Reagents and solvents were purchased from Sigma Aldrich and used without further
purification except for 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-propionic acid 7 which was
purchased from Alfa Aesar. All solvents were dried and freshly distilled prior to use.
Tetrahydrofuran (THF) was distilled under a nitrogen atmosphere from sodium and
benzophenone. Dichloromethane was distilled under a nitrogen atmosphere from calcium
hydride. Thin layer chromatography (TLC) was performed on aluminium sheets coated with
Merck silica gel 60 F . Spots were visualised under ultra-violet light (254 nm) with
24
potassium permanganate as the visualising agent. Column chromatography was performed
using Merck silica gel 60 (40-63 µm particle size) and a mobile phase as specified. Melting
1
13
points were recorded using a Stuart MP10 melting point apparatus. H NMR and C NMR
spectra were recorded using either CDCl or DMSO-d as solvent on either a Bruker
3
6
1
13
Nanobay 400 or Bruker DPX 400 operating at 400 MHz for H NMR or at 100 MHz for C
NMR. Infrared (IR) spectroscopic analysis was carried out using a Perkin Elmer 100 FT-IR
instrument with a diamond ATR sampling attachment with samples either as solids or oils.
Mass spectrometry analysis was carried out on a Thermo-Fisher Scientific Orbitrap XL LC-
MS. Samples were prepared as methanol solutions (1 mg/mL) and were ionised using
electrospray ionisation (ESI) and the parent mass ions were quoted. Thermogravimetric
analysis (TGA) was performed using a TA instrument TGA 2950. TGA was carried out
ᵒ
ᵒ
under a nitrogen atmosphere from ambient temperature to 500 C at a rate of 10 C/min
using a sample of approximately 10 mg. Pressurised differential scanning calorimetry
1
0

(PDSC) was carried out at the BP Technology Centre, Pangbourne. Oxidation induction
time (OIT) was performed using a TA instrument Q10 (0010-0141) or Q20 (0020P-0137).
The industry standard CEC L 085-99 method was followed whereby 2 mg of sample was
added to an aluminium crucible. The cell was pressurised to 6.9 bar with cylinder air and
ᵒ
the temperature was raised to 50 C and held isothermally for 5 minutes. The temperature
ᵒ
ᵒ
was then ramped at 20 C/min to 210 C and held isothermally until the oxidation of the
sample was induced. The time of onset of the exotherm minus the time taken to reach 210
ᵒ
C was reported. PDSC oxidation onset temperature (OOT) was performed using a TA
instrument 2910. An in-house method was used whereby 0.5 mg of sample was added to
an aluminium crucible. The cell was pressurised to 34.5 bar with cylinder air with a flow of
ᵒ
6
0 mL/min. The temperature was raised to 50 C and was allowed to stabilise before
ᵒ
ᵒ
heating at 50 C/min to 350 C. The temperature at which the oxidation exotherm occurred
was reported. All tests were carried out in duplicate and error bars in the figures represent
the standard deviations.
4
4
.2. Synthesis
.2.1. Preparation of methyl 3-(phenylamino)benzoate (3) [41]
In a 25 mL round-bottomed flask, toluene (10 mL) was degassed with argon for 20 minutes.
Under a flow of argon, Pd(OAc) (0.05 g, 0.23 mmol), BINAP (0.23 g, 0.37 mmol) and
2
Cs CO (2.12 mmol, 6.51 mmol) were added and left to stir for a further 20 minutes. To the
2
3
mixture, methyl (3-bromobenzoate) 1 (1.01 g, 4.65 mmol) and aniline 2 (0.51 mL, 5.58
ᵒ
mmol) were added. The reaction was stirred at 120 C and monitored by thin layer
chromatography (TLC) for 24 hours. Upon completion, the reaction was cooled to room
®
temperature and filtered through Celite , with hexane as the eluent, followed by
concentration under reduced pressure. The residue was purified by flash column
1
1

chromatography on silica eluting with hexane/ethyl acetate (90:10) (R = 0.23) to afford 0.87
f
ᵒ
ᵒ
1
g (82%) of 3 as a pale yellow solid; M.p. 110-112 C (literature M.p. 110-111 C) [41]; H
NMR (400 MHz/CDCl )/ppm, δ = 3.90 (s, 3H,-COOCH ), 5.81 (s, 1H, -NH), 6.98 (app. t, 1H,
3
3
app J=8 Hz, CHparaC H -NH), 7.09 (app. d, 2H, CH C H
C H2ortho-NH), 7.23 (m, 1H,
2meta 2
4
4
para
2
HN-CH-C(COOCH )-CHCHCH-), 7.29 (m, 3H, C H
-HN-CH-C(COOCH )-CHCHCH-),
2ortho 3
3
2
13
7
.57 (app. d, 1H, HN-CH-C(COOCH )-CH), 7.72 (m, 1H, HN-CH-C(COOCH )); C NMR
3 3
(
100 MHz/CDCl )/ppm, δ = 52.2, 118.2, 118.4, 121.5, 121.77, 121.80, 129.4, 129.3, 131.4,
3
+
1
42.4, 143.6, 167.1; Found [M+H] (C H NO ) m/z = 228.1019 (Calc. 228.1025); IR (ATR)
14
14
2
-1
v/cm : 3358, 3030, 1694, 1578, 1294, 744.
4
.2.2. Preparation of 3-(phenylamino)benzoic acid (4) [42]
To a solution of 3 (0.50 g, 2.20 mmol) in ethanol (10 mL), aqueous potassium hydroxide
(0.25 g, 4.40 mmol) was added at room temperature. The mixture was then allowed to stir
ᵒ
at 100 C for a minimum of 1 hour and was monitored closely by TLC until consumption of 3
was observed. Upon completion, the reaction was allowed to cool and the ethanol was
ᵒ
removed in vacuo. The remaining solution was cooled to 0 C and acidified to pH 2 with 2M
HCl. The resulting precipitate was collected via vacuum filtration and washed with water (15
ml). The precipitate was then dissolved in chloroform (20 mL) and washed with brine (20
mL). The organic layer was dried over MgSO , filtered and the solvent removed in vacuo to
4
ᵒ
ᵒ
yield 0.38 g (81 %) of 4 as a white solid; M.p. 140-142 C (literature M.p. 140-141 C) [42];
1
H NMR (400 MHz/CDCl )/ppm, δ = 6.99 (app. t, 1H, app J = 8 Hz, CH C H -NH), 7.10
3
para
4
4
(
app. d, 2H, CHparaC H
C H
-NH), 7.30 (m, 4H, C H2ortho-HN-CH-C(COOH)-
2ortho 2
2
2meta
2
CHCHCH-), 7.64 (app. d, 1H, HN-CH-C(COOH)-CH), 7.77 (m, 1H, HN-CH-C(COOCH ));
3
13
C NMR (100 MHz/CDCl )/ppm, δ = 118.5, 118.6, 122.0, 122.2, 129.5, 129.6, 130.5,
3
+
1
42.2, 143.8, 172.2; Found [M+H] (C H NO ) m/z = 214.0863 (Calc. 214.0868); IR (ATR)
13
12
2
-1
v/cm : 3398, 2992-2540 (br), 1682, 1584, 1464, 1294, 748.
1
2

4
.2.3. Preparation of the mono-phenolic linker (5)
The first generation hydroxyl linker 6 (5.01 g, 22.3 mmol), N,N’-dicyclohexylcarbodiimide
(DCC) (0.92 g, 4.46 mmol) and DPTS (60%) were dissolved in dry dichloromethane
ᵒ
(
50 mL) and cooled to 0 C. To this, a solution of 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-
propionic acid 7 (1.24 g, 4.46 mmol) in dry dichloromethane (20 mL) was added dropwise to
the solution. The reaction was left to stir at room temperature and was monitored closely by
TLC (90:10 hexane/ethyl acetate) until any small formation of the diphenol was observed
(
Rf = 0.38). The reaction mixture was filtered to remove the white N, N’-dicyclohexylurea
DCU) precipitate and the filtrate was concentrated in vacuo. The crude product was
(
immediately subjected to flash column chromatography on silica eluting with hexane/ethyl
1
acetate (80:20) (R = 0.24) to afford 2.15 g (95%) of 5 as a colourless oil; H NMR (400
f
MHz/CDCl )/ppm, δ = 0.89 (t, 6H, -CH CH ), 1.15 (s, 3H, -CH ), 1.28-1.37 (m, 8H, COO-
3
2
3
3
CH -CH(CH CH )-CH CH CH CH ), 1.43 (s, 18H, CH tert-butyl), 1.59 (m, 1H, COO-CH -
2
2
3
2
2
2
3
3
2
CH(CH CH )-C H ), 2.53 (s(br), 1H, -OH), 2.62 (t, 2H, Ar-CH CH -COO-), 2.86 (t, 2H, Ar-
2
3
4
9
2
2
CH CH -COO-), 3.57 (m, 2H, HO-CH -C,), 4.05 (m, 2H, COO-CH -CH(CH CH )-C H ),
2
2
2
2
2
3
4
9
4
6
3
.20 (d, 1H, COO-CH-C equatorial), 4.33 (d, 1H, COO-CH-C axial), 5.09 (s, 1H, Ar-OH),
13
.98 (s, 2H, Ar-CH); C NMR (100 MHz/CDCl )/ppm, δ = 11.0, 14.1, 17.6, 23.0, 23.8, 28.9,
3
0.4, 30.9, 34.3, 36.3, 38.7, 48.3, 64.9, 65.7, 67.3, 124.7, 130.7, 136.0, 152.3, 173.4, 174.6;
+
-1
Found [M+Na] (C H O Na) m/z = 529.3500 (Calc. 529.3505); IR (ATR) v/cm : 3528,
30
50
6
2
960, 1726, 1140, 1042.
4
.2.4. Preparation of the mixed amine-phenol (8)
The mono-phenolic linker 5 (0.34 g, 0.67 mmol), 3-(phenylamino)benzoic acid 4 (0.16 g,
.74 mmol) and DPTS (60%) were dissolved in dry dichloromethane (10 mL) and stirred at
room temperature for 30 minutes. To the solution, DCC (0.15 g, 0.74 mmol) dissolved in dry
0
1
3

dichloromethane (10 mL) was added over 15 minutes. The reaction was left overnight at
room temperature under a nitrogen atmosphere. The reaction mixture was filtered to
remove the white DCU precipitate and the filtrate was concentrated. The residue was
purified by flash column chromatography on silica eluting with hexane/ethyl acetate (80:20)
1
(
R = 0.32) to afford 0.31 g (46%) of 8 as a viscous yellow oil; H NMR (400
f
MHz/CDCl )/ppm, δ = 0.84 (t, 6H, -CH CH ), 1.23-1.36 (m, 12H, alkyl -CH , -CH ), 1.42 (s,
3
2
3
2
3
1
8H, CH tert-butyl), 1.56 (m, 1H, -CH), 2.60 (t, 2H, Ar-CH CH -COO), 2.85 (t, 2H, Ar-
3 2 2
CH CH -COO), 4.04 (m, 2H, COO-CH -CH(CH CH )-C H ), 4.34 (s, 2H, Ar-COO-CH -C),
2
2
2
2
3
4
9
2
4
.44 (s, 2H, Ar-COO-CH -C), 5.08 (s, 1H, -OH), 5.87 (s, 1H, -NH), 6.97 (m, 3H,
2
ArCHparaC H -NH and Ph-CH), 7.09 (app. d, 2H, ArCH C H
C H2ortho-NH), 7.30 (m,
2
4
4
para
2
2meta
4
H, ArC H2ortho-HN-ArCH-C(COOH)-CHCHCH-), 7.50 (app. d, 1H, HN-ArCH-C(COOH)-
2
13
CH), 7.67 (m, 1H, HN-ArCH-C(COOCH3); C NMR (100 MHz/CDCl )/ppm, δ =11.0, 14.1,
3
1
1
1
3
8.0, 22.9, 23.7, 28.9, 30.3, 30.9, 34.3, 36.2, 38.7, 46.6, 65.6, 66.1, 67.5, 118.0, 118.5,
21.5, 121.7, 121.9, 124.7, 129.4, 129.5, 130.8, 136.0, 142.2, 143.7, 152.2, 166.0, 172.7,
+
-1
72.9; Found [M+Na] (C H NO Na) m/z = 724.4184 (Calc. 724.4189); IR (ATR) v/cm :
43
59
7
641, 3385, 2960, 1731, 1517, 1132, 749.
4
.2.5. Preparation of the bis(diphenylamine) (9)
The first generation hydroxyl linker 6 (0.28 g, 1.12 mmol), 3-(phenylamino)benzoic acid 4
0.50 g, 2.34 mmol) and DPTS (60%) were dissolved in dry dichloromethane (20 mL). To
(
the solution, DCC (0.48 g, 2.34 mmol) dissolved in dry dichloromethane (10 mL) was added
over 15 minutes. The reaction was left overnight at room temperature under a nitrogen
atmosphere. The reaction mixture was filtered to remove the white DCU precipitate and the
filtrate was concentrated. The crude product was purified by flash column chromatography
on silica eluting with hexane/ethyl acetate (80:20) (R = 0.4) to afford 0.47 g (66%) of 9 as a
f
1
viscous orange oil; H NMR (400 MHz/CDCl )/ppm, δ = 0.81(m, 6H, -CH CH ), 1.20-1.33
3
2
3
1
4

(
m, 8H, alkyl -CH ), 1.41 (s, 3H, -CH ), 1.54 (m, 1H, -CH), 4.06 (m, 2H, COO-CH -
2
3
2
CH(CH CH )-C H ), 4.55 (s, 4H, Ar-COO-CH -C), 5.79 (s(br), 2H, -NH), 6.97 (app. t, 2H,
2
3
4
9
2
app. J = 8 Hz, CHparaC H -NH), 7.08 (app. d, 4H, app. J = 8 Hz, CH C H
C H2ortho-
2meta 2
4
4
para
2
NH), 7.29 (m, 8H, C H
-HN-CH-C(COOCH )-CHCHCH-), 7.51 (app. d, 2H, app. J = 4
2ortho 3
2
13
Hz, HN-CH-C(COOCH )-CH), 7.65 (app. s, 2H, HN-CH-C(COOCH )); C NMR (100
3
3
MHz/CDCl )/ppm, δ = 10.9, 14.0, 18.1, 22.9, 23.7, 28.9, 30.3, 38.7, 46.8, 66.3, 67.5, 118.1,
3
+
1
18.5, 121.4, 121.7, 121.9, 129.5, 130.8, 142.2, 146.7, 166.0, 172.9; Found [M+H]
-1
(
C H N O ) m/z = 637.3272 (Calc. 637.3278); IR (ATR) v/cm :3380, 2960, 1714, 1590,
39 45 2 6
1
494, 1204, 1104, 746.
4
.2.6. Preparation of mixed amine-phenol (11)
The mono-phenolic linker 5 (0.74 g, 1.46 mmol), 2-(4-(phenylamino)phenyl)acetic acid 12
0.50 g, 2.20 mmol), DPTS (60%) and DCC (0.45 g, 2.20 mmol) were allowed to react
(
according to the general mixed amine-phenol procedure. The crude product was purified by
flash column chromatography on silica eluting with hexane/ethyl acetate (80:20) (R = 0.31)
f
1
to afford 0.75 g (72%) of 11 as a viscous pale yellow oil; H NMR (400 MHz/CDCl )/ppm, δ
3
=
0.87 (m, 6H, -CH CH ), 1.16 (s, 3H, -CH ), 1.31-1.36 (m, 8H, alkyl -CH ), 1.42 (s, 18H,
2 3 3 2
CH tert-butyl), 1.54 (m, 1H, -CH), 2.57 (t, 2H, J = 8 Hz, Ar-CH CH -COO), 2.83 (t, 2H, J =
3
2
2
8
Hz, Ar-CH CH -COO), 3.54 (s, 2H, Ar-CH -COO), 4.01 (m, 2H, COO-CH -CH(CH CH )-
2 2 2 2 2 3
C H ), 4.22 (m, 4H, CH -COO-CH -C), 5.07 (s, 1H, ArOH), 5.68 (s, 1H, -NH), 6.92 (app. t,
4
9
2
2
1
H, app. J = 8 Hz, CHparaC H -NH), 6.97 (s, 2H, Ph-CH), 7.03 (m, 4H, ArCHortho-NH-
4 4
ArCHortho), 7.14 (app. d, 2H, J = 12 Hz, NH-ArCHCH-C(CH COO-)), 7.25 (app. t, 4H, J = 8
2
13
Hz, ArCHparaCHmetaCHortho-NH); C NMR (100 MHz/CDCl )/ppm, δ = 10.9, 14.0, 17.8, 22.9,
3
2
1
3.7, 28.9, 30.3, 30.8, 34.3, 36.2, 38.7, 40.5, 46.4, 65.4, 65.8, 67.4, 117.8, 121.0, 124.7,
+
26.0, 129.3, 130.2, 130.8, 136.0, 142.2, 143.0, 152.2, 171.3, 172.6, 172.8; Found [M+H]
1
5

-1
(
C H NO ) m/z = 716.4524 (Calc. 716.4526); IR (ATR) v/cm : 3641, 3385, 2960, 1731,
44 62 7
1
517, 1132, 749.
4
.2.7. Preparation of bis(diphenylamine) (13)
The first generation hydroxyl linker 6 (0.43 g, 1.91 mmol), 2-(4-(phenylamino)phenyl)acetic
acid 12 (1.01 g, 4.40 mmol), DPTS (60%) and DCC (0.91 g, 4.40 mmol) were allowed to
react according to the general bis(diphenylamine) procedure. The crude product was
purified by flash column chromatography on silica eluting with hexane/ethyl acetate (80:20)
1
(
R = 0.43) to afford 0.98 g (77%) of 13 as a viscous dark red oil; H NMR (400
f
MHz/CDCl )/ppm, δ = 0.86 (m, 6H, -CH CH ), 1.16 (s, 3H, -CH ), 1.25-1.35 (m, 8H, alkyl -
3
2
3
3
CH ), 1.54 (m, 1H, -CH), 3.52 (s, 4H, Ar-CH -COO), 3.98 (m, 2H, COO-CH -CH(CH CH )-
2
2
2
2
3
C H ), 4.17 (d, 2H, J = 8 Hz, Ar-COO-CH -C), 4.24 (d, 2H, J = 12 Hz, Ar-COO-CH -C), 5.67
4
9
2
2
(
s, 2H, -NH), 6.92 (app. t, 2H, app. J = 8 Hz, CHparaC H -NH), 6.99 (app. d, 4H, app. J = 8
4 4
Hz, NH-CHCH-(CH COO-)), 7.04 (app. d, 4H, app. J = 8 Hz, ArCHparaCHmetaCHortho-NH),
2
7
.10 (app. d, 4H, app. J = 8 Hz, NH-CHCH-(CH COO-)), 7.25 (app. t, 4H, app. J = 8 Hz,
2
13
ArCHparaCHmetaCHortho-NH); C NMR (100 MHz/CDCl )/ppm, δ = 10.9, 14.1, 17.9, 22.9,
3
2
1
3.7, 28.8, 30.3, 38.6, 40.4, 46.3, 65.6, 67.4, 117.9, 121.0, 126.0, 129.3, 130.2, 142.2,
+
43.0, 171.3, 172.8; Found [M+H] (C H N O ) m/z = 665.3585 (Calc. 665.3591); IR
41
49
2
6
-1
(
ATR) v/cm : 3385, 2960, 1727, 1596, 1516, 1132, 746.
4
.2.8. Preparation of methyl 2-((4-butylphenyl)amino)benzoate (14)
Methyl (2-bromobenzoate) 15 (1.00 g, 4.65 mmol) and 4-butylaniline 16 (0.88 mL, 5.58
mmol) were added to Pd(OAc) (0.02 g, 0.09 mmol), BINAP (0.12 g, 0.18 mmol) and K CO
3
2
2
(0.90 g, 6.51 mmol) and were allowed to react according to the general Buchwald-Hartwig
amination procedure. The crude residue was purified by flash column chromatography on
silica eluting with hexane/ethyl acetate (80:20) (R = 0.38) to afford 0.70 g (53%) of 14 as a
f
1
6

ᵒ
1
white solid; M.p. 135-137 C; H NMR (400 MHz/CDCl )/ppm, δ = 0.95 (t, 3H, J = 8 Hz, -
3
CH CH CH CH Ar), 1.39 (sex., 2H, J = 8 Hz, -CH CH CH CH Ar), 1.61 (quin., 2H, J = 8
3
2
2
2
3
2
2
2
Hz, -CH CH CH CH Ar), 2.61 (t, 2H, J = 8 Hz, -CH CH CH CH Ar), 3.91 (s, 3H,-COOCH ),
3
2
2
2
3
2
2
2
3
6
7
.70 (app. t, 1H, app J = 8 Hz, H COOC-CHCHCHCHC-NH), 7.17 (app. s, 4H, C H -ArCH),
3 4 9
.20 (app. d, 1H, H COOC-CHCHCHCHC-NH), 7.29 (app. t, 1H, H COOC-CHCHCHCHC-
3
3
13
NH), 7.96 (app. d, 1H, H COOC-CHCHCHCHC-NH), 9.40 (s, 1H,-NH); C NMR (100
3
MHz/CDCl )/ppm, δ = 14.0, 22.4, 33.8, 35.1, 51.7, 111.4, 113.8, 116.6, 122.6, 123.1, 126.2,
3
+
1
29.3, 131.6, 134.1, 138.2, 138.6, 148.6, 169.0; Found [M+H] (C H NO ) m/z = 284.1645
18
22
2
-1
(
Calc. 284.1651); IR (ATR) v/cm : 3321, 2928, 1684, 1514, 1230, 1082, 746.
4
.2.9. Preparation of methyl 3-((4-butylphenyl)amino)benzoate (17) [43]
Methyl (3-bromobenzoate) 18 (0.50 g, 2.33 mmol) and 4-butylaniline 16 (0.44 mL, 2.79
mmol) were added to Pd(OAc) (0.02 g, 0.08 mmol), BINAP (0.10 g, 0.16 mmol) and
2
Cs CO (1.06 g, 3.26 mmol) and were allowed to react according to the general Buchwald-
2
3
Hartwig amination procedure. The crude residue was purified by flash column
chromatography on silica eluting with hexane/ethyl acetate (80:20) (R = 0.36) to afford
f
ᵒ
ᵒ
0
.35 g (55%) of 17 as a pale yellow solid; M.p. 101-103 C (literature M.p. 101-103 C) [43];;
1
H NMR (400 MHz/CDCl )/ppm, δ = 0.93 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.36 (sex.,
3
3
2
2
2
2
2
2
H, J = 8 Hz, -CH CH CH CH Ar), 1.59 (quin., 2H, J = 8 Hz, -CH CH CH CH Ar), 2.57 (t,
3 2 2 2 3 2 2 2
H, J = 8 Hz, -CH CH CH CH Ar), 3.89 (s, 3H,-COOCH ), 5.72 (s, 1H, -NH), 7.03 (app. d,
3
2
2
2
3
H, app. J = 8 Hz, HN-ArCHCH), 7.11 (app. d, 2H, app. J = 8 Hz, C H -ArCHCH), 7.19
4
9
(
app. d, 1H, app. J = 8 Hz, HN-CH-C(COOCH )-CHCHCH-NH), 7.28 (app. t, 1H, J = 8 Hz,
3
HN-CH-C(COOCH )-CHCHCH-NH), 7.52 (app. d, 1H, J = 8 Hz, HN-CH-C(COOCH )-
3
3
13
CHCHCH-NH), 7.66 (app. s, 1H, HN-CH-C(COOCH )); C NMR (100 MHz/CDCl )/ppm, δ
3
3
=
14.0, 22.4, 33.8, 35.0, 52.1, 117.4, 119.3, 120.7, 121.1, 129.3, 129.4, 131.3, 136.9,
1
7

+
1
39.7, 144.3, 167.2; Found [M+H] (C H NO ) m/z = 284.1646 (Calc. 284.1651); IR (ATR)
18 22 2
-1
v/cm : 3364, 2927, 1700, 1288, 1217, 750.
4
.2.10.
Preparation of methyl 4-((4-butylphenyl)amino)benzoate (19)
Methyl (4-iodobenzoate) 20 (1.00 g, 3.82 mmol) and 4-butylaniline 16 (0.72 mL, 4.58 mmol)
were added to Pd(OAc) (0.02 g, 0.08 mmol), BINAP (0.10 g, 0.16 mmol) and Cs CO (1.74
2
2
3
g, 5.35 mmol) and were allowed to react according to the general Buchwald-Hartwig
amination procedure. The crude residue was purified by flash column chromatography on
silica eluting with hexane/ethyl acetate (80:20) (R = 0.36) to afford 0.54 g (50 %) of 19 as a
f
ᵒ
1
waxy brown solid; M.p. 51-53 C; H NMR (400 MHz/CDCl )/ppm, δ = 0.94 (t, 3H, J = 8 Hz,
3
-
CH CH CH CH Ar), 1.38 (sex., 2H, J = 8 Hz, -CH CH CH CH Ar), 1.61 (quin., 2H, J = 8
3 2 2 2 3 2 2 2
Hz, -CH CH CH CH Ar), 2.59 (t, 2H, J = 8 Hz, -CH CH CH CH Ar), 3.87 (s, 3H,-COOCH ),
3
2
2
2
3
2
2
2
3
5
.94 (s, 1H, -NH), 6.93 (app. d, 2H, app. J =12 Hz, HN-ArCHCH-CHCH-C(COOCH )), 7.09
3
(
app. d, 2H, app. J = 8 Hz, HN-ArCHCH), 7.15 (app. d, 1H, app. J = 8 Hz, C H -ArCHCH),
4 9
1
3
7
1
.89 (app. d, 2H, J = 8 Hz, ArCHCH-C(COOCH )); C NMR (100 MHz/CDCl )/ppm, δ =
3 3
4.0, 22.4, 33.7, 35.1, 51.7, 114.0, 120.6, 121.2, 129.4, 131.5, 138.2, 138.3, 148.7, 167.0;
+
-1
Found [M+H] (C H NO ) m/z = 284.1645 (Calc. 284.1651); IR (ATR) v/cm :3340, 2922.
18
22
2
1
689, 1591, 1435, 1285, 754.
4
.2.11.
Preparation of 2-((4-butylphenyl)amino)benzoic acid (21) [44]
Aqueous potassium hydroxide (36 mL, 7.27 mmol) was added to 14 (1.03 g, 3.63 mmol) in
ethanol (20 mL) at room temperature and allowed to react according to the general ester
ᵒ
hydrolysis procedure to yield 0.90 g (92 %) of 21 as a pale yellow solid; M.p. 147-148 C
ᵒ
1
(
literature M.p. 147-150 C) [44]; H NMR (400 MHz/CDCl )/ppm, δ = 0.95 (t, 3H, J= 8 Hz, -
3
CH CH CH CH Ar), 1.39 (sex., 2H, J = 8 Hz, -CH CH CH CH Ar), 1.61 (quin., 2H, J = 8
3
2
2
2
3
2
2
2
Hz, -CH CH CH CH Ar), 2.61 (t, 2H, J = 8 Hz, -CH CH CH CH Ar), 6.72 (app. t, 1H, app J
3
2
2
2
3
2
2
2
1
8

=
8 Hz, HOOC-CHCHCHCHC-NH), 7.15 (app. d, 1H, HOOC-CHCHCHCHC-NH), 7.18
(
app. s, 4H, C H -ArCH), 7.33 (app. t, 1H, HOOC-CHCHCHCHC-NH), 8.01(app. d, 1H,
4
9
13
HOOC-CHCHCHCHC-NH), 9.25 (s, 1H,-NH); C NMR (100 MHz/CDCl )/ppm, δ = 14.0,
3
2
1
2.4, 33.7, 35.1, 109.9, 113.9, 116.7, 123.1, 123.7, 126.3, 129.4, 132.5, 135.2, 137.8,
+
39.1, 149.5, 173.2; Found [M+H] (C H NO ) m/z = 270.1490 (Calc. 270.1494); IR (ATR)
17
22
2
-1
v/cm :3333, 3000-2480 (br), 2922, 1650, 1574, 1514, 1441, 1256, 746.
4
.2.12.
Preparation of 3-((4-butylphenyl)amino)benzoic acid (22) [45]
Aqueous potassium hydroxide (14 mL, 2.76 mmol) was added to 17 (0.39 g, 1.38 mmol) in
ethanol (7 mL) at room temperature and allowed to react according to the general ester
ᵒ
hydrolysis procedure to yield 0.30 g (81 %) of 22 as a pale yellow solid; M.p. 146-148 C
ᵒ
1
(
literature M.p. 146-149 C) [45]; H NMR (400 MHz/CDCl )/ppm, δ = 0.94 (t, 3H, J = 8 Hz, -
3
CH CH CH CH Ar), 1.38 (sex., 2H, J = 8 Hz, -CH CH CH CH Ar), 1.60 (quin., 2H, J = 8
3
2
2
2
3
2
2
2
Hz, -CH CH CH CH Ar), 2.58 (t, 2H, J = 8 Hz, -CH CH CH CH Ar), 7.04 (app. d, 2H, app.
3
2
2
2
3
2
2
2
J = 8 Hz, HN-ArCHCH), 7.13 (app. d, 2H, app. J = 8 Hz, C H -ArCHCH), 7.23 (app. d, 1H,
4
9
app. J = 8 Hz, HN-CH-C(COOH)-CHCHCH-NH), 7.32 (app. t, 1H, J = 8 Hz, HN-CH-
C(COOH)-CHCHCH-NH), 7.60 (app. d, 1H, J = 8 Hz, HN-CH-C(COOH)-CHCHCH-NH),
1
3
7
1
1
3
.72 (app. s, 1H, HN-CH-C(COOH)-CHCHCH-NH); C NMR (100 MHz/CDCl )/ppm, δ =
3
4.0, 22.4, 33.8, 35.0, 117.6, 119.5, 121.4, 121.7, 129.4, 129.5, 130.4, 137.1, 139.5, 144.5,
+
-1
72.0; Found [M+H] (C H NO ) m/z = 270.1489 (Calc. 270.1494); IR (ATR) v/cm : 3386,
17
22
2
000-2500 (br), 2928, 1687, 1520, 1288, 746.
4
.2.13.
Preparation of 4-((4-butylphenyl)amino)benzoic acid (23) [46]
Aqueous potassium hydroxide (18 mL, 3.53 mmol) was added to 19 (0.50 g, 1.76 mmol) in
ethanol (9 mL) at room temperature and allowed to react according to the general ester
ᵒ
hydrolysis procedure to yield 0.41 g (86%) of 23 as a white solid; M.p. 138-140 C (literature
1
9

ᵒ
1
M.p. 138-140 C) [46]; H NMR (400 MHz/CDCl )/ppm, δ = 0.94 (t, 3H, J = 8 Hz, -
3
CH CH CH CH Ar), 1.39 (sex., 2H, J = 8 Hz, -CH CH CH CH Ar), 1.61 (quin., 2H, J = 8
3
2
2
2
3
2
2
2
Hz, -CH CH CH CH Ar), 2.60 (t, 2H, J = 8 Hz, -CH CH CH CH Ar), 6.00 (s, 1H, -NH), 6.94
3
2
2
2
3
2
2
2
(app. d, 2H, app. J = 12 Hz, HN-ArCHCH-CHCH-C(COOH));), 7.11 (app. d, 2H, app. J = 8
Hz, HN-ArCHCH), 7.17 (app. d, 1H, app. J = 8 Hz, C H -ArCHCH), 7.96 (app. d, 2H, J = 8
4
9
13
Hz, ArCHCH-C(COOH)); C NMR (100 MHz/CDCl )/ppm, δ = 14.0, 22.4, 33.7, 35.1, 113.9,
3
+
1
2
1
19.4, 121.6, 129.4, 132.3, 137.9, 138.6, 149.5, 171.5; Found [M+H] (C H NO ) m/z =
17
22
2
-1
70.1489 (Calc. 270.1494); IR (ATR) v/cm : 3406, 3070-2545 (br), 2921, 1663, 1598,
513, 1288, 1175, 755.
4
.2.14.
Preparation of mixed amine-phenol (24)
The mono-phenolic linker 5 (0.21 g, 0.40 mmol), 2-((4-butylphenyl)amino)benzoic acid 21
0.40 g, 1.49 mmol), DPTS (60%) and DCC (0.31 g, 1.49 mmol) were allowed to react
(
according to the general mixed amine-phenol procedure. The crude product was purified by
flash column chromatography on silica eluting with hexane/ethyl acetate (90:10) (R =0.25)
f
1
to afford 0.25 g (82%) of 24 as a yellow oil; H NMR (400 MHz/CDCl )/ppm, δ = 0.85 (m,
3
6
H, -CH CH ), 0.94 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.25-1.38 (m, 13H, -CH CH , -
2 3 3 2 2 2 2 3
CH and CH CH CH CH Ar), 1.42 (s, 18H, CH tert-butyl), 1.60 (m, 3H, -CH CH CH CH Ar
3
3
2
2
2
3
3
2
2
2
and -CH(CH CH )), 2.61 (m, 4H, Ph-CH CH -COO- and -C H CH Ar), 2.85 (t, 2H, J = 8 Hz,
2
3
2
2
3
7
2
Ph-CH CH -COO-), 4.08 (m, 2H, COO-CH -CH(CH CH )-C H ), 4.37 (s, 2H, COO-CH -C),
2
2
2
2
3
4
9
2
4
6
1
.42 (s, 2H, COO-CH -C), 5.07 (s, 1H, -OH), 6.67 (app. t, 1H, -OOC-CHCHCHCHC-NH),
2
.97 (s, 2H, Ph-CH), 7.15 (m, 5H, C H -ArCH and -OOC-CHCHCHCHC-NH), 7.29 (app. d,
4
9
H, J = 8 Hz, -OOC-CHCHCHCHC-NH), 7.85 (app. d, 1H, J = 8 Hz, -OOC-CHCHCHCHC-
13
NH), 9.31 (s, 1H, -NH); C NMR (100 MHz/CDCl )/ppm, δ = 10.9, 14.0, 18.0,22.4, 22.9,
3
2
1
3.7, 28.9, 30.3, 30.9, 33.7, 34.3, 35.1, 36.2, 38.7, 46.6, 65.8, 67.5, 110.7, 113.8, 116.7,
23.3, 124.7, 129.3, 130.8, 131.4, 135.9, 137.9, 138.8, 148.8, 152.2, 167.8, 172.7, 173.0;
2
0

+
-1
Found [M+Na] (C H NO Na) m/z = 780.4810 (Calc. 780.4815); IR (ATR) v/cm : 3636,
47
67
7
3
324, 2960, 1731, 1516, 1225, 1134, 748.
4
.2.15.
Preparation of mixed amine-phenol (25)
The mono-phenolic linker 5 (0.61 g, 1.20 mmol), 3-((4-butylphenyl)amino)benzoic acid 22
0.48 g, 1.80 mmol), DPTS (60%) and DCC (0.37 g, 1.80 mmol) were allowed to react
(
according to the general mixed amine-phenol procedure. The crude product was purified by
flash column chromatography on silica eluting with hexane/ethyl acetate (90:10) (R =0.23)
f
1
to afford 0.75 g (82%) of 25 as a dark yellow oil; H NMR (400 MHz/CDCl )/ppm, δ = 0.84
3
(m, 6H, -CH CH ), 0.93 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.23-1.39 (m, 13H, -CH CH ,
2 3 3 2 2 2 2 3
-
CH3 and CH CH CH CH Ar), 1.42 (s, 18H, CH tert-butyl), 1.57 (m, 3H, -
3
2
2
2
3
CH CH CH CH Ar and -CH(CH CH )), 2.59 (m, 4H, Ph-CH CH -COO- and -C H CH Ar),
3
2
2
2
2
3
2
2
3
7
2
2
.84 (t, 2H, J = 8 Hz, Ph-CH CH -COO-), 4.05 (m, 2H, COO-CH -CH(CH CH )-C H ), 4.34
2 2 2 2 3 4 9
(
s, 2H, COO-CH -C), 4.43 (s, 2H, COO-CH -C), 5.07 (s, 1H, -OH), 5.75 (s, 1H, -NH), 6.97
2 2
(
s, 2H, Ph-CH), 7.02 (app. d, 1H, app. J = 8 Hz, ArCH-C(C H )), 7.11 (app. d, 2H, app. J =
4 9
8
1
7
2
1
Hz, ArCH-CNH), 7.21(app. d, 2H, app. J = 8 Hz, HN-CH-C(COO-)-CHCHCH-), 7.28 (m,
H, HN-CH-C(COO-)-CHCHCH-), 7.46 (app. d, 1H, J = 8 Hz, HN-CH-C(COO-)-CHCHCH-),
13
.60 (m, 1H, HN-CH-C(COO-)); C NMR (100 MHz/CDCl )/ppm, δ = 11.0, 14.0, 17.9, 22.4,
3
2.9, 23.7, 28.9, 30.3, 30.9, 33.8, 34.3, 35.0, 36.2, 38.7, 46.6, 65.7, 66.1, 67.4, 117.3,
19.4, 120.7, 121.0, 124.7, 129.4, 130.8, 130.9, 136.0, 144.4, 152.2, 166.1, 172.7, 172.9;
+
-1
Found [M+H] (C H NO ) m/z = 758.4961 (Calc. 758.4996); IR (ATR) v/cm :3633, 3381,
47
68
7
2
955, 1725, 1213, 749.
4
.2.16.
Preparation of mixed amine-phenol (26)
The mono-phenolic linker 5 (0.50 g, 0.99 mmol), 4-((4-butylphenyl)amino)benzoic acid 23
0.40 g, 1.49 mmol), DPTS (60%) and DCC (0.31 g, 1.49 mmol) were allowed to react
(
2
1

according to the general mixed amine-phenol procedure. The crude product was purified by
flash column chromatography on silica eluting with hexane/ethyl acetate (80:20) (R =0.33)
f
1
to afford 0.65 g (86%) of 26 as an orange oil; H NMR (400 MHz/CDCl )/ppm, δ = 0.84 (m,
3
6
H, -CH CH ), 0.94 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.24-1.21 (m, 11H, -CH CH , -
2 3 3 2 2 2 2 3
CH ), 1.36 (m, 2H, CH CH CH CH Ar), 1.42 (s, 18H, CH tert-butyl), 1.58 (m, 3H, -
3
3
2
2
2
3
CH CH CH CH Ar and -CH(CH CH )), 2.60 (m, 4H, Ph-CH CH -COO- and -C H CH Ar),
3
2
2
2
2
3
2
2
3
7
2
2
.84 (t, 2H, J=8 Hz, Ph-CH CH -COO-), 4.06 (m, 2H, COO-CH -CH(CH CH )-C H ), 4.34
2 2 2 2 3 4 9
(s, 2H, COO-CH -C), 4.40 (s, 2H, COO-CH -C), 5.07 (s, 1H, -OH), 5.97 (s, 1H, -NH), 6.91
2 2
(app. d, 2H, app. J = 8 Hz, NH-ArC-CH), 6.97 (s, 2H, Ph-CH), 7.06 (app. d, 2H, app. J = 8
Hz, ArCH-C(C H )), 7.15 (app. d, 2H, app. J = 8 Hz, ArCH-CNH), 7.84 (app. d, 2H, app. J =
4
9
1
3
8
2
1
1
3
Hz, ArCH-C(COO-)); C NMR (100 MHz/CDCl )/ppm, δ = 11.0, 14.0, 14.1, 17.9, 22.3,
3
2.9, 23.7, 28.9, 30.3, 30.9, 33.7, 34.3, 35.0, 36.2, 38.7, 46.7, 65.6, 65.7, 67.4, 114.0,
19.9, 121.3, 124.7, 129.4, 130.9, 131.6, 135.9, 138.1, 138.4, 149.0, 152.2, 165.9, 172.8,
+
-1
73.1; Found [M+Na] (C H NO Na) m/z = 780.4810 (Calc. 780.4815); IR (ATR) v/cm :
47
67
7
636, 3361, 2960, 1715, 1598, 1517, 1170, 754.
4
.2.17.
Preparation of bis(diphenylamine) (27)
The first generation hydroxyl linker 6 (0.20 g, 0.91 mmol), 2-((4-butylphenyl)amino)benzoic
acid 21 (0.56 g, 2.09 mmol), DPTS (60%) and DCC (0.43 g, 2.09 mmol) were allowed to
react according to the general bis(diphenylamine) procedure. The crude product was
purified by flash column chromatography on silica eluting with chloroform/hexane (70:30)
1
(
R =0.56) to afford 0.56 g (82%) of 27 as a yellow oil; H NMR (400 MHz/CDCl )/ppm, δ
f
3
=
0.83 (m, 6H, -CH CH ), 0.92 (t, 6H, J = 8 Hz, -CH CH CH CH Ar), 1.21-1.40 (m, 12H, -
2 3 3 2 2 2
CH CH and CH CH CH CH Ar), 1.46 (s, 3H, -CH ), 1.60 (m, 5H, -CH CH CH CH Ar and -
2
3
3
2
2
2
3
3
2
2
2
CH(CH CH )), 2.59 (t, 4H, J = 8 Hz, -CH CH CH CH Ar), 4.10 (m, 2H, COO-CH -
2
3
3
2
2
2
2
CH(CH CH )-C H ), 4.56 (s, 4H, COO-CH -C), 6.66 (app. t, 2H, app. J = 8 Hz, -OOC-
2
3
4
9
2
2
2

CHCHCHCHC-NH), 7.15 (m, 10H, C H -ArCH and -OOC-CHCHCHCHC-NH), 7.30 (m, 2H,
4
9
-OOC-CHCHCHCHC-NH), 7.88 (app. d, 2H, app. J = 8 Hz, -OOC-CHCHCHCHC-NH), 9.32
13
(
s, 2H, -NH); C NMR (100 MHz/CDCl )/ppm, δ = 10.9, 14.0, 22.4, 22.9, 23.7, 28.9, 30.3,
3
3
1
7
3.7, 35.1, 46.9, 66.0, 67.6, 110.7, 113.8, 116.6, 123.3, 126.2, 129.3, 131.4, 134.4, 138.0,
+
38.7, 148.8, 167.8, 173.1; Found [M+Na] (C H N O Na) m/z = 771.4344 (Calc.
47
60
2
6
-1
71.4349); IR (ATR) v/cm :3320, 2960, 1683, 1514, 1216, 1074, 745.
4
.2.18.
Preparation of bis(diphenylamine) (28)
The first generation hydroxyl linker 6 (0.17 g, 0.74 mmol), 3-((4-butylphenyl)amino)benzoic
acid 22 (0.46 g, 1.70 mmol), DPTS (60%) and DCC (0.35 g, 1.70 mmol) were allowed to
react according to the general bis(diphenylamine) procedure. The crude product was
purified by flash column chromatography on silica eluting with hexane/ethyl acetate (80:20)
1
(
R = 0.50) to afford 0.42 g (75%) of 28 as a pale yellow oil; H NMR (400 MHz/CDCl )/ppm,
f
3
δ = 0.80 (m, 6H, -CH CH ), 0.93 (t, 6H, J = 8 Hz, -CH CH CH CH Ar), 1.19-1.37 (m, 12H, -
2
3
3
2
2
2
CH CH and CH CH CH CH Ar), 1.40 (s, 3H, -CH ), 1.58 (m, 5H, -CH CH CH CH Ar and -
2
3
3
2
2
2
3
3
2
2
2
CH(CH CH )), 2.56 (t, 4H, J = 8 Hz, -C H CH Ar), 4.05 (m, 2H, COO-CH -CH(CH CH )-
2
3
3
7
2
2
2
3
C H ), 4.55 (s, 4H, COO-CH -C), 5.74 (s, 2H, -NH), 7.00 (app. d, 4H, app. J = 8 Hz, ArCH-
4
9
2
C(C H )), 7.10 (app. d, 4H, app. J = 8 Hz, ArCH-CNH), 7.18 (m, 2H, HN-CH-C(COO-)-
4
9
CHCHCH-), 7.25 (m, 2H, HN-CH-C(COO-)-CHCHCH-), 7.46 (app. d, 2H, app. J = 8 Hz,
13
HN-CH-C(COO-)-CHCHCH-), 7.60 (m, 2H, HN-CH-C(COO-));
C NMR (100
MHz/CDCl )/ppm, δ = 11.0, 14.0, 18.1, 22.3, 22.9, 23.7, 28.9, 30.3, 33.8, 35.0, 38.7, 46.8,
3
6
1
6.3, 67.5, 117.3, 118.9, 119.4, 120.6, 121.0, 126.3, 129.3, 130.8, 136.9, 139.6, 144.4,
+
66.1, 172.9; Found [M+Na] (C H N O Na) m/z = 771.4343 (Calc. 771.4349); IR (ATR)
47
60
2
6
-1
v/cm :3376, 2960, 1721, 1515, 1208, 1103, 747.
4
.2.19.
Preparation of bis(diphenylamine) (29)
2
3

The first generation hydroxyl linker 6 (0.15 g, 0.65 mmol), 4-((4-butylphenyl)amino)benzoic
acid 23 (0.40 g, 1.49 mmol), DPTS (60%) and DCC (0.31 g, 1.49 mmol) were allowed to
react according to the general bis(diphenylamine) procedure. The crude product was
purified by flash column chromatography on silica eluting with hexane/ethyl acetate (80:20)
1
(
R = 0.53) to afford 0.44 g (90%) of 29 as a pale orange oil; H NMR (400
f
MHz/CDCl )/ppm, δ = 0.82 (m, 6H, -CH CH ), 0.94 (t, 6H, J = 8 Hz, -CH CH CH CH Ar),
3
2
3
3
2
2
2
1
.20-1.38 (m, 15H, -CH CH , -CH , and CH CH CH CH Ar), 1.61 (m, 5H, -
2 3 3 3 2 2 2
CH CH CH CH Ar and -CH(CH CH )), 2.59 (t, 4H, J = 8 Hz, -CH CH CH CH Ar), 4.08 (m,
3
2
2
2
2
3
3
2
2
2
2
H, COO-CH -CH(CH CH )-C H ), 4.52 (s, 4H, COO-CH -C), 5.96 (s, 2H, -NH), 6.90 (app.
2 2 3 4 9 2
d, 4H, app. J = 8 Hz, ArCH-CNH), 7.08 (app. d, 4H, app. J = 8 Hz, ArCH-C(C H )), 7.15
4
9
(app. d, 4H, app. J = 8 Hz, ArCH-CNH), 7.85 (app. d, 4H, app. J = 8 Hz ArCH-C(COO-));
13
C NMR (100 MHz/CDCl )/ppm, δ = 10.9, 14.0, 18.1, 22.3, 22.9, 23.7, 28.9, 30.3, 33.7,
3
3
1
3
5.0, 38.7, 47.0, 65.9, 67.4, 114.0, 120.0, 121.2, 129.4, 131.6, 138.1, 138.1, 148.9, 165.9,
+
-1
73.2; Found [M+Na] (C H N O Na) m/z = 771.4344 (Calc. 771.4349); IR (ATR) v/cm :
47
60
2
6
345, 2960, 1696, 1596, 1514, 1265, 1168, 1100, 755.
4
.2.20.
Preparation of methyl 3-(3-((4-butylphenyl)amino)phenyl)propanoate (30)
Methyl 3-(3-bromophenyl)propanoate 31 (1.00 g, 4.11 mmol) and 4-butylaniline 16 (0.78
mL, 4.93 mmol) were added to Pd(OAc) (0.02 g, 0.08 mmol), BINAP (0.10 g, 0.16 mmol)
2
and Cs CO (1.87 g, 5.75 mmol) and were allowed to react according to the general
2
3
Buchwald-Hartwig amination procedure. The crude residue was purified by flash column
chromatography on silica eluting with hexane/ethyl acetate (80:20) (R = 0.41) to afford
f
1
0
.43 g (34%) of 30 as an orange oil; H NMR (400 MHz/CDCl )/ppm, δ = 0.93 (t, 3H, J = 8
3
Hz, -CH CH CH CH Ar), 1.36 (sex., 2H, J = 8 Hz, -CH CH CH CH Ar), 1.58 (quin., 2H, J =
3
2
2
2
3
2
2
2
8
Hz, -CH CH CH CH Ar), 2.56 (t, 2H, J = 8 Hz, -CH CH CH CH Ar), 2.61 (t, 2H, J = 8 Hz,
3 2 2 2 3 2 2 2
ArC-CH CH -COOCH ), 2.89 (t, 2H, J = 8 Hz, ArC-CH CH -COOCH ), 3.67 (s, 3H,-
2
2
3
2
2
3
2
4

COOCH ), 5.60 (s, 1H, -NH), 6.71 ( app. d, app. J = 8 Hz, 2H, HN-CH-
3
C(CH CH (COOCH ))-CHCHCH-), 6.86 (app. d, app. J = 8 Hz, 2H, HN-CH-
2
2
3
C(CH CH (COOCH ))-CHCHCH-), 7.00 (app. d, 2H, app. J = 8 Hz, HN-ArCHCH), 7.09
2
2
3
(
app. d, 2H, app. J = 8 Hz, C H -ArCHCH), 7.14 (app. d, 1H, app. J = 8 Hz, HN-CH-
4 9
13
C(COOCH )-CHCHCH-NH); C NMR (100 MHz/CDCl )/ppm, δ = 14.0, 22.4, 31.0, 33.8,
3
3
3
1
2
5.0, 35.7, 51.7, 114.8, 116.7, 118.8, 120.2, 129.2, 129.4, 136.1, 140.4, 141.8, 144.1,
+
-1
73.4; Found [M+H] (C H NO ) m/z = 312.1958 (Calc. 312.1964); IR (ATR) v/cm : 3380,
20
26
2
925, 1725, 1591, 1514, 1166, 778.
4
.2.21.
Preparation of ethyl 2-(4-((4-butylphenyl)amino)phenyl)acetate (32)
Ethyl 2-(4-(bromophenyl)acetate 33 (0.50 g, 2.06 mmol) and 4-butylaniline 16 (0.39 mL,
.47 mmol) were added to Pd(OAc) (0.01 g, 0.04 mmol), BINAP (0.05 g, 0.08 mmol) and
2
2
Cs CO (0.94 g, 2.88 mmol) and were allowed to react according to the general Buchwald-
2
3
Hartwig amination procedure. The crude residue was purified by flash column
chromatography on silica eluting with hexane/ethyl acetate (85:15) (R = 0.33) to afford
f
1
0
8
=
8
.43 g (67%) of 32 as an orange oil; H NMR (400 MHz/CDCl )/ppm, δ = 0.92 (t, 3H, J =
3
Hz, -CH CH CH CH Ar), 1.25 (t, 3H, J = 8 Hz, ArC-CH -COOCH CH ), 1.35 (sex., 2H, J
3
2
2
2
2
2
3
8 Hz, -CH CH CH CH Ar), 1.57 (quin, 2H, J = 8 Hz, -CH CH CH CH Ar), 2.55 (t, 2H, J =
3
2
2
2
3
2
2
2
Hz, -CH CH CH CH Ar), 3.53 (s, 2H, ArC-CH -COOCH CH ), 4.14 (q, 2H, J = 8 Hz, ArC-
3
2
2
2
2
2
3
CH -COOCH CH ), 5.62 (s, 1H, -NH), 6.97 (m, 4H, HN-ArCH -CH (COOCH CH )), 7.00
2
2
3
4
2
2
3
(
app. d, 2H, app. J = 8 Hz, HN-ArCHCH), 7.07 (app. d, 2H, app. J = 8 Hz, C H -ArCHCH);
4 9
13
C NMR (100 MHz/CDCl )/ppm, δ = 14.0, 14.3, 22.4, 33.9, 35.0, 40.7, 60.8, 117.1, 118.6,
3
+
1
25.8, 129.2, 130.1, 136.0, 140.6, 142.9, 172.1; Found [M+H] (C H NO ) m/z = 312.1958
20
26
2
-1
(
Calc. 312.1964); IR (ATR) v/cm : 3385, 2928, 1725, 1608, 1514, 1308, 1140, 750.
4
.2.22.
Preparation of methyl 3-(4-((4-butylphenyl)amino)phenyl)propanoate (34)
2
5

Methyl 3-(4-(bromophenyl)propanoate 35 (1.01 g, 4.11 mmol) and 4-butylaniline 16 (0.78
mL, 4.93 mmol) were added to Pd(OAc) (0.02 g, 0.08 mmol), BINAP (0.10 g, 0.16 mmol)
2
and Cs CO (1.87 g, 5.75 mmol) and were allowed to react according to the general
2
3
Buchwald-Hartwig amination procedure. The crude residue was purified by flash column
chromatography on silica eluting with hexane/ethyl acetate (80:20) (R = 0.37) to afford
f
ᵒ
1
1
=
1
2
.61 g (91%) of 34 as a waxy yellow solid; M.p. 48-50 C; H NMR (400 MHz/CDCl )/ppm, δ
3
0.93 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.36 (sex., 2H, J = 8 Hz, -CH CH CH CH Ar),
3
2
2
2
3
2
2
2
.57 (quin, 2H, J = 8 Hz, -CH CH CH CH Ar), 2.55 (t, 2H, J = 8 Hz, -CH CH CH CH Ar),
3
2
2
2
3
2
2
2
.61 (t, 2H, Ar-CH CH -(COOCH )), 2.89 (t, 2H, Ar-CH CH -(COOCH )), 3.67 (s, 3H, -
2
2
3
2
2
3
COOCH ), 5.56 (s, 1H, -NH), 6.97 (m, 4H, HN-ArCH -CH (COOCH CH )), 7.07 (app. d, 2H,
3
4
2
2
3
13
app. J = 8 Hz, C H -ArCH ); C NMR (100 MHz/CDCl )/ppm, δ = 14.0, 22.4, 30.2, 33.9,
4
9
4
3
3
4.9, 36.0, 51.6, 117.5, 118.2, 129.1, 129.2, 132.5, 135.7, 140.8, 142.0, 173.5; Found
+
-1
[
M+H] (C H NO ) m/z = 312.1958 (Calc. 312.1964); IR (ATR) v/cm : 3384, 2960, 1726,
20 26 2
1
514, 1191, 823.
4
.2.23.
Preparation of 3-(3-((4-butylphenyl)amino)phenyl)propanoic acid (36)
Aqueous potassium hydroxide (11 mL, 2.24 mmol) was added to 30 (0.35 g, 1.12 mmol) in
ethanol (6 mL) at room temperature and allowed to react according to the general ester
ᵒ
1
hydrolysis procedure to yield 0.25 g (70%) of 36 as a waxy red solid; M.p. 45-47 C; H
NMR (400 MHz/CDCl )/ppm, δ = 0.93 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.38 (sex., 2H,
3
3
2
2
2
J = 8 Hz, -CH CH CH CH Ar), 1.58 (quin., 2H, J = 8 Hz, -CH CH CH CH Ar), 2.56 (t, 2H, J
3
2
2
2
3
2
2
2
=
8
6
8 Hz, -CH CH CH CH Ar), 2.67 (t, 2H, J = 8 Hz, ArC-CH CH -COOCH ), 2.89 (t, 2H, J =
3 2 2 2 2 2 3
Hz, ArC-CH CH -COOCH ), 6.72 (app. d, 1H, HN-CH-C(CH CH (COOH))-CHCHCH),
2
2
3
2
2
.86 (m, 2H, HN-CH-C(CH CH (COOH))-CHCHCH), 7.00 (app. d, 2H, app. J = 8 Hz, HN-
2
2
ArCHCH), 7.09 (app. d, 1H, app. J = 8 Hz, C H -ArCHCH), 7.16 (app. t, 2H, J = 8 Hz,
4
9
13
HN-CH-C(CH CH (COOH))-CHCHCH); C NMR (100 MHz/CDCl )/ppm, δ = 14.0, 22.4,
2
2
3
2
6

3
1
3
0.6, 33.8, 34.9, 35.5, 114.8, 116.6, 118.9, 120.1, 129.2, 129.5, 136.2, 140.3, 141.4, 144.1,
+
-1
78.8; Found [M+Na] (C H NO Na) m/z = 320.1622 (Calc. 320.1626); IR (ATR) v/cm :
19
23
2
407, 3102-2601 (br), 2960, 1687, 1605, 1519, 1303, 792.
4
.2.24.
Preparation of 2-(4-((4-butylphenyl)amino)phenyl)acetic acid (37)
Aqueous potassium hydroxide (41 mL, 8.16 mmol) was added to 32 (1.27 g, 4.08 mmol) in
ethanol (20 mL) at room temperature and allowed to react according to the general ester
ᵒ
1
hydrolysis procedure to yield 0.73 g (63%) of 37 as a pale orange solid; M.p. 105-108 C; H
NMR (400 MHz/CDCl )/ppm, δ = 0.93 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.38 (sex., 2H,
3
3
2
2
2
J = 8 Hz, -CH CH CH CH Ar), 1.58 (quin, 2H, J = 8 Hz, -CH CH CH CH Ar), 2.56 (t, 2H, J
3
2
2
2
3
2
2
2
=
8 Hz, -CH CH CH CH Ar), 3.58 (s, 2H, ArC-CH -COOH), 6.99 (m, 4H,
3 2 2 2 2
HN-ArCH -CH (COOCH)), 7.08 (app. d, 2H, app. J = 8 Hz, HN-ArCHCH), 7.14 (app. d, 2H,
4
2
13
app. J = 8 Hz, C H -ArCHCH); C NMR (100 MHz/CDCl )/ppm, δ = 14.0, 22.4, 33.8, 34.9,
4
9
3
+
4
0.2, 117.0, 118.8, 124.8, 129.2, 130.3, 136.2, 140.3, 143.2, 177.4; Found [M+H]
-1
(
C H NO ) m/z = 284.1645 (Calc. 284.1651); IR (ATR) v/cm : 3374, 3088-2535 (br),
18 22 2
2
923, 1696, 1611, 1515, 1177, 803.
4
.2.25.
Preparation of 3-(4-((4-butylphenyl)amino)phenyl)propanoic acid (38)
Aqueous potassium hydroxide (32 mL, 6.42 mmol) was added to 34 (1.00 g, 3.21 mmol) in
ethanol (16 mL) at room temperature and allowed to react according to the general ester
ᵒ
1
hydrolysis procedure to yield 0.91 g (95%) of 38 as a pale orange solid; M.p. 118-120 C; H
NMR (400 MHz/CDCl )/ppm, δ = 0.93 (t, 3H, J = 8 Hz, -CH CH CH CH Ar), 1.39 (sex., 2H,
3
3
2
2
2
J = 8 Hz, -CH CH CH CH Ar), 1.58 (quin, 2H, J = 8 Hz, -CH CH CH CH Ar), 2.55 (t, 2H, J
3
2
2
2
3
2
2
2
=
8 Hz, -CH CH CH CH Ar), 2.66 (t, 2H, Ar-CH CH -(COOCH )), 2.90 (t, 2H, Ar-CH CH -
3 2 2 2 2 2 3 2 2
(
COOCH )), 6.97 (m, 4H, HN-ArCH -CH (COOCH CH )), 7.08 (m, 4H, C H -ArCH );
3 4 2 2 3 4 9 4
13
C NMR (100 MHz/CDCl )/ppm, δ = 14.0, 22.4, 30.0, 33.8, 34.9, 35.8, 117.4, 118.3, 129.1,
3
2
7

+
1
29.2, 132.1, 135.8, 140.7, 142.2, 178.5; Found [M+Na] (C H NO Na) m/z = 320.1622
19 23 2
-1
(
Calc. 320.1626); IR (ATR) v/cm : 3402, 3090-2607 (br), 2920, 1689, 1514, 1305, 818.
4
.2.26.
Preparation of mixed amine-phenol (39)
The
butylphenyl)amino)phenyl)propanoic acid 36 (0.35 g, 1.18 mmol), DPTS (60%) and DCC
0.24 g, 1.18 mmol) were allowed to react according to the general mixed amine-phenol
mono-phenolic
linker
5
(0.40
g,
0.79
mmol),
3-(3-((4-
(
procedure. The crude product was purified by flash column chromatography on silica
eluting with hexane/ethyl acetate (80:20) (R = 0.39) to afford 0.52 g (84%) of 39 as a dark
f
1
orange oil; H NMR (400 MHz/CDCl )/ppm, δ = 0.87 (m, 6H, -CH CH ), 0.93 (t, 3H, J = 8
3
2
3
Hz, -CH CH CH CH Ar), 1.16 (s, 3H, -CH ), 1.26-1.35 (m, 10H, -CH CH ), 1.42 (s, 18H, -
3
2
2
2
3
2
3
CH tert-butyl), 1.58 (m, 3H, -CH CH CH CH Ar and -CH(CH CH )), 2.59 (m, 6H, Ph-
3
3
2
2
2
2
3
CH CH -COO-, -C H CH Ar, ArC-CH CH -COO), 2.85 (m, 4H, Ph-CH CH -COO-, ArC-
2
2
3
7
2
2
2
2
2
CH CH -COO), 4.03 (m, 2H, COO-CH -CH(CH CH )-C H ), 4.21 (s, 4H, COO-CH -C), 5.07
2
2
2
2
3
4
9
2
2
4
5
6
(
s, 1H, -OH), 5.69 (s, 1H, -NH), 6.69 (app. d, 1H, HN-ArCH -C(CH CH COO-)-CH CH CH -
2
3
2
2
)
, 6.82 (app. s, 1H, HN-ArCH -C(CH CH COO-)), 6.87 (app. d, 1H, HN-ArCH -
2
3
4
5
6
C(CH CH COO-)-CH CH CH -), 6.97 (s, 2H, Ph-CH), 7.00 (app. d, 2H, ArCHCHC-NH),
2
3
2
7
.08 (app. d, 2H, C H -ArCHCH), 7.14 (app. t, 1H, HN-ArCH -C(CH CH COO-)-
4 9 2 3
4
5
6
13
CH CH CH -); C NMR (100 MHz/CDCl )/ppm, δ =11.0, 14.0, 17.8, 22.4, 22.9, 23.7, 28.9,
3
3
1
1
3
0.2, 30.3, 30.8, 33.8, 34.3, 34.9, 36.2, 38.7, 46.4, 65.4, 65.6, 67.4, 114.6, 116.7, 118.7,
24.7, 126.1, 129.2, 129.4, 130.8, 135.9, 136.0, 140.4, 141.5, 144.1, 152.2, 172.4, 172.7,
+
-1
72.9; Found [M+H] (C H NO ) m/z = 786.5303 (Calc. 786.5309); IR (ATR) v/cm : 3634,
49
72
7
380, 2960, 1731, 1515, 1135, 752.
4
.2.27.
Preparation of mixed amine-phenol (40)
2
8