Phenol as a modulator in the chemical reactivity of 2,4,6-Trichloro-1,3,5-triazine: Rules of the Game II

Article abstract of DOI:10.1071/CH19524

2,4,6-Trichloro-1,3,5-triazine (TCT) is a privileged core that has the capacity to undergo sequential nucleophilic substitution reactions. Three nucleophiles, namely phenol, thiol and amine, were studied and the preferential order of incorporation on TCT

Full text of DOI:10.1071/CH19524

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
https://doi.org/10.1071/CH19524
Phenol as a Modulator in the Chemical Reactivity of
2,4,6-Trichloro-1,3,5-triazine: Rules of the Game II*
A
A B
,
C D
,
Rotimi Sheyi, Anamika Sharma,
Ayman El-Faham,
B
A C E F
, , ,
Beatriz G. de la Torre, and Fernando Albericio
A
Peptide Science Laboratory, School of Chemistry and Physics, University of
KwaZulu-Natal, Durban 4001, South Africa.
B
KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of
Laboratory Medicine and Medical Sciences, College of Health Sciences, University of
KwaZulu-Natal, Durban 4041, South Africa.
C
Department of Chemistry, College of Science, King Saud University, PO Box 2455,
Riyadh 11451, Saudi Arabia.
D
Department of Chemistry, Faculty of Science, Alexandria University, PO Box 426,
Alexandria 21321, Egypt.
E
CIBER-BBN (Networking Centre on Bioengineering, Biomaterials and Nanomedicine)
and Department of Organic Chemistry, University of Barcelona, 08028 Barcelona,
Spain.
F
Corresponding author. Email: albericio@ukzn.ac.za
2,4,6-Trichloro-1,3,5-triazine (TCT) is a privileged core that has the capacity to undergo sequential nucleophilic
substitution reactions. Three nucleophiles, namely phenol, thiol and amine, were studied and the preferential order of
incorporation on TCT was found to be first phenol, second thiol and third amine. The introduction of phenol was achieved
at ꢀ208C. The incorporation of this nucleophile in TCT helped to replace the third ‘Cl’ at 358C, which is compatible with a
biological context. The atomic charges on ‘Cl’ calculated by theoretical approaches were consistent with the experimental
findings.
Manuscript received: 17 October 2019.
Manuscript accepted: 18 December 2019.
Published online: 5 February 2020.
Introduction
introduced in 1977 by Barany and Merrifield to explain the
context of a protecting group,[12] while chemoselectivity was
coined by Trost in 1983 to differentiate between reactive
sites.[13] In 1985, Barany and Albericio introduced and demon-
strated triorthogonality to explain the removal of different
protecting groups in any sequential order.[14] We recently
reported the concept of ‘orthogonal chemoselectivity’, which
is defined as the discrimination between reactive sites in any
order, and demonstrated the concept preserving TCT as the core
unit.[15] Triorthogonality has been demonstrated using azide,
thiol and phenol as nucleophiles. The concourse of alcohol (due
The s-triazine, 2,4,6-trichloro-1,3,5-triazine (TCT), is one of the
most privileged core units, finding applications ranging from
industrial usage, such as melamine resins[1,2] and energetics,[3]
to pharmaceutical molecules.[4,5] The major advantage associ-
ated with TCT is the reactivity of the ‘Cl’ atoms, which is easily
controlled by temperature.[6,7] This feature thus allows the
incorporation of nucleophiles to prepare mono-, di- and tri-
substituted triazines (Scheme 1).[8–11]
Orthogonality and chemoselectivity are two common termi-
nologies in the field of synthetic chemistry. Orthogonality was
Nu3
Cl
N
Cl
Cl
N
>100°C
rt
0°C
N
N
N
N
N
N
N
N
N
Nu1
Nu2
Nu1
Cl
Nu1
Nu2
Nu = Nucleophile
N
Cl
Cl
TCT
Scheme 1. Nucleophilic substitution reaction for TCT.
*This paper is dedicated to Paul Alewood for his inestimable contributions to solid-phase peptide synthesis and for his friendship as well.
Journal compilation ꢀ CSIRO 2020
www.publish.csiro.au/journals/ajc

B
R. Sheyi et al.
to the poor reactivity and deactivation of the aromatic ring as a
result of its electron-donating behaviour)[16] and amine (as once
it is substituted, only one further amine can be incorporated) was
not present in the previous study as these compounds restrict the
triorthogonality principle.[17] However, TCT carrying amines as
substituents is a key player in the biological arena.[11] Further-
more, phenol can mimic the side chain of Tyr and a priori should
be electron withdrawing, a property that can enhance the
reactivity. Given these considerations, here we examined the
preferential order of incorporation of phenol, thiol and amine.
We demonstrate the influence of phenol on the TCT core for
undergoing further nucleophilic substitution and unveil the
preferential order of incorporation of three distinct nucleophiles
onto this core.
To study the order of nucleophile incorporation, several
reactions were attempted using ethyl acetate as solvent and N,
N diisopropylethyamine (DIEA) as base, as shown in Scheme 2.
Three routes were tested for the synthesis of 8, which contains
phenol, thiol and amine as three substituents on the TCT core. In
route 1, TCT was reacted with amine first to form an amine
derivative (2). This was followed by thiol and then phenol, or
phenol and finally thiol. In route 2, TCT was reacted with thiol
first to form a thiol derivative (3), then followed by amine and
then phenol, or phenol and then amine. In route 3, a phenol
derivative (4) was formed first by reaction of TCT with phenol,
followed by amine and thiol, or thiol and amine to form 8. The
routes are shown in Scheme 2.
Upon reaction with the above-mentioned nucleophiles at 08C
for 30 min, TCT formed di-chloro substituted triazine (DST).
When amine and thiol were used, the reaction was completed in
30 min, as monitored by thin layer chromatography (TLC),
affording an amine and thiol derivative (2 and 3) in high yields
(see Figs S1–S6, Supplementary Material). However, in the case
of the synthesis of a phenol derivative (4), two spots were
formed on TLC. The reaction condition for 4 was further
optimized by lowering the temperature to ꢀ208C, which yielded
4 in high purity and good yield (as confirmed by HPLC) (see
Figs S7–S9, Supplementary Material). This result was explained
by the high nucleophilicity of phenol caused by the greater
stability of the phenoxide ion compared with that of phenol
Results and Discussion
As a model, we used phenol, thiol and amine as nucleophiles
(Fig. 1).
OH
NH2
SH
3-methylbutane-1-thiol
phenol
3-methylbutan-1-amine
Fig. 1. Nucleophiles chosen for the study.
Cl
N
N
N
Cl
Cl
1
Route 1
Route 2
Route 3
Cl
N
Cl
NH
N
N
N
N
N
O
N
N
Cl
Cl
S
4
3
N
Cl
Cl
2
NH
Cl
N
NH
N
N
N
N
N
N
N
S
Cl
S
O
O
N
Cl
5
7
6
NH
N
N
N
O
S
8
Scheme 2. A priori approaches to form compound 8.

Chemical Reactivity of TCT
C
alone. This result was the first indication of support for the
hypothesis regarding the suitability of phenol to enhance reac-
tivity. After the synthesis of DST, we addressed the preparation
of mono-chloro substituted triazine (MST). The reactions were
performed at room temperature (rt) using the same conditions as
explained previously. The next possibility for an amine deriva-
tive (2) was the reaction with thiol or phenol. Therefore, 2 was
reacted with thiol and phenol at rt for 3 h using ethyl acetate as
solvent. However, no product was observed. The reaction was
then stirred at rt overnight, but still only the amine derivative (2)
was present in the reaction mixture. This agrees well with our
earlier findings where we reported once an amine is incorpo-
rated, it is not possible to incorporate any other nucleophile
except another amine owing to its high nucleophilicity.[15] Thus,
route 1 was ruled out for the synthesis of 8. In parallel, the thiol
derivative (3) was left to react with amine and phenol at rt for 3 h
using the reaction conditions mentioned before. These condi-
tions led to the formation of a thiol-amine derivative (5) (see
Figs S10–S12, Supplementary Material) and a thiol-phenol
derivative (7) (see Figs S16–S18, Supplementary Material).
Compound 5 was obtained in good yield and high purity, while
poorer results were obtained for 7. TLC monitoring showed a
spot corresponding to product 7, in addition to several other
spots including the starting material (3). It was concluded that
these results arise from the high reactivity of phenol. Therefore,
another attempt was made to conduct the reaction at 08C for 3 h.
Under these conditions, only thiol derivative (3) was observed
by TLC. Thus, the thiol-phenol route is not a suitable approach
for the synthesis of 8.
The reaction of the thiol-amine derivative (5) with phenol
was first carried out for the third position to form 8 at .608C.
Several attempts were made at a higher temperature, as TCT
usually requires a more elevated temperature for the replace-
ment of the third ‘Cl’. However, no product was observed. These
results are consistent with our earlier work, in that no nucleo-
phile can be incorporated after the amine has been introduced.
Therefore, this route was ruled out for the synthesis of 8.
Following route 3, compound 4 was reacted with amine and
thiol separately for its incorporation at position 2 to form the
phenol-amine derivative (6) (see Figs S13–S15, Supplementary
Material) and phenol-thiol derivative (7). The reaction was
attempted at rt for 3 h using the same reaction condition as
earlier. Compounds 6 and 7 were obtained in good yield and
high purity. Replacement of the third ‘Cl’ in 6 was attempted
with a thiol at 358C. However, no product was observed. The
reaction was also attempted at .608C. As expected, no product
formation was detected, since amine had already been incorpo-
rated onto the TCT core. However, in the case of 7, the reaction
was carried out at 358C for 12 h with amine as nucleophile. TLC
showed complete consumption of 7, affording the formation of 8
(see Figs S19–S21, Supplementary Material).
Table 1. Charges carried by ‘Cl’ in the molecules
Compound no.
Charges carried by ‘Cl’
Second ‘Cl’
First ‘Cl’
Third ‘Cl’
1
2
3
4
5
6
7
0.088
0.088
0.088
0.049
0.062
0.069
0.025
0.030
0.044
-
-
-
-
-
-
0.049
0.062
0.069
-
-
-
charges.[19] The charges carried by ‘Cl’ in each case were
compared (Table 1).
The atomic charges carried by ‘Cl’ in each molecule reveals
important details about the chemical reactivity of each one upon
reaction with nucleophiles.[15,17] In the case of 1, the charge
carried by ‘Cl’ was 0.088, which accounts for the high reactivity
of TCT when treated with nucleophiles. Hence, the reaction was
carried out at lower temperature (08C or even lower). Upon the
first substitution, the charges present on ‘Cl’ decreased, lower-
ing the reactivity of DST. In the case of 2, 3 and 4, the charges
decreased to 0.049, 0.062 and 0.069 respectively. Therefore, the
conditions for further reactions required a longer time and
higher temperature (rt in this case). Of 2, 3 and 4, the former
carried the least charge, whereas 4 carried the highest, thereby
indicating the high reactivity of this compound. Based on these
results, the incorporation of phenol as the first substituent
emerged as the best approach to maintain the reactivity of
triazine core.
To further determine the preferential order of substitution,
we compared the charges carried by last ‘Cl’ present on
disubstituted TCT. The charge carried by ‘Cl’ in the case of
5, 6 and 7 was 0.025, 0.030 and 0.044 respectively (Table 1).
Of all the derivatives, 7 showed the highest charge, thus
confirming it as the best choice to afford 8. In contrast, 5 and
6 might require elevated temperature or harsh conditions to
afford 8. Our findings therefore show that the ideal order to
incorporate the nucleophiles was first phenol, second thiol and
third amine.
Conclusion
Here we report on the preferential incorporation of nucleophiles
(phenol, amine and thiol) onto TCT. The order was found to be
first phenol, second thiol and third amine. Taking advantage of
the high chemical reactivity of phenol, the third replacement
with amine was done at 358C, a temperature compatible with
biological systems. However, the presence of amine on TCT
blocks the incorporation of phenol, despite its high reactivity. A
comparison of these results with our previous findings[15]
reveals that both alcohol and phenol show the same trend of
incorporation. However, the presence of phenol facilitates the
incorporation of the rest of the nucleophiles. This is significant
in the case of amine incorporation in the third position, which
was carried out at 358C instead of 758C when the alcohol was
present. Theoretical calculations were performed and compared
with the experimental findings. NBO calculations helped to
determine the atomic charges of ‘Cl’ in each molecule. The
charges found supported the experimental results, thus validat-
ing the findings. Replacement of the third ‘Cl’ at 358C extends
the use of TCT beyond a triorthogonal linker in the biological
Theoretical Calculations
To understand the electronic effect on TCT and several inter-
mediates (as shown in Scheme 2) for the synthesis of 8,
including the charges carried by ‘Cl’ after each substituent, we
performed a density functional theory (DFT) geometry opti-
mization using the Gaussian09 program package and employing
the B3LYP (Becke three parameters Lee–Yang–Parr exchange
correlation functional) and the 6–311Gþþ(d,p) basis set in the
gas phase.[18] Natural bond orbital (NBO) calculations were
performed on the optimized geometries to determine the atomic

D
R. Sheyi et al.
context, thereby paving the way for nucleophilic reactions
involving various peptides, antibodies and drugs.
CH, Ar), 7.40 (t, 2H, J ¼ 2.0 Hz, CH, Ar); 13C NMR (100 MHz,
CDCl3): 114.2 (C2,C6), 120.0 (C4), 125.9 (C3,C5), 128.9 (C-O),
170.0 (ClꢀC=N, triazine), 172.0 (O-C=N, triazine).
Experimental
Synthesis of 2-Chloro-4,6-disubstituted s-triazine (MST)
Materials and Methods
Nucleophile (0.27 mmol) was added to DST (0.27 mmol) in
EtOAc (1 mL), followed by addition of DIEA (47 mL,
0.27 mmol). The reaction was stirred at rt for 3 h. The progress of
the reaction was monitored by TLC (ethyl acetate/hexane as
mobile phase) until the complete consumption of the starting
material. The solution was concentrated to dryness and the
residue was dissolved in EtOAc and washed several times with
water to remove DIEA salts. The organic layer was collected,
dried over MgSO4, filtered and concentrated to afford pure
product, which was used for the next step without further
purification.
2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride, TCT),
3-methylbutan-1-amine, 3-methylbutane-1-thiol, phenol and
diisopropylethylamine were purchased from Sigma-Aldrich
(Sigma-Aldrich, Germany). The solvents used were of analyti-
cal and HPLC reagent grade. Magnetic resonance spectra
(1H and 13C) were recorded on a Bruker 400 MHz instrument.
Chemical shift values were reported in d units (ppm) using TMS
as internal standard. Follow-up of the reactions and checks of
the purity of the compound was done by TLC on silica-gel-
protected aluminium sheets 60 F254 (Merck), and the spots were
detected by exposure to UV light at l ¼ 254 nm. Analytical
HPLC was performed on an Agilent 1100 system using a Phe-
nomenex C18 column (3 mm, 4.6 ꢁ 50 mm). Data were processed
using Chemstation software. Buffer A: 0.1 % TFA in H2O; and
buffer B: 0.1 % TFA in CH3CN were used in HPLC. Liquid
chromatography–mass spectrometry (LCMS) was performed
on Shimadzu 2020 UFLC using a YMC-Triart C18 (5 mm,
4.6 ꢁ 150 mm) column and data processing was carried out
using Laboratory Solution software. Buffer A: 0.1 % formic acid
in H2O; and buffer B: 0.1 % formic acid in CH3CN were used.
4-Chloro-N-isopentyl-6-(isopentylthio)-1,3,5-triazin-2-
amine (5)
Creamy oil; HPLC [30–95 % of CH3CN (0.1 % TFA/H2O
1
(0.1 % TFA) over 15 min] tR ¼ 10.7 min; H NMR (400 MHz,
CDCl3): 0.86 (m, 12H, 4CH3), 1.39 (m, 2H, 2CH), 1.51 (m, 4H,
2CH2), 3.00 (m, 2H, CH2), 3.36 (m, 2H, CH2), 5.28 (brs, -NH);
13C NMR (100 MHz, CDCl3): 21.3 (CH3), 21.5 (CH3), 26.5
(CH), 26.6 (CH), 27.0 (CH2-S), 27.2 (CH2), 37.4 (CH2), 38.1
(CH2-N), 161.7 (-N-C=N, triazine), 178.2 (ClꢀC=N, triazine),
179.2 (-S-C=N, triazine).
Synthesis of 4,6-Dichloro 2-Substituted s-Triazine (DST)
TCT (50 mg, 0.27 mmol) was dissolved in EtOAc (1 mL) and
cooled to 08C for 5 min. The nucleophile (0.27 mmol) was then
added to the above solution with stirring, followed by the
addition of DIEA (47 mL, 0.27 mmol). The reaction was stirred
at 08C (ꢀ208C in the case of phenol) for 30 min. The progress of
the reaction was monitored by TLC (EtOAc/hexane as mobile
phase) until no starting material was observed. The solution was
then concentrated to dryness, and the residue was dissolved in
EtOAc and washed several times with water to remove DIEA
salts. The organic layer was collected, dried over MgSO4,
filtered and concentrated to afford pure product, which was
used for the next step without further purification.
4-Chloro-N-isopentyl-6-phenoxy-1,3,5-triazin-2-amine (6)
Off-white solid; HPLC [30–95 % of CH3CN (0.1 % TFA/H2O
1
(0.1 % TFA) over 15 min] tR ¼ 9.1 min; H NMR (400 MHz,
CDCl3): 0.80 (d, 6H, J ¼ 6.6 Hz, 2CH3), 1.45 (m, 2H, CH2), 1.55
(m, 1H, CH), 3.27 (m, 2H, CH2), 7.05–7.33 (m, 5H, ArH); 13
C
NMR (100 MHz, CDCl3): 22.5 (CH3), 25.7 (CH), 38.6 (CH2),
39.1 (CH2-O), 122.1 (C2,C6), 124.9 (C4), 129.1 (C3,C5), 152.5
(Ph-O, phenoxy), 167.4 (ClꢀC=N, triazine), 175.4 (-O-C=N,
triazine), 179.7 (PhO-C=N, triazine).
2-Chloro-4-(isopentylthio)-6-phenoxy-1,3,5-triazine (7)
Yellowish semi-solid; HPLC [30–95 % of CH3CN (0.1 % TFA/
H2O (0.1 % TFA) over 15 min] tR ¼ 12.4 min; 1H NMR
(400 MHz, CDCl3): 0.90 (d, 6H, 2CH3), 1.50 (m, 2H, CH2), 1.60
(m, 1H, CH), 3.0 (m, 2H, CH2), 7.10–7.40 (m, 5H, ArH); 13C
NMR (100 MHz, CDCl3): 21.1 (CH3), 26.4 (CH), 27.7 (CH2),
36.9 (CH2-O), 120.5 (C2,C6), 124.9 (C4), 128.4 (C3,C5), 150.7
(Ph-O, phenoxy), 170.0 (ClꢀC=N, triazine), 172.6 (PhO-C=N,
triazine), 185.6 (-S-C=N, triazine).
4,6-Dichloro-N-isopentyl-1,3,5-triazin-2-amine (2)
Off-white semi-solid; HPLC [30–95 % of CH3CN (0.1 % TFA/
H2O (0.1 % TFA) over 15 min] tR ¼ 7.6 min; 1H NMR
(400 MHz, CDCl3): 0.90 (d, 2H, J ¼ 6.8 Hz, 2CH3), 1.40 (m, 2H,
CH2), 1.60 (m, 1H, CH), 3.4 (m, 2H, CH2-N), 5.7 (s, -NH); 13
C
NMR (100 MHz, CDCl3): 22.5 (2CH3), 25.7 (CH), 29.7 (CH2),
39.1 (CH2-N), 166.5 (N-C=N, triazine moiety), 166.8 (ClꢀC=N,
triazine moiety).
Synthesis of N-isopentyl-4-(isopentylthio)-6-phenoxy-1,3,5-
triazin-2-amine (8)
2,4-Dichloro-6-(isopentylthio)-1,3,5-triazine (3)
Isopentyl amine (0.27 mmol) was added to a stirred solution of
MST (0.27 mmol) in EtOAc (1 mL), followed by addition of
DIEA (0.27 mmol). The reaction mixture was heated to 358C for
8 h. The progress of the reaction was monitored by TLC (ethyl
acetate/hexane as mobile phase) until the complete consumption
of the starting material. Solvent was removed under vacuum,
and the residue was dissolved in EtOAc (5 mL). The organic
layer was washed several times with water to remove DIEA
salts. The organic layer was collected, dried over MgSO4, fil-
tered and concentrated to afford pure product.
Yellowish oil; HPLC [30–95 % of CH3CN (0.1 % TFA/H2O
1
(0.1 % TFA) over 15 min] tR ¼ 10.5 min; H NMR (400 MHz,
CDCl3): 0.90 (d, 6H, J ¼ 6.4 Hz, 2CH3), 1.55 (m, 2H, CH2), 1.65
(m, 1H, CH), 3.1 (m, 2H, CH2-S); 13C NMR (100 MHz, CDCl3):
21.2 (2CH3), 26.5 (CH), 28.3 (CH2-S), 36.2 (CH2), 169.0
(ClꢀC=N, triazine), 185.6 (S-C=N).
2,4-Dichloro-6-phenoxy-1,3,5-triazine (4)
Off-white solid; HPLC [30–95% of CH3CN (0.1% TFA/H2O
1
(0.1% TFA) over 15 min] tR ¼ 6.7 min; H NMR (400MHz,
Brownish semi-solid; HPLC [30–95% of CH3CN (0.1%
1
TFA/H2O (0.1% TFA) over 15 min] tR ¼ 13.3 min; H NMR
CDCl3): 7.10 (d, 2H, J ¼ 1.6 Hz, CH, Ar), 7.30 (t, 1H, J ¼ 1.6 Hz,

Chemical Reactivity of TCT
E
(400 MHz, CDCl3): 0.85 (m, 12H, 4CH3), 1.38 (m, 2H, CH), 1.45
(m, 4H, 2CH2), 2.88 (m, 2H, CH2), 3.37 (m, 2H, CH2), 5.82 (brs,
NH), 7.05–7.30 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3):
21.2 (CH3), 21.4 (CH3), 26.4 (CH), 26.6 (CH), 27.1 (CH2-S), 27.3
(CH2), 38.2 (CH2), 38.4 (CH2-N), 120.9 (C2,C6), 124.4 (C4),
128.2 (C3,C5), 151.1 (Ph-O, phenoxy), 164.6 (-N-C=N, triazine),
168.6 (Ph-O-C=N, triazine, 182.6 (-S-C=N, triazine).
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The models were drawn using GaussView05,[20] and all quan-
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with B3LYP functional and 6–311Gþþ(d,p) basis set. No sol-
vent corrections were made with these calculations. Vibration
analysis showed that the optimized structure indeed represented
a minimum on the potential energy surface (no negative
eigenvalues). NBO calculations were performed on the opti-
mized geometries to determine atomic charges.
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Supplementary Material
HPLC, 1H NMR, and 13C NMR spectra and optimized geometry
coordinates for NBO calculations for all compounds are avail-
able on Journal’s website.
Conflicts of Interest
[17] A. Sharma, R. Sheyi, A. Kumar, A. El-Faham, B. G. de la Torre,
F. Albericio, Org. Lett. 2019, 21, 7888. doi:10.1021/ACS.ORGLETT.
9B02878
The authors declare no conflicts of interest.
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Acknowledgement
This work was funded in part by the following: the International Scientific
Partnership Program ISPP at King Saud University (ISPP# 0061) (Saudi
Arabia); National Research Foundation (NRF, Blue Skies #120386) and the
University of KwaZulu-Natal (South Africa); the Spanish Ministry of
Economy, Industry, and Competitiveness (MINECO) (RTI2018–093831-B-
100), CIBER-BBN, the Generalitat de Catalunya (2017 SGR 1439) (Spain).
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