Exploiting intramolecular hydrogen bonding for the highly (: Z)-selective & metal free synthesis of amide substituted β-aminoenones

Article abstract of DOI:10.1039/c7gc00909g

Herein, we report the metal free and intramolecular hydrogen bonding (IMHB) directed (Z)-selective synthesis of amide substituted β-aminoenones. Systematically, we confirm the role of dual IMHB (CO?H-N) on the Z-direction using single-crystal X-ray analysis and 1D and 2D NMR studies. High stereoselectivity, atom efficiency, excellent yields and high purity are achieved by mere filtration. We avoid column purification and the formed by-product in the process is environmentally friendly.

Full text of DOI:10.1039/c7gc00909g

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: P. Subramaniam,
C. Ramasubbu and S. Athiramu, Green Chem., 2017, DOI: 10.1039/C7GC00909G.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Please do not adjust margins
Green Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C7GC00909G
Green Chemistry
COMMUNICATION
Exploiting Intramolecular Hydrogen Bond for Highly (Z)-Selective
& Metal Free Synthesis of Amide Substituted β-aminoenones†
Palaniraja Subramaniam,*ab Chandrasekaran Ramasubbuc and Selvaraj Athiramub
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein, we report metal free and intramolecular hydrogen
bonding (IMHB) directed (Z)-selective synthesis of amide
substituted β-aminoenones. Systematically, we have confirmed
the role of dual IMHB (C=O∙∙∙H‒N) on Z-direction using single-
crystal X-ray structure and 1D, 2D NMR studies. High stereo
selectivity, atom efficiency, excellent yields and high purity were
achieved by mere filtration. We avoided column purification and
the formed by-product in the process is enviromental friendly.
Intramolecular hydrogen bond (IMHB) induces prominent
effect on molecular structure and properties. IMHBs can
naturally alter the properties of a drug molecule and make
them more lipophilic by guarding the hydrogen bonding
groups from solvent.1 Teriflunomide is used for treating
multiple sclerosis and the Z-isomer of teriflunomide is highly
favoured due to the presence of an IMHB in the molecule.2
These observations prompted us to design a new stereo
selective synthetic strategy using IMHB.3
Integrating IMHB into a molecule is gaining a great deal of
interest in drug design. Compounds with IMHB are potential
drug candidates because of the existence of IMHB in molecules
which alters its solubility, cell permeability, protein binding
affinity and physiochemical properties beyond rule of five.4
Enamines of β-dicarbonyl compounds belong to a pivotal class
Scheme 1. Synthesis of β-aminoenones Using Different Strategies
transition metal catalyst by the aminolysis of ethoxy
methylidine derivatives (EMD) of β-keto amides. One of the
ultimate advantage of this protocol is EMD of β-keto amides
and the amines used in the synthesis were highly soluble in
methanol whereas the synthesized (Z)-selective amide
substituted β-aminoenones is comparatively less soluble in
methanol due to the presence of IMHB; which helps to afford
high purity product by filtration and drying without column
purification. Solvent usages were minimized by avoiding
column purification makes the process greener and
sustainable. Generally, the solvents are main materials in any
chemical process; they also provide the greatest opportunity
for reducing waste and environmental impact.9 The propensity
of the amide group to form hydrogen bonds plays a vital role
in stereo specific synthesis.
of
compounds
with
multifarious
applications
as
pharmacophore and building blocks in organic synthesis.5,6
Synthesis of stereo defined β-aminoenones using transition
metal catalysts such as silver, copper and iron in dioxane, N,N-
dimethylformamide (DMF), and tetrahydrofuran as solvents
has been reported7 (Scheme 1). However, to the best of our
knowledge, metal-free synthesis of stereo defined β-
aminoenones is not yet reported. Our aim is to develop an
efficient stereo selective synthetic strategy without transition
metal catalysts and toxic solvents.8 Herein, we report IMHB
directed highly stereo selective synthesis of (Z)-selective amide
substituted β-aminoenones under mild conditions without any
EMD of β-dicarbonyl compounds can be easily synthesized
by condensation of triethyl orthoformate and β-dicarbonyl
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 6
View Article Online
DOI: 10.1039/C7GC00909G
COMMUNICATION
Journal Name
compounds in the presence of acetic anhydride; the products with free amino group (Table 2). EMD of β-keto amides with
exist as mixtures of E/Z isomers.10 They are most commonly different substituted amides and different aliphatic chain
used in cyclisation reactions for the preparation of lengths were synthesized using literature methods.9 N-
pyrimidines, pyrimidones, pyrazoles, azaheterocycles, thiazoles acylated-L-homoserine lactones were used as β-keto amide to
and oxazolidinones etc.11 Exploration of their synthetic utility synthesis the EMD (1d
,
1e and 1f); which are the class of
signalling molecules involved in bacterial quorum sensing.12 As
summarized in Table 2, stereo defined β-aminoenones ( ) with
in stereo defined synthesis under mild conditions is still rare.
2
Table 1. Optimization of Reaction Conditions.a
an unprotected amino group were prepared in short reaction
times (10-30 min) with an excellent yields (91-98%). In all the
examples studied herein, only the (Z)-β-aminoenone isomer
was formed. Certainly, lactones are known to undergo ring
opening reactions, though no such reactions were observed in
the above optimal conditions (2d, 2e and 2f). These results
demonstrated that IMHB has served as a useful strategy for
efficient and stereo selective synthesis of amide substituted β-
aminoenones bearing a free amino group under transition
Entry
Solvent
Temp (oC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Acetonitrile
Methanol
Ethanol
RT
RT
RT
RT
60
60
60
60
24
12
12
12
06
0.2
06
06
16
79
75
70
61
95
82
80
metal free conditions.
We have synthesised compound 2h with the optimised
reaction conditions; which is a β-aminoenone with no amide
substitution. The product (2h) exists as mixture of E/Z isomer
(65:35) and confirms that amide substitution plays a vital role
in IMHB formation and Z-selectivity of amide substituted β-
aminoenones.
2-Propanol
Acetonitrile
Methanol
Ethanol
2-Propanol
aReactions were performed with Ethoxy methylidine β-dicarbonyl amide 1a
and ammonium hydroxide solution with the mole ratio of 1:2 in solvent (5 ml)
bIsolated yields. The isomer configuration was assigned by 1H NMR & NOE
experiment.
Table 2. Synthesis of β-aminoenones with Free Amino Group.a-c
We commenced our aminolysis using 2-(ethoxymethyl-
idene)-3-oxo-N-[4-phenyl]butanamide (1a) as a test substrate
and the optimal conditions were first sought by varying the
solvents and temperature. DMF and dioxane have been
substituted by greener solvents to reduce the environmental
impact.8,9 We started our optimization with acetonitrile and
the conversion (16%) was very poor at room temperature after
24 hours (Table 1, entry 1). Methanol, ethanol and 2-propanol
as temperature solvents showed moderate conversions at
room temperature (Table 1, entry 2-4). Aminolysis of 1a at 60
oC showed faster conversion rate than room temperature and
found that the yield of 2a dramatically improved to 95% in 0.2
hours and the conversion rate was almost 100% in methanol
(Table 1, entry 6). As we expected, the formation of 2a was
O
O
O
O
O
O
H
N
H
H
N
(Z)
(Z)
(Z)
Br
N
NH2
NH2
NH2
F3C
2c
2a
2b
(10 min, 95.0%)
(10 min, 98.5%)
(15 min, 96.0%)
(CH2)7CH3
(CH2)3CH3
O
O
O
O
O
H
(Z)
N
O
H
H
O
O
O
(Z)
(Z)
N
N
O
O
O
NH2
NH2
NH2
2e
(25 min, 93.1%)
2d
2f
(30 min, 94.3%)
(25 min, 93.7%)
O
O
(CH2)7CH3
1
O
O
completely (Z)-selective and confirmed by H NMR & nuclear
F3C
H2N
O
H
(Z)
N
overhauser effect (NOE) analysis of crude product. Notably,
tedious column chromatographic purification with organic
solvents was not required because the reaction conversion
was almost 100% and the formed by-product is ethanol. After
completion of reaction, the mixture was cooled to room
temperature and then poured into ice cold water. The
precipitated solid was collected by filtration and dried under
high vacuum to afford the target product. The isolated yield
was slightly less than 100% due to transfer loss during filtration
and drying, otherwise this process has almost afforded 100%
conversion with >98% purity by HPLC. The IMHB effect plays a
critical role in this reaction to afford high geometrical purity
N
N
NH2
2h
2g
(30 min, 91.7%)
(15 min, 93.3%)
E/Z Mixture (2:1)
aReactions were performed with Ethoxy methylidine-β-dicarbonyl amide 1 and
ammonium hydroxide solution with the mole ratio of 1:2 in methanol (10 ml) at
60 oC. bIsolated yields. cThe isomer configuration was assigned by 1H NMR &
NOE experiment.
The scope and limitations of this aminolysis process were
examined further. The reaction between EMD of β-keto
amides with various amines was carried out aiming to prepare
Z selective N-Substituted β-aminoenones. A range of primary
amines was used and the corresponding β-aminoenones
and easier isolation of 2a
.
With the optimized reaction conditions in hand, we set out
to expand our strategy for the synthesis of β-aminoenones
products (3a
-
3x) were obtained with high stereo selectivity
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 3 of 6
View Article Online
DOI: 10.1039/C7GC00909G
Journal Name
COMMUNICATION
and excellent isolated yields (Table 3). We found that there is diaminomaleonitrile (3k) and no ring opening reactions were
no progress of reaction with secondary amines under the observed under the optimal conditions (3x 3v). The above
&
optimized conditions. Synthetic versatility of this method has procedure, though efficient, required further refinement to
been explored by using different classes of amines such as determine whether there was racemization of chiral amino
aliphatic amine (3a), aryl amines (3b
hetero aryl amines 3l 3s), amino sugars
nucleobases (3p 3s), nucleoside (3u) and diamines (3b
-
3e), amino acids (3f
-3j), acids during the transformation. Enantiomeric ratio (er) of 3g
(
-
(
3t
&
3w), and 3h were determined by chiral HPLC analysis. Racemic
3k). material was prepared by mixing both 3g and 3h. To our
delight, an excellent er of 100:0 was obtained for 3g and
99.2:0.8 for 3h (see the Supporting Information). The
purification process was much easier than Table 2, after the
completion of reaction; the reaction mixture was allowed to
&
&
Table 3. Substrate Scope.a-c
o
cool to RT and further cooled to 0 C. Precipitated solids were
collected by filtration and dried in vacuum to afford the
product with >98% purity monitored by HPLC. In all examples
studied, only the (Z)-β-aminoenone isomer was formed
allowing isolation of the β-aminoenone in high geometrical
purity. The propensity of the amide group to form hydrogen
bonds plays a vital role in stereo specific synthesis. EMD of β-
keto amides and amines used in the synthesis were highly
soluble in methanol whereas the synthesized amide
substituted β-aminoenones is comparatively less soluble in
methanol which helps to afford high purity product without
column purification makes this process simpler and greener.
IMHB directed stereospecific nature has significant influence
on solubility1,4 of stereoisomers which results in the lower
solubility of amide substituted β-aminoenones when
compared to EMD of β-keto amides in methanol which in turn
eases purification and affords excellent yields. If the hydrogen
bonding is intermolecular in nature, it would have increased
the solubility; instead the resultant product has lesser
solubility in methanol which indirectly confirms the IMHB.
Most importantly, equimolar quantities of amine and EMD of
β-keto amides were used in the process making
straightforward and atom-efficient.
aReactions were performed with Ethoxy methylidine-β-dicarbonyl amide 1 and
amine with the mole ratio of 1:1.01 in methanol (10 ml) at 60oC. bIsolated yields.
cThe isomer configuration was assigned by 1H NMR & NOE experiment
Figure 1. 1H NMR spectra of 2b in DMSO-d6 (i) & CDCl3 (ii) at various concentrations
Noticeably, a variety of functional groups were tolerant in this
process. Unlike in Table 2, equivalent moles of EMD of β-keto
amides and primary amines were used (Table 3). Most
interestingly, there is no cyclisation reaction occurred even
when we used diamines such as o-Phenylenediamine (3b) and
To confirm our hypothesis of IMHB directed Z specificity;
we conducted representative 1H NMR experiment of
compound 2b in deuterated solvents DMSO-d6 and CDCl3 with
varying concentrations between 2.5 mM and 100 mM. It is well
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 6
View Article Online
DOI: 10.1039/C7GC00909G
COMMUNICATION
Journal Name
known that upon increasing the concentration, if molecule has interactions which in turn serves as a strong support for our
intermolecular hydrogen bonding there is a change in the hypothesis (Figure 2). This dual IMHB influences the
chemical shift value of the respective proton.13 Interestingly, conformational stability and leads to stereo selective reaction
both DMSO-d6 and CDCl3 solutions shows no apparent changes pathway.
in chemical shifts of NH protons indicating that the NH protons
In Summary, We have successfully demonstrated IMHB
in 2b are involved in the IMHB rather than the intermolecular directed highly stereo specific and transition metal free
hydrogen bonding as represented in the Figure 1. The 1H NMR synthetic protocol for the synthesis of (Z)-selective amide
results are clear evidence for the fact that both NH protons (a substituted β-aminoenones. The synthetic versatility of this
& b) form strong IMHBs (C=O∙∙∙H‒N) with carbonyl groups.
method has been explored using various classes of amines
(aliphatic amines, aryl amines, hetero aryl amines, amino
sugars, nucleobases, nucleosides, diamines) and amino acids.
Overall this protocol offers a lot of advantages such as: high
stereo selectivity, high atom efficiency, high purity, mild
reaction conditions, less solvent usage, easy purification,
excellent yields, tolerant to lactones and diamines, and no
racemization with chiral amino acids. Out of 31 examples
reported in this work 20 were synthesized in gram scale which
demonstrates the simplicity of this protocol. Our strategy may
open new prospective in the field of stereo selective synthesis.
Table 4. Comparison of 1H NMR Chemical Shifts (δ 1H, in ppm) in DMSO-d6.
Entry
Compound
δNH(6)
12.26
10.35
10.81
δNH(14)
δNH(15)
1
2
3
2b
4a
4b
9.82
8.82
-
-
-
-
Acknowledgements
We thank Sigma-Aldrich chemicals Pvt. Ltd., Bangalore for
financial support as a part of educational assistance policy.
Sigma-Aldrich Chemicals Pvt. Ltd. is a subsidiary of Merck
KGaA.
To confirm Z-selectivity is due to the amide substitution of
β-aminoenones; we conducted a comparative 1H NMR study of
2b with Leflunomide (4a) and Teriflunomide (4b). Both the
compounds were synthesized using literature methods.14 4a
and 4b have similar amide substitution like in 2b but the amide
NH group doesn’t participate in IMHB. We investigated the 1H
Notes and references
NMR chemical shifts of 2b,
4a and 4b in DMSO-d6. 1H NMR
1
(a) B. Kuhn, P. Mohr, M. Stahl, J. Med. Chem. 2010, 53,
2601. (b) B. Over, P. McCarren, P. Artursson, M. Foley,
F. Giordanetto, G. Grönberg, C. Hilgendorf, M. D.Lee, P.
Matsson, G. Muncipinto, M. Pellisson, M. W. D. Perry,
R. Svensson, J. R. Duvall, J. Kihlberg, J. Med. Chem.
2014, 57, 2746.
signals of amide proton NH(6) in 2b were shifted downfield
(12.26 ppm) with the chemical shift difference of 1.91 ppm
and 1.45 ppm when compared to 4a and 4b respectively. The
difference in chemical shift value confirms the IMHB between
NH(6) and CO(12) of 2b (Table 4).
2
3
4
J. Kujawski, M. K. Bernard, E.Jodłowska, K. Czaja, B.
Drabińska, J Mol Model. 2015, 21, 105.
P. Gilli, V. Bertolasi, V. Ferretti, G. Gilli, J. Am. Chem.
Soc., 2000, 122, 10405.
(a) A. Alex, D S. Millan, M. Perez, F. Wakenhut, G. A.
Whitlock, Med. Chem. Commun., 2011, 2, 669. M.
Shalaeva, G. Caron, Y. A. Abramov, T. N. O’Connell, M.
S. Plummer, G. Yalamanchi, K. A. Farley, G. H. Goetz, L.
Philippe, M. J. Shapiro, J. Med. Chem. 2013, 56, 4870.
B. C. Doak, B. Over, F. Giordanetto, J. Kihlberg, Chem.
Biol. 2014, 21, 1115.
5
6
(a) B. Stanovnik, J. Svete, J. Chem. Rev. 2004, 104,
2433. (b) A-Z A. Elassara, A. A. El-Khair, Tetrahedron
2003, 59, 8463. (c) J. V. Greenhill, Chem. Soc. Rev.
1977, 6, 277. (d) N. D. Eddingtona, D. S. Cox, R. R.
Roberts, J. P. Stables, C. B. Powell,; K. R. Scotte, Curr.
Med. Chem. 2000, 7, 417. (e) H. M. Gaber, M. C. Bagley,
Z. A. Muhammad, S. M. Gomha, RSC Adv., 2017, 7,
14562.
(a) R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi, Angew.
Chem., Int. Ed. 2009, 48, 8078. (b) J-P. Wan, Y-J. Pan,
Chem. Commun. 2009, 2768. (c) A. Ilangovan, R. K.
Kumar, Chem. Eur. J. 2010, 16, 2938. (d) A. Saito, T.
Konishi, Y. Hanzawa, Org. Lett. 2010, 12, 372. (e) J. Lu,
X. Cai, S. M. Hecht, Org. Lett. 2010, 12, 5189. (f) E.
Gayon, M. Szymczyk, H. Gerard, E. Vrancken, J-M.
Campagne, J. Org. Chem. 2012, 77, 9205.
Figure 2. Single-crystal X-ray structure of 2b. Dual IMHB between Carbonyl and NH
group (C=O∙∙∙∙H‒N) is highlighted by dotted lines and hydrogen bond distances are
displayed in Å.
IMHB was further confirmed by solid state conformational
analysis using single crystal studies of 2b. Compound 2b was
crystallized from a mixture of Ethanol and water (90:10) by
slow evaporation over a period of two weeks. Single-crystal X-
ray structure of 2b clearly reveals the existence of dual
intramolecular hydrogen bonding through C=O∙∙∙∙H‒N
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 5 of 6
View Article Online
DOI: 10.1039/C7GC00909G
Journal Name
COMMUNICATION
7
(a) Y. Wang, X. Bi, W-Q. Li, D. Li, Q. Zhang, Q. Liu, B.S.
Ondon, Org. Lett. 2011, 13, 1722. (b) J. Liu, Z. Liu, P.
Liao, L. Zhang, T. Tu, X. Bi, Angew. Chem. Int. Ed. 2015
,
54, 10618. (c) J. Kang, F. Liang, S-G. Sun, Q. Liu, X. Bi,
Org. Lett., 2006, 8, 2547.
8
9
(a) D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R.
McElroy, S. Abou-Shehada and P. J. Dunn, Green Chem.
2016, 18, 288. (b) L. J. Diorazio, D. R. J. Hose, N. K.
Adlington, Org. Process Res. Dev. 2016, 20, 760.
D. Prat, O. Pardigon, H-W. Flemming, S. Letestu, V.
Ducandas, P. Isnard, E. Guntrum, T. Senac, S. Ruisseau,
P. Cruciani, P. Hosek, Org. Process Res. Dev. 2013, 17,
1517.
10 (a) A. Riahi, M. Shkoor, O. Fatunsin, R. A. Khera, C.
Fischer, P. Langer, Org. Biomol. Chem. 2009, 7, 4248.
(b) A. X. Wang, O. Xie, B. Lane, K. W. Mollison, G. C.
Hsieh, K. Marsh, M. P. Sheets, J. R. Luly, M. J. Coghlan,
Bioorg. Med. Chem. Lett. 1998, 8, 2787. (c) A. E.
Bouakher, R. L. Goff, J. Tasserie, J. Lhoste, A. Martel, S.
Comesse, Org. Lett. 2016, 18, 2383.
11 (a) Y.S. Kudyakova, D. N. Bazhin, M. V. Goryaeva, Y. V.
Burgart, V. I. Saloutin, Russ. Chem. Rev. 2014, 83, 120.
(b) A. E. Bouakher, R. L. Goff, J. Tasserie, J. Lhoste, A.
Martel, S. Comesse, Org. Lett. 2016, 18, 2383. (c) M. T.
Gabr, N. S. El-Gohary, E. R. El-Bendary, M. M. El-
Kerdawy, Eur. J. Med. Chem. 2014, 85, 576. (d) A. Riahi,
M. Shkoor, O. Fatunsin, R. A. Khera, C. Fischer, P.
Langer, Org. Biomol. Chem. 2009, 7, 4248.
12 (a) G. D. Geske, J. C. O’Neill, D. M. Miller, M. E.
Mattmann, H. E. Blackwell, J. Am. Chem. Soc. 2007,
129, 13613 (b) D. M. Stacy, S. T. Le Quement, C. L.
Hansen, J. W. Clausen, T. Tolker-Nielsen, J. W.
Brummond, M. Givskov, T. E. Nielsen, H. E. Blackwell
Org. Biomol. Chem., 2013, 11, 938.
13 V. Lazić, M. Jurković, T. Jednačak, T. Hrenar, J. P.
Vuković, P. Novak, J. Mol. Struct, 2015, 1079, 243.
14 (a) K. P. Hirth, E. Mann, L. K. Shawyer, A.Ullrich,
I.Szekely,
T.Bajor, J.Haimichael, L.Orfi, A.Levitzki,
A.Gazit, P. C. Tang, R.Lammers, US Pat., 6,331,555 B1,
2001. (b) T-X. Metro, J. Bonnamour, T. Reidon, A.
Duprez, J. Sarpoulet, J. Martinez, F. Lamaty, Chem.
Commun., 2012, 48, 11781.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C7GC00909G
COMMUNICATION
Journal Name
TABLE OF CONTENT
A prospective in stereo selective methodology: Intramolecular hydrogen bonding directed highly stereo specific,
transition metal free synthetic protocol for amide substituted β-aminoenones. High stereo selectivity, atom
efficiency, excellent yields and high purity were achieved by mere filtration and drying without using any metal
catalyst or column chromatographic purifications.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins