Pro-fragrant ionic liquids with stable hemiacetal motifs: Water-triggered release of fragrances

Article abstract of DOI:10.1039/c5cc00099h

Stable liquid and solid salts in the form of elusive hemiacetals, appended with fragrant alcohols, have been synthesised as pro-fragrances, and the controlled release of these fragrances, triggered by water, is demonstrated.

Full text of DOI:10.1039/c5cc00099h

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Pro-fragrant ionic liquids with stable hemiacetal
motifs: water-triggered release of fragrances†‡
Cite this: Chem. Commun., 2015,
51, 4455
H. Q. Nimal Gunaratne,* Peter Nockemann and Kenneth R. Seddon
Received 6th January 2015,
Accepted 4th February 2015
DOI: 10.1039/c5cc00099h
www.rsc.org/chemcomm
Stable liquid and solid salts in the form of elusive hemiacetals, of a suitable wavelength,8 or thermal dissociation of the pro-
appended with fragrant alcohols, have been synthesised as pro- substance.9 For PRM alcohols, pro-fragrances in the form of
fragrances, and the controlled release of these fragrances, triggered predesigned esters, where the release of the fragrance may be
by water, is demonstrated.
effected by a lipase enzyme,10 or changing to a higher pH of the
medium.6 Furthermore, acetals and ketals have been used as pro-
Natural and synthetic perfume raw materials (PRMs) contain fragrances of alcohols; at more acidic pH, the fragrance would be
a multitude of chemical functional groups such as alcohols, released.11 Orthoesters and orthocarbonates derived from fragrant
aldehydes, ketones, esters, lactones, ethers, and nitriles.1 Encapsula- alcohols have also been used with acid mediated release.12
tion of active compounds into suitable material matrices, or speci-
In this communication, the synthesis of rare linear hemi-
fically designed polymer capsules, is the most widely used technique acetals13 of fragrant alcohols14 is described, as part of a reactive
to prolong the longevity of a fragrance.2 Fragrance- and flavour- class of ionic liquids.15 These pro-fragrant materials were
containing oil-in-water (o/w) emulsions2c are used in numerous synthesised with a labile reaction centre intentionally incorpo-
applications, including personal care products, to control rate of rated. The hemiacetal is attached to a non-volatile ionic matrix,
release of these materials in order to enhance the quality of the to form a new class of pro-fragrances, where the release trigger
product. Fragrances encapsulated in polymeric micro-capsules, that is neutral water (see Fig. 1), and the fragrance molecule is
are susceptible to disintegrate slowly in contact with water, are also released cleanly and near quantitatively. To our knowledge,
widely used in laundry applications where the compatibility of the hemiacetal motifs have not previously been explored for delivery
polymer material with the fabric is thought to play a key role.3 From of materials such as fragrances, drugs or sensors. However, Davis
a supramolecular point of view, bio-compatible molecular container et al. have demonstrated a related class of interesting materials,16
molecules such as cyclodextrins,4 and some of their derivatives have where a reactive ionic liquid system participates in a multi-
also been utilised in slow or controlled delivery of materials such as component equilibrium with alcohols and amines.
fragrances or drugs, through their weakly formed inclusion com-
When 1-methyl-4-formylpyridinium iodide was treated with
plexes.5 These inclusion complexes would set up an equilibrium a four-fold excess of fragrant alcohols without any solvent
between the entrapped guest molecules (fragrance or drug) in the (see Scheme 1), the corresponding hemi-acetals were isolated
host, and the released form, where that release can be designed to cleanly after removing the excess alcohols by treating the reaction
occur in a controlled fashion.
mixture with dry diethyl ether, from which excess fragrant alcohol
The final category of materials that are used for controlled can be recovered.
delivery of substances are known as pro-substances (i.e. pro-drugs
or pro-fragrances), where the substance is covalently bound to a
matrix with a trigger mechanism initiated by a pH change,6 action
of an enzyme targeting a covalent bond,7 photo-cleavage by light
The QUILL Research Centre, School of Chemistry and Chemical Engineering,
the Queen’s University of Belfast, Stranmillis Road, Belfast BT9 5AG, UK.
E-mail: n.gunaratne@qub.ac.uk, quill@qub.ac.uk
† This article is dedicated to Professor Ronald Grigg.
‡ Electronic supplementary information (ESI) available: Additional DSC, NMR, MS,
crystal data and synthetic procedures are included here. CCDC 1042672. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc00099h
Fig. 1 An illustration of the release of volatile alcohol perfumes from a
non-volatile hemiacetal ionic liquid matrix, triggered by neutral water.
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Scheme 1 Reaction scheme for the synthesis of ionic liquids from fragrance
alcohols. (2a) and (2b) are derived from 2-phenylethanol and majantol,
respectively.
As shown in the scheme, two known alcohols, viz. 2-phenyl-
ethanol (R = PhCH2CH2) and majantol (R = 3-MeC6H4CH2-
CMe2CH2), were used in this study. Compound (2a) was isolated
as a crystalline solid (m.p. 105 1C) and (2b) as a liquid (Tg of
À37 1C).
Fig. 3 A stack plot of 1H (400 MHz) NMR spectra taken at varying times, at
30 1C, monitoring the reaction (at times from 1–16 h) between (2a) and
water; concentration of (2a) is 15 mM in DMSO-d6/D2O (72 : 28; v/v).
Single crystals of (2a), suitable for X-ray crystallography,
were obtained from a CH3CN–Et2O mixture. The X-ray crystal
structure of (2a) is shown in Fig. 2. The clear presence of a
hydrogen bond between –OH and the iodide anion with an
O–HÁ Á ÁI distance of 2.662(1) Å is observed, clearly stabilising
the hemiacetal.
The interaction between (2a) and water was monitored by
1H NMR spectroscopy: a stack plot is shown in Fig. 3 for the case
where 28% water (v/v) was added to a DMSO-d6 solution. A kinetic
run was performed to monitor the release of 2-phenylethanol.
It was clearly shown that the release of the fragrant alcohol,
triggered by neutral water, is clean and nearly quantitative. The
two singlets seen between d 6.0 and 5.5 belong to the acetal CH
groups. The effect of water concentration upon the kinetics of
fragrance release was then investigated. A set of data was obtained
Fig. 4 A kinetic reaction profile, at 30 1C, for releasing 2-phenylethanol
for the reaction profile for the release of 2-phenylethanol from (2a) from (2a) in DMSO-d6 with 28% (red diamonds), 38% (green squares), 44%
(orange triangles) and 50% (magenta circles) of added D2O. The concen-
tration of (2a) is 15 mM in all cases.
in the presence of varying amounts of water; viz. at 28%, 38%,
44% and 50% in DMSO-d6 (see Fig. 4). As expected, the rate of
release of the fragrant alcohol, 2-phenylethanol, increased with
the amount of water present in the solvent mixture.
Similar results were obtained for pro-fragrance (2b) where the
release of majantol is shown to be nearly quantitative (Fig. 5).
It is noteworthy that, in contrast to many known pro-fragrances
with diverse release mechanisms,10a,17 the loss of fragrance
Fig. 5 A kinetic reaction profile, at 30 1C, for releasing majantol from (2b)
in CD3CN–D2O(60 : 40 v/v); mole fraction of (2b) vs. time (blue diamonds);
mole fraction of majantol vs. time (red squares). The concentration of (2b)
is 15 mM in all cases.
material here due to side reactions is minimal. In particular,
Fig. 2 Partial X-ray crystal structure of the stable hemi-acetal, (2a).
4456 | Chem. Commun., 2015, 51, 4455--4457
in cases where enzymes were used as the trigger, up to
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In conclusion, a new pro-fragrant motif that responds to
neutral water as a release trigger for the fragrance is introduced
here, demonstrating that control of release is dependent on the
amount of water available. In addition, as these materials are
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We thank Dr Marijana Blesic for valuable discussions, and
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Chem. Commun., 2015, 51, 4455--4457 | 4457