Synthesis of tertiary and quaternary amine derivatives from wood resin as chiral NMR solvating agents

Article abstract of DOI:10.3390/molecules201119732

Chiral tertiary and quaternary amine solvating agents for NMR spectroscopy were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution of enantiomers of model compounds [Mosher's acid (3) and its n-Bu₄N salt (4)] (guests) by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts (hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu₄N salts in enantiomeric excess (ee) determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is described, allowing the enhancement of enantiomeric discrimination when the resolution of multiplets is insufficient.

Full text of DOI:10.3390/molecules201119732

Article
Synthesis of Tertiary and Quaternary Amine
Derivatives from Wood Resin as Chiral NMR
Solvating Agents
Tiina Laaksonen, Sami Heikkinen and Kristiina Wähälä *
Received: 14 October 2015; Accepted: 8 November 2015; Published: 23 November 2015
Academic Editor: Jean Jacques Vanden Eynde
Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, P. O. Box 55, FI-00014,
Helsinki 00100, Finland; tiina.laaksonen@helsinki.fi (T.L.); sami.heikkinen@helsinki.fi (S.H.)
*
Correspondence: kristiina.wahala@helsinki.fi; Tel.: +358-9-191-50356
Abstract: Chiral tertiary and quaternary amine solvating agents for NMR spectroscopy
were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution
of enantiomers of model compounds [Mosher’s acid (3) and its n-Bu4N salt (4)] (guests)
by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts
(hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best
enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium
bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation
behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers
of various α-substituted carboxylic acids and their n-Bu4N salts in enantiomeric excess (ee)
determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is
described, allowing the enhancement of enantiomeric discrimination when the resolution of
multiplets is insufficient.
Keywords: chiral resolution; chiral solvating agent; (+)-dehydroabietylamine; NMR spectroscopy
1. Introduction
Wood resin is a natural product that after losing its volatile components hardens and is then
called rosin. Resin functions in wood as a protective agent against micro-organisms and as a reserve
nutrient supply [1]. Resin, a mixture of compounds (e.g., resin acids, fatty acids, sitosterol) can be
collected from the tree itself, but can be also obtained from the pulp industry where it is a by-product
of pulp milling [2]. For example, pine resin is a mixture of resin acids (ca. 90%) and neutral compounds
(ca. 10%). The most abundant resin acid in pine rosin is abietic acid (1, Figure 1), amounting
up to 90%. Rosin can be derivatized to an amine mixture (known as Rosin Amine D) containing
60% of (+)-dehydroabietylamine (2, Figure 1) [3–5], able to resolve chiral carboxylic acids by
crystallization [6,7]. We have previously reported [8] that neutral and ammonium forms of secondary
amines derived from dehydroabietylamine may be used in the chiral recognition of enantiomers of
certain carboxylic acids. To evaluate the corresponding tertiary amines for chiral recognitions we have
examined in the present study the behaviour of dehydroabietylamine (2)-derived tertiary amines and
their ammonium salts as chiral solvating agents (CSAs) that can be used in the discrimination of
enantiomers of both aromatic and aliphatic carboxylic acids by NMR. In particular, it was of interest to
develop ionic CSAs to see if the ionic functionality would provide improved enantiomeric resolution.
Especially in medicinal and biological chemistry, where enantiopurity is important, analytical
applications such as NMR spectroscopy for determining the enantiomeric purity are highly useful. In
NMR, enantiomeric excess (ee) may be determined up to the level of 99% but generally for ee values
Molecules 2015, 20, 20873–20886; doi:10.3390/molecules201119732
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Molecules 2015, 20, 20873–20886
over 95% more sensitive chromatographic methods (e.g., chiral HPLC and GC) have been used [9–12].
Compared to the most commonly used method HPLC, the minimal sample preparation, ease of use
and fast analysis make CSAs an optimal tool for expedient ee determinations.
Figure 1. Abietic acid (1) and (+)-dehydroabietylamine (2).
Enantiomeric resolution by CSAs is based on the formation of a diastereomeric complex
(or diastereomeric salt) [13,14]. There are several factors that may have an effect on the
complex formation. It is known in the literature that the ability of CSAs (host) to bind a chiral
compound (guest) is affected by the deuterated solvent used, the possible anion of the chiral
host [15], concentration, host:guest ratio, temperature and the functional groups of the host
and guest [13,14]. Since polar solvents can solvate ions and protic solvents can interfere in
hydrogen bond formation, it is preferable to use non-polar or weakly polar aprotic NMR solvents
such as CDCl3 in recognition studies, especially when the analyte and CSA used are ionic (or
when the formation of a diastereomeric salt pair is expected) [13]. The most frequently used
compound to test the discrimination ability of a CSA, especially an ionic one, is Mosher’s acid (3,
3,3,3-trifluoro-2-methoxy-2-phenyl-propanoic acid, Figure 2) and its sodium or potassium salt. In our
enantiomeric discrimination tests, also Mosher’s acid n-Bu4N salt (4, Figure 2) was employed.
Figure 2. Mosher’s acid (3) and its n-Bu4N salt (4).
With 4 being readily soluble in CDCl3, unlike its potassium or sodium salt, this modification
obviates the use of solubilizing additives such as crown ethers [16]. We also report a modification of
the RES-TOCSY 2D-NMR technique to enhance enantiomeric discrimination when the resolution of
multiplets is insufficient for ee determination. In the various publications concerning the use of CSAs
in NMR spectroscopy, all [17–30] or most [31–36] of the racemic carboxylic acids or salts studied
contain an aromatic moiety, and acids lacking an aromatic ring are largely ignored or deemed [37]
poorly resolvable at best. As described in the following, our new ionic and non-ionic tertiary amine
CSA agents enable efficient enantiomeric resolution and the determination of ee values of racemic
carboxylic acids or salts, including those that lack an aromatic ring.
2. Results and Discussion
Starting material 2 was purchased as 60% grade. It was converted to its acetate salt, which was
then purified by crystallisation. Pure (+)-dehydroabietyl acetate was then treated with NaOH solution
to release 2 in pure form. The synthesis of CSAs based on 2 consists of two steps (Scheme 1). First, 2 is
reacted with formaldehyde and formic acid to form 5 (63.8%). This tertiary amine is then quaternized
with an alkyl halide under microwave irradiation. Three different alkyl halides were used: methyl
iodide to obtain an uncrowded ammonium terminus (7a, 82.9%), 2-hydroxyethyl bromide to give
hydrogen bonding capability (8a, 59.4%), and benzyl bromide to provide a bulky group at the
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ammonium terminus (9a, 46.5%). It is known that the more delocalised and bulky anions can enhance
binding between the cationic CSA and (ionic or non-ionic) chiral substrate due to a weaker binding
between the cation and anion of CSA [23]. To tune the binding properties of 7a, 8a and 9a, anion
exchange was performed with NH4BF4 or LiNTf2 to obtain 7b, 8b, 9b or 7c, 8c, 9c, respectively,
in high yield (89.9%–97.8%). The delocalization and increased size of the anion also affect the
physical properties of the ionic CSAs [23]. The melting points of ionic compounds decrease when the
anion is bulky and/or weakly coordinating. Molar rotations for compounds were also determined.
Alternatively, compound 5 may be protonated with bis(trifluoromethane)-sulfonimide (HNTf2) to
give 6. Table 1 presents the collected physical property data of the compounds synthesized.
HCO2H
R
X
and H2CO
MY
X
H
H
H
H
Y
2
NH2
5
N
N R
N R
6
R = H, X = NTf2
7b R = Me, Y = BF4
7c R = Me, Y = NTf2
8b R = Bn, Y = BF4
8c R = Bn, Y = NTf2
7a R = Me, X = I
8a R = Bn, X = Br
9a R = (CH2)2OH, X = Br
9b R = (CH2)2OH, Y = BF4
9c R = (CH2)2OH, Y = NTf2
Scheme 1. Synthesis of chiral CSAs from 2. (MY = LiNTf2 or NH4BF4).
Table 1. Physical properties of compounds prepared from 2.
[α]2D3
rMsD
(a)
23 (b)
CSA
R
X
mp (˝C)
+52.05 (c)
+7.45
+20.91
+19.93 (d)
+7.79
5
6
-
-
liquid at rt.
+161.71
+44.29
+95.19
+82.77
+47.41
+34.83
+11.18
+11.67
+72.12
+83.43
+41.90
H
Me
Me
Me
Bn
NTf2
I
BF4
NTf2
Br
BF4
NTf2
Br
BF4
NTf2
114.2
250.3
246.8
46.6
188.6
179.9
48.8
213.5
188.5
7a
7b
7c
8a
8b
8c
9a
9b
9c
+7.19
+2.28
+1.70
Bn
Bn
(CH2)2OH
(CH2)2OH
(CH2)2OH
+16.45 (e)
+18.73
+6.56
viscous liquid at rt.
(a) [α]2D3 = deg cm3¨ g´1¨ dm´1, c = 1.0 g¨ cm´3, CHCl3; (b) Molar rotation calculated from [α]2D3 ˆ M/100, where
M is the molar mass; (c) Temperature 22 ˝C; (d) Solvent CHCl3 + 3% MeOH; (e) Solvent MeOH.
To investigate the ability of the synthesized compounds 5–9c to resolve ionic and non-ionic
racemic carboxylic acids both 3 and 4 were used as model compounds as 22.0 mM solutions in
CDCl3. Compounds 5–9c (1.0 eq or 2.0 eq) were dissolved in 0.5 mL (1.0 eq) of the prepared solution
1
and H- and 19F-NMR spectra were recorded (Supplementary Material Figures S1 and S2). Both
1:1 and 2:1 host:guest molar ratios were studied since according to literature, the magnitude of
non-equivalence (∆δ) increases when the amount of host is higher than that of the guest [13,14].
Compounds 5 and 6 gave the best results both in 1:1 and 2:1 host:guest ratios (Table 2). The
1
former efficiently resolved the enantiomers of 3 according to H- and 19F-NMR. The magnitude of
1
non-equivalence was 0.036 ppm (18.1 Hz) in H-NMR and 0.12 ppm (58.5 Hz) in 19F-NMR. Only
very weak resolution was achieved when compound 5 was used in the enantiomeric resolution of 4.
1
However, compound 6 resolved 4 highly efficiently, 0.030 ppm (15.0 Hz) in H-NMR and 0.10 ppm
(48.3 Hz) in 19F-NMR. No resolution was detected when 6 and 3 were used as host and guest. It is
not surprising that the non-ionic host resolves poorly an ionic guest and vice versa since no ionic
interaction can exist between them. This indicates that the resolution is based on the formation
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of a diastereomeric salt pair. Among the quaternized amine compounds only 8a, 8c and 9c were
able to differentiate the enantiomers of 4 while 7c, 8b, 8c and 9c differentiated enantiomers of 3.
Compared to 5 and 6 the resolution obtained was not as high (between 8.3 and 0.8 Hz). Interestingly
the quaternization of the tertiary amine seems to make the recognition of enantiomers unfeasible.
This may be due to a crowding in the active bonding site, i.e., ammonium terminus, caused by the
side chain (methyl, benzyl, 2-hydroxyethyl) so that the guest cannot get close enough. In regard
to this it is surprising that 7a–c (max. 1.3 Hz) are less effective than 8a–c (max. 8.3 Hz) and 9a–c
(max. 8.2 Hz). This may be caused not only by the crowding but also by the failure of the methyl
group (7a–c) to give specific enough resolution between the enantiomers compared e.g., to benzyl
(8a–c) and hydroxyethyl (9a–c) groups. When the concentration of CSA was increased (host:guest
ratio 2:1) no significant increase in the ∆δ was observed although in the case of 5 ∆δ was increased by
3.5 Hz in 1H-NMR and 13.2 Hz in 19F-NMR. Interestingly, in the case of 6 ∆δ decreased in 1H-NMR
by 1.9 Hz although it increased in 19F-NMR by 5.9 Hz.
Table 2. Determination of the magnitude of non-equivalence (∆δ) with 3 and 4 as model compounds
in the presence of different 2-based CSAs, using both 1H (500 MHz) and 19F-NMR (470 MHz) in CDCl3
at 27 ˝C (-indicates resolution not detected).
3 (ppm, (Hz))
4 (ppm, (Hz))
CSA Host:Guest
1H
19F
1H
19F
1:1
2:1
0.036 (18.1)
0.042 (21.6)
0.12 (58.5)
0.15 (71.7)
0.0018 (0.9)
-
-
5
-
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.030 (15.0)
0.026 (13.1)
0.10 (48.3)
0.12 (54.2)
6
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
7a
7b
0.027 (1.3)
7c
-
-
-
8a
0.015 (6.8)
0.0015 (0.8)
-
-
-
-
-
8b
-
0.0017 (0.9)
0.0037 (1.9)
0.010 (5.1)
8c
-
-
-
-
0.018 (8.3)
-
-
-
-
-
-
-
-
-
-
9a
1:1
2:1
1:1
2:1
9b
-
0.0017 (0.9)
-
0.0052 (2.6)
0.016 (8.2)
9c
The discrimination ability of the best performing CSAs 5 and 6 was further investigated by
titration to find the optimum conditions. Since 5 gave best resolution for 3, and 6 for 4, 3 was
titrated by 5 and 4 was titrated by 6. The guest solution (0.5 mL, 2.0 mM) was measured into an
NMR tube and titrated with the host solution (46.6 mM). NMR spectra were recorded and ∆δ 3 a 4
1
1
(both in H- and 19F-NMR) shown in Figure 3a,b. Results from H- and 19F-NMR spectra suggest
that a maximum resolution with 5 and 6 is obtained when the concentrations of host and guest are
the same (2.0 mM) indicating a 1:1 complexation of host and guest (Job’s plot in Supplementary
material Figures S8 and S12). According to the results both enantiomers of 3 interact with 5 (and both
enantiomers of 4 with 6). This can be detected from the chemical shift changes experienced by both
the S and R enantiomers (Figure 3c,d) during the titration.
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The possibility of using compounds 5 and 6 in enantiomeric excess (ee) measurements by NMR
spectroscopy was also tested using solutions of racemic 3 and S-3 (as well as 4 and S-4) (2.0 mM).
Mixtures of enantiomerically enriched samples were prepared in an NMR tube (0.5 mL, 1.0 eq) and
CSA (46.6 mM, 22.5 µL, 1.0 eq) was added. A clear correlation was detected between the expected and
measured ee% values, when just one equivalent of host with respect to the guest in a CDCl3 solution
was used (Figure 4). Line shape fitting was used for ee estimation to enhance accuracy.
1
Figure 3. The magnitude of non-equivalence (∆δ): (a) of 3 with 5 (white triangle: H-NMR and black
diamond: 19F-NMR) and (b) of 4 with 6 (white triangle: 1H-NMR and black diamond: 19F-NMR).
The change of chemical shifts of S and R enantiomers: (c) of 3 as a function of the concentration of 5
1
(white square: R enantiomer and plus sign: S enantiomer) at H-NMR; and (d) of 4 as a function of
the concentration of 6 (white square: R enantiomer and plus sign: S enantiomer) at 1H-NMR.
Figure 4. Determination of enantiomeric purities of (a) 3 in the presence of 5 and (b) 4 in the presence
of 6 by 1H-NMR (500 MHz) in CDCl3 at 27 ˝C. (Expected ee% (S): (A) 80, (B) 75, (C) 70, (D) 60, (E) 50).
The resolution of various racemic aromatic or non-aromatic α-substituted carboxylic acids
10a–16a, or their n-Bu4N salts 10b–16b, by 5 and 6 was tested (Table 3). In general, 5 and 6 are
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Molecules 2015, 20, 20873–20886
able to discriminate the corresponding guest and no major differences between the resolution of
aromatic and non-aromatic carboxylic acids were detected. Especially 5 gave excellent resolution for
the non-aromatic carboxylic acids 13a, 15a and 16a. According to the results, the best enantiomeric
resolutions are obtained with racemic carboxylic acids bearing an electronegative atom (e.g., O, N,
Br) at the α site. Therefore, it is interesting that compound 5 cannot discriminate the chiral proton
in 12a, nor does 6 discriminate the chiral proton in 12b. This indicates that not only the polarity but
also the size of the α-group (e.g., 14a,b) and/or crowding at the α site (e.g., 3 and 4) may have an
effect. Intriguingly both 5 and 6 discriminate the prochiral CH2 protons of the R and S enantiomers
of 14a and 14b. The resolution of carboxylic acids containing an electropositive (methyl group) at
the α-site (10 and 11, a and b) was less efficient. In 14b the CH2 peaks overlapped with those
of 6. This was overcome by using the 2D NMR techniques HSQC and NOESY (Supplementary
Material Figures S17 and S18). Also other 2D experiments such as HMBC may be utilized among
1D experiments such as selective TOCSY as well as carbon selective 1D-HSQC when an overlap
of CSA and substrate signals occurs. When the peaks are not baseline resolved (e.g., in case of
13a and 14a), certain specialised NMR techniques are available. Obviously, traditional line shape
fitting of an ordinary 1D 1H spectrum can significantly enhance the accuracy of estimated ee
values. Other possiblities for ee determination include pure shift experiments [38,39], J-resolved
techniques [40] and the recently published RES-TOCSY [41]. Naturally, the use of 2D methods
for reliable ee determination requires, that relevant, quantification-affecting NMR properties in the
presence of chiral auxiliary for both enantiomers remain essentially similar (cf. Supplementary
Material Figure S6). In the current study, the RES-TOCSY pulse sequence was modified to incorporate
only one selective pulse (selective refocusing pulse) and gradients for coherence selection. The
resulting 2D spectrum is phase sensitive, which allows the extraction of 1D traces with line shapes
1
as encountered in the normal H spectrum. A more detailed description of the aforementioned
pulse sequence as well as the actual pulse sequence code are given in Supplementary Material
(Figures S15–S23). The use of this modified RES-TOCSY to enhance multiplet resolution in an
indirectly detected dimension is demonstrated for compounds 13a and 14a in Figure 5.
Figure 5. RES-TOCSY experiment performed on (a) 13a (∆δ 11.1 Hz, CH3) and (b) 14a (∆δ 6.1 Hz, CH)
with CSA 5 showing the resolution of R and S enantiomer in an indirect dimension.
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Molecules 2015, 20, 20873–20886
Table 3. The magnitude of non-equivalences (∆δ) of five racemic carboxylic acids in the presence of 5
and their n-Bu4N salts in the presence of 6 (1H-NMR (500 MHz) in CDCl3 at 27 ˝C). The experiment
was performed by adding a solution containing CSA (46.6 mM, 22.5 µL, 1.0 eq) to a solution of the
guest (2.0 mM, 0.5 mL, 1.0 eq) (- indicates resolution was not detected).
∆δ
∆δ
Racemic
Carboxylic Acid
n-Bu4N Salt of Racemic
Cmpd.
10a
Cmpd.
10b
Carboxylic Acid
ppm
Hz
ppm
Hz
Me
CH
0.0023
-
1.1
-
Me
CH
-
-
-
-
Me
CH
0.0059
0.0047
3.0
2.4
Me
CH
0.0041
0.0021
2.0
1.0
11a
11b
12a
13a
CH
-
-
12b
13b
CH
-
-
CH
Me
0.0081
0.022
4.1
11.1
CH
Me
0.0068
0.017
3.4
8.6
CH
NH
Me
Ha
0.012
0.013
0.0028
0.072
0.027
6.1
6.5
1.4
36.2
13.4
CH
NH
Me
0.012
0.014
0.0039
0.065
0.036
6.0
6.8
1.9
32.5
17.8
14a
14b
(a)
Ha
Hb
(a)
Hb
CH
Me
-
-
CH
Me
-
-
0.9
15a
16a
15a
16b
0.023
11.5
0.002
CH
NH
0.016
0.020
7.9
10.2
CH
NH
0.003
0.020
1.4
10.0
(a)
Due to overlapping with protons of [n-Bu4N]+ values are from HSQC/NOESY experiment.
3. Experimental Section
3.1. General Methods
All reagents and solvents were obtained from commercial suppliers and were used
without further purification unless otherwise stated. (+)-Dehydroabietylamine was purchased
(Sigma Aldrich, St. Louis, MO, USA) as 60% grade and purified using a method described in the
literature [42] with slight modifications (see below). Flash chromatography was performed using
40–63 mesh silica gel. Microwave oven reactions were performed in closed vessel using the CEM
Focused Microwave™ Synthesis System with an external infrared temperature control system (CEM,
Matthews, NC, USA). NMR spectra were recorded using UNITY INOVA 500 (500 MHz 1H-frequency)
1
˝
and Mercury Plus 300 (300 MHz H-frequency) instruments (Varian, Palo Alto, CA, USA) at 27 C.
1H-NMR spectra were recorded at 500 MHz, 13C-NMR spectra were recorded at 125 or 75 MHz,
19F-NMR spectra were recorded at 470 MHz. All 2D NMR experiments (NOESY, HSQC and
RES-TOCSY) were recorded at 500 MHz (1H) and 125 (13C). Melting points were determined in a
digital melting point apparatus (B 545, Büchi, Flawil, Switzerland). Optical rotations were determined
˝
with a digital polarimeter (DIP-1000, JASCO, Halifax, NS, Canada) at 22–23 C in CHCl3 or MeOH
as solvent. The exact mass was obtained using high-resolution mass spectrometry (MicroTOF LC,
Bruker, Billerica, MA, USA) with electrospray ionisation (ESI).
3.2. Synthesis of Chiral Solvating Agents
3.2.1. Purification of (+)-Dehydroabietylamine (2)
Acetic acid (9.65 g) in toluene (30.0 mL) was slowly added to 60% (+)-dehydroabietylamine
(42.0 g) in toluene (70.0 mL). The product (+)-dehydroabietylaminium acetate was left to crystallise in
a fridge, filtered, washed with hexane and recrystallised from MeOH. The salt (21.0 g) was dissolved
in hot water and 10% NaOH solution (28.0 mL) was added. (+)-Dehydroabietylamine was extracted
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Molecules 2015, 20, 20873–20886
by Et2O and the organic phase was washed with water until neutral. The organic phase was dried
over Na2SO4. The solvent was evaporated and (+)-dehydroabietylamine was dried under vacuum;
˝
˝
mp 44.2 C (lit. 44–45 C) [43]; HRMS-ESI (m/z) calc. for C20H32N [M + H]+ 286.2529 found 286.2540;
[α]2D2 +44.35 (c 1.0, CHCl3) (lit. +58.0, c 0.2, DMSO, 20 C) [43]; H-NMR (500 MHz, CDCl3) δ ppm
0.85 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.22 (d, J = 6.98 Hz, 6H, 2ˆ CH3), 1.33 (m, 2H, CH2), 1.39
(m, 1H, CHH), 1.52 (dd, J = ´11.75, 3.31 Hz, 1H, CH), 1.69 (m, 2H, CH2), 1.74 (m, 2H, CH2), 2.29
(dt, J = ´13.14, 1.72 Hz, 1H, CHH), 2.40 (d, J = ´13.46 Hz, 1H, CHH), 2.61 (d, J = ´13.46 Hz, 1H,
CHH), 2.82 (sep, J = 6.98 Hz, 1H, CH), 2.88 (m, 2H, CH2), 6.89 (d, J = 1.94 Hz, 1H, CHAr), 6.99 (dd,
J = 8.08, 1.94 Hz, 1H, CHAr), 7.18 (d, J = 8.08 Hz, 1H, CHAr); 13C-NMR (125 MHz, CDCl3) δ ppm 18.8
(CH2), 18.9 (CH3), 18.895 (CH2), 24.1 H3), 24.130 (CH3), 25.4 (CH3), 30.3 (CH2), 33.6 (CH), 35.355 (CH2),
37.4 (C), 37.527 (C), 38.7 (CH2), 45.0 (CH), 53.9 (CH2), 123.9 (CHAr), 124.4 (CHAr), 126.9 (CHAr),
134.8 (CAr), 145.7 (CAr), 147.6 (CAr).
˝
1
3.2.2. Synthesis of (+)-Dehydroabietyl-N,N-dimethylmethanamine (5)
˝
Formic acid (3.96 mL, 0.105 mol, 5.0 eq) was added to 2 (6.0 g, 0.021 mol, 1.0 eq) at 0 C.
Formaldehyde (37% H2O solution, 3.81 mL, 0.048 mol, 2.3 eq) was added dropwise and the reaction
mixture was refluxed for 4 h. The reaction mixture was cooled to rt. and made basic by adding NaOH
solution (2.0 M). The product was extracted with diethyl ether. The organic phase was washed with
water until neutral, dried over Na2SO4, concentrated and dried in vacuum. The product was purified
by column chromatography (2:3 DCM:EtOAc). Colorless liquid (4.2 g 63.8%); HRMS-ESI (m/z) calc.
for C22H36N [M + H]+ 314.2842, found 314.2840; [α]D22 +52.05 (c 1.0, CHCl3); H-NMR (500 MHz,
1
CDCl3) δ ppm 0.85 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.23 (d, J = 6.91 Hz, 6H, 2ˆ CH3), 1.34 (m, 1H,
CHH), 1.43 (td, J = ´13.21, 4.15 Hz, 1H, CHH), 1.56 (td, J = ´13.21, 4.15 Hz, 1H, CHH), 1.65 (m, 2H,
CH2), 1.701 (m, 1H, CH), 1.704 (m, 1H, CHH), 1.79 (m, 1H, CHH), 1.95 (d, J = ´14.25 Hz, 1H, CHH),
2.26 (m, 1H, CHH), 2.28 (s, 6H, 2ˆ CH3), 2.29 (d, J = ´14.25 Hz, 1H, CHH), 2.83 (sep, J= 6.91 Hz, 1H,
CH), 2.88 (m, 2H, CH2), 6.88 (d, J = 1.90 Hz, 1H, CHAr), 6.98 (dd, J = 8.14, 1.90 Hz, 1H, CHAr), 7.18
(d, J = 8.14 Hz, 1H, CHAr); 13C-NMR (75 MHz, CDCl3) δ ppm 19.0 (CH3), 19.1 (CH2), 19.3 (CH2), 24.2
(2ˆ CH3), 25.8 (CH3), 30.3 (CH2), 33.6 (CH), 36.6 (CH2), 37.6 (C), 38.6 (CH2), 38.9 (C), 44.3 (CH), 49.3
(2ˆ CH3), 71.2 (CH2), 123.8 (CHAr), 124.3 (CHAr), 126.9 (CHAr), 134.9 (CAr), 145.5 (CAr), 147.9 (CAr).
3.2.3. Synthesis of (+)-Dehydroabietyl-N,N-dimethylmethanaminium
bis(trifluoromethanesulfon-imide) (6)
˝
HNTf2 (89.7 mg, 1.0 eq) was added at 0 C to the tertiary amine 5 (0.1 g, 0.319 mmol, 1.0 eq)
in DCM (0.5 mL). After stirring for 1 h at rt water was added. The layers were separated and the
organic phase washed with water (3 ˆ 2.0 mL). The organic solvent was evaporated and the product
˝
dried under vacuum. White solid (0.18 g, 93.3%;); mp 114.2 C; HRMS-ESI (m/z) calc. for C22H36N [M
´ NTf2]+314.2842, found 314.2834; calc. for C2F6NO4S2 [NTf2] 279.9167, found 279.9170; [α]2D3 +7.45
(c 1.0, CHCl3); 1H-NMR (500 MHz, CDCl3) δ ppm 1.16 (s, 3H, CH3), 1.21 (d, J = 6.88 Hz, 6H, 2ˆ CH3),
1.24 (s, 3H, CH3), 1.33 (m, 1H, CHH), 1.37 (dd, J = ´12.67, 2.07 Hz, 1H, CH), 1.43 (m, 1H, CHH), 1.65
(dt, J = ´13.45, 7.69 Hz, 1H, CHH), 1.67 (dt, J = ´13.45, 7.69 Hz, 1H, CHH), 1.79 (m, 2H,CH2), 1.84 (m,
1H, CHH), 2.34 (dt, J = ´13.27, 2.97 Hz, 1H, CHH), 2.82 (sep, J = 6.88 Hz, 1H, CH), 2.85 (m, 1H, CHH),
2.94 (d, J = ´13.22 Hz, 1H, CHH), 2.95 (m, 1H, CHH), 3.01 (s, 6H, 2ˆ CH3), 3.28 (d, J = ´13.22 Hz,
1H,CHH), 6.88 (d, J = 1.65 Hz, 1H, CHAr), 6.99 (dd, J = 8.14, 1.65 Hz, 1H, CHAr), 7.14 (d, J = 8.14 Hz,
1H, CHAr); 13C-NMR (125 MHz, CDCl3) δ ppm 17.6 (CH3), 18.1 (CH2), 19.5 (CH2), 24.1 (2ˆ CH3), 25.4
(CH3), 29.7 (CH2), 33.6 (CH), 35.9 (CH2), 37.7 (C), 37.7 (CH2), 37.7(C), 47.4 (CH), 48.4 (2ˆ CH3), 73.3
(CH2), 119.8 (q, J = 319.79, CF3), 124.1 (CHAr), 124.4 (CHAr), 126.9 (CHAr), 133.7 (CAr), 146.2 (CAr),
146.3 (CAr).
20880

Molecules 2015, 20, 20873–20886
3.2.4. Synthesis of (+)-Dehydroabietyl-N,N,N-trimethylmethanaminium iodide (7a)
The tertiary amine 5 (0.15 g, 0.479 mmol, 1.0 eq), iodomethane (0.68 g 0.30 mL, 4.79 mmol,
10.0 eq, caution toxic) and CHCl3 (1.0 mL) were measured into a microwave tube. The reaction was
˝
irradiated in microwave oven at 120 W, 30 min, 47 C. Et2O was added and the product was collected
by filtration and washed with Et2O. The product was dried in vacuum. White solid (0.18 g, 82.9%);
˝
˝
mp 250.3 C (lit. 249–252 C) [44]; HRMS-ESI (m/z) calc. for C23H38N [M ´ I]+ 328.2999, found
328.2988; [α]2D3 = +20.91 (c 1.0, CHCl3) (lit. +22.0, c 1.20, CHCl3, 20 C) [44]; H-NMR (500 MHz,
CDCl3) δ ppm 1.19 (d, J = 7.01 Hz, 6H, 2ˆ CH3), 1.23 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.40 (dd,
J = ´12.32, 1.87 Hz, 1H, CH), 1.42 (m, 1H, CHH), 1.73 (m, 1H, CHH), 1.74 (m, 2H, CH2), 1.86 (m,
1H, CHH), 2.00 (m, 1H, CHH), 2.05 (m, 1H, CHH), 2.30 (dt, J = ´13.03 Hz, 1H, CHH), 2.80 (sep,
J = 7.01 Hz, 1H, CH), 2.94 (m, 2H, CH2), 3.39 (d, J = ´14.04 Hz, 1H, CHH), 3.57 (s, 9H, 3ˆ CH3), 3.94
(d, J = ´14.04 Hz, 1H, CHH), 6.88 (d, J = 1.75 Hz, 1H, CHAr), 6.96 (dd, J = 8.20, 1.75 Hz, 1H, CHAr),
7.09 (d, J = 8.20 Hz, 1H, CHAr); 13C-NMR (125 MHz, CDCl3) δ ppm 18.6 (CH2), 20.06 (CH3), 20.08
(CH2), 24.18 (CH3), 24.22 (CH3), 25.8 (CH3), 29.9 (CH2), 33.7 (CH), 37.7 (CH2), 38.2 (C), 39.3 (CH2),
40.9 (C), 48.1 (CH), 56.9 (3ˆ CH3), 78.7 (CH2), 123.8 (CHAr), 124.2 (CHAr), 127.2 (CHAr), 134.4 (CAr),
146.3 (CAr), 146.8 (CAr).
˝
1
3.2.5. Synthesis of N-Benzyl-1-(+)-dehydroabietyl-N,N-dimethylmethanaminium bromide (8a)
The tertiary amine 1 (0.3 g, 0.956 mmol, 1.0 eq) and benzyl bromide (0.491 g, 0.341 mL, 2.87 mmol,
l.3 eq) were measured into a microwave tube and EtOAc (1.0 mL) was added. The reaction was
˝
irradiated in the oven at 170 W, 13 min, 80 C. The crystalline solid formed was filtered and washed
˝
˝
with EtOAc. White solid (0.27 g, 59.4%;); mp 188.6 C (lit. 225–231 C) [44]; HRMS-ESI (m/z) calc.
for C29H42N [M ´ Br]+ 404.3312, found 404.3310; [α]D23 +7.19 (c 1.0, CHCl3) (lit. +11.0, c 1.07, CHCl3,
˝
1
20 C) [44]; H-NMR (500 MHz, CDCl3) δ ppm 1.20 (d, J = 7.00 Hz, 6H, 2ˆ CH3), 1.21 (s, 3H, CH3),
1.32 (m, 1H, CH), 1.33 (s, 3H, CH3), 1.34 (m, 1H, CHH), 1.59 (m, 1H, CHH), 1.70 (m, 2H, CH2), 1.82 (m,
1H, CHH), 1.99 (m, 1H, CHH), 1.99 (m, 1H, CHH), 2.26 (dt, J = ´12.88, 3.00 Hz, 1H, CHH), 2.80 (sep,
J = 7.00 Hz, 1H, CH), 2.85 (m, 1H, CHH), 2.93 (m, 1H, CHH), 3.32 (s, 3H, CH3), 3.33 (d, J = ´14.11 Hz,
1H, CHH), 3.42 (s, 3H, CH3), 4.08 (d, J = ´14.11 Hz, 1H, CHH), 5.23 (d, J = ´12.44 Hz, 1H, CHH), 5.33
(d, J = ´12.44 Hz, 1H, CHH), 6.86 (d, J = 1.59 Hz, 1H, CHAr), 6.96 (dd, J = 8.23, 1.59 Hz, 1H, CHAr),
7.07 (d, J = 8.23 Hz, 1H, CHAr), 7.37 (m, 1H, CHAr), 7.40 (m, 1H, CHAr), 7.70 (d, J = 7.14 Hz, 1H,
CHAr); 13C-NMR (125 MHz, CDCl3) δ ppm 18.5 (CH2), 19.9 (CH2), 20.1 (CH3), 24.0 (CH3), 24.1 (CH3),
25.6 (CH3), 29.8 (CH2), 33.5 (CH), 37.6 (CH2), 38.1 (C), 39.6 (CH2), 40.6 (C), 48.4 (CH), 51.4 (CH3), 51.6
(CH3), 71.9 (CH2), 75.9 (CH2), 123.7 (CHAr), 124.1 (CHAr), 127.0 (CHAr), 127.7 (CAr), 129.2 (CHAr),
130.8 (CHAr), 133.8 (CHAr), 134.3 (CAr), 146.1 (CAr), 146.8 (CAr).
3.2.6. Synthesis of 2-Hydroxy-N-(+)-dehydroabietyl-N,N-dimethylethanaminium bromide (9a)
The tertiary amine 5 (0.3 g, 0.956 mmol, 1.0 eq) and benzyl bromide (0.359 g, 0.204 mL, 2.87 mmol,
3.0 eq) were measured into a microwave tube and CHCl3 was added. The mixture was irradiated in
˝
the oven at 120 W, 2 h, 110 C. The solvent was evaporated and product washed with Et2O (3 mL ˆ 3).
The product was purified by column chromatography (1:9 MeOH:DCM). White powder (0.20 g,
23
˝
46.5%); mp 213.5 C; HRMS-ESI (m/z) calc. for C24H40NO [M ´ Br]+ 358.3104, found 358.3095; [α]D
1
+16.45 (c 1.0, MeOH); H-NMR (500 MHz, CD3OD) δ ppm 1.71 (d, J = 6.91 Hz, 6H, 2ˆ CH3), 1.79
(s, 3H, CH3), 1.88 (s, 3H, CH3), 1.97 (m, 1H, CHH), 1.99 (dd, J = ´11.85, 2.49 Hz, 1H, CH), 2.25 (m,
1H, CHH), 2.31 (m, 1H, CHH), 2.37 (m, 1H, CHH), 2.40 (m, 1H, CHH), 2.47 (m, 1H, CHH), 2.63 (dt,
J = ´11.93 Hz, 1H, CHH), 2.89 (dt, J = ´12.68 Hz, 1H, CHH), 3.31 (sep, J = 6.91 Hz, 1H, CH), 3.43 (m,
1H, CHH), 3.48 (ddd, J = ´17.37, 7.17, 2.13 Hz, 1H, CHH), 3.83 (s, 6H, 2ˆ CH3), 3.91 (d, J = ´14.01 Hz,
1H, CHH), 4.16 (m, 2H, CH2), 4.27 (d, J = ´14.01 Hz, 1H, CHH), 4.56 (m, 2H, CH2), 7.39 (d, J = 1.94 Hz,
1H, CHAr), 7.48 (dd, J = 8.27, 1.94 Hz, 1H, CHAr), 7.66 (d, J = 8.27 Hz, 1H, CHAr); 13C-NMR (125 MHz,
CD3OD) δ ppm 19.5 (CH2), 19.9 (CH3), 20.6 (CH2), 24.5 (2ˆ CH3), 25.9 (CH3), 30.8 (CH2), 34.8 (CH),
20881

Molecules 2015, 20, 20873–20886
38.9 (C), 39.2 (CH2), 39.7 (CH2), 41.6 (C), 49.6 (CH), 54.3 (CH3), 54.6 (CH3), 57.1 (CH2), 70.3 (CH2), 79.0
(CH2), 124.7 (CHAr), 124.9 (CHAr), 127.7 (CHAr), 135.3 (CAr), 147.2 (CAr), 148.3 (CAr).
3.2.7. General Procedure for Anion Exchange
Anion exchange reactions were performed as described in the literature [32]. LiNTf2 or NH4BF4
solution (1.0 M in H2O, 1.0 eq) was added to CSA (1.0 eq, in DCM) at rt. and stirred for 1 h. Phases
were separated and the organic phase was washed with water, concentrated and dried in vacuum.
(+)-Dehydroabietyl-N,N,N-trimethylmethanaminium tetrafluoroborate (7b). White solid (0.085 g, 93.3%);
23
˝
mp 246.8 C; HRMS-ESI (m/z) calc. for C23H38N [M – BF4]+ 328.2999, found 328.2990; [α]D = +19.93
1
(c 1.0, CHCl3 + 3% MeOH); H-NMR (500 MHz, CDCl3 + 3% CD3OD) δ ppm 1.21 (d, J = 7.02 Hz,
6H, 2ˆ CH3), 1.25 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.40 (dd, J = ´11.63, 2.60 Hz, 1H, CH), 1.43 (m, 1H,
CHH), 1.64 (m, 1H, CHH), 1.76 (m, 2H, CH2), 1.89 (m, 2H, CH2), 2.00 (dt, J = ´13.10, 2.87 Hz, 1H,
CHH), 2.32 (dt, J = ´12.83, 2.60 Hz, 1H, CHH), 2.81 (sep, J = 7.03 Hz, 1H, CH), 2.91 (m, 1H, CHH),
2.96 (ddd, J = ´17.17, 7.06, 1.86 Hz, 1H, CHH), 3.22 (d, J = ´14.33 Hz, 1H, CHH), 3.34 (s, 9H, 3ˆ CH3),
3.67 (d, J = ´14.33 Hz, 1H, CHH), 6.89 (d, J = 2.23 Hz, 1H, CHAr), 6.98 (dd, J = 8.22, 2.23 Hz, 1H,
CHAr), 7.11 (d, J = 8.22 Hz, 1H, CHAr); 13C-NMR (125 MHz, CDCl3, +3% CD3OD) δ ppm 18.4 (CH2),
19.5 (CH3), 19.6 (CH2), 23.9 (CH3), 24.0 (CH3), 25.6 (CH3), 29.6 (CH2), 33.5 (CH), 37.6 (CH2), 38.0 (C),
38.8 (CH2), 40.6 (C), 47.9 (CH), 56.5 (3ˆ CH3), 78.8 (CH2), 123.6 (CHAr), 124.1 (CHAr), 126.9 (CHAr),
134.1 (CAr), 146.1 (CAr), 146.6 (CAr).
(+)-Dehydroabietyl-N,N,N-trimethylmethanaminium bis(trifluoromethanesulfonimide) (7c). White solid
˝
(0.13 g, 97.3%); mp 46.6 C; HRMS-ESI (m/z) calc. for C23H38N [M ´ NTf2]+ 328.2999, found 328.3011;
calc. for C2F6NO4S2 [NTf2] 279.9167, found 279.9169; [α]2D3 = +7.79 (c 1.0, CHCl3); 1H-NMR (500 MHz,
CDCl3) δ ppm 1.21 (d, J = 7.04 Hz, 6H, 2ˆ CH3), 1.26 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.39 (dd,
J = ´12.30, 2.70 Hz, 1H, CH), 1.42 (m, 1H, CHH), 1.60 (m, 1H, CHH), 1.76 (m, 2H, CH2), 1.83 (m, 2H,
CH2), 1.99 (m, 1H, CHH), 2.33 (dt, J = ´13.31, 3.12 Hz, 1H, CHH), 2.82 (sep, J = 7.04 Hz, 1H, CH), 2.87
(m, 1H, CHH), 2.98 (dd, J = ´17.20, 6.70 Hz, 1H, CHH), 3.11 (d, J = ´14.21 Hz, 1H, CHH), 3.29 (s, 9H,
3ˆ CH3), 3.53 (d, J = ´14.21 Hz, 1H, CHH), 6.89 (d, J = 1.88 Hz, 1H, CHAr), 6.99 (dd, J = 8.21, 1.88 Hz,
1H, CHAr), 7.11 (d, J = 8.21 Hz, 1H, CHAr); 13C-NMR (125 MHz, CDCl3) δ ppm 18.4 (CH2), 19.4 (CH3),
19.6 (CH2), 24.0 (CH3), 24.1 (CH3), 25.6 (CH3), 29.5 (CH2), 33.6 (CH), 37.6 (CH2), 38.1 (C), 38.9 (CH2),
40.7 (C), 47.9 (CH), 56.7 (3ˆ CH3), 79.3 (CH2), 119.9 (q, J = 320.54, CF3), 123.7 (CHAr), 124.2 (CHAr),
127.1 (CHAr), 134.0 (CAr), 146.3 (CAr), 146.5 (CAr).
N-Benzyl-1-(+)-dehydroabietyl-N,N-dimethylmethanaminium tetrafluoroborate (8b). White solid (0.19 g,
˝
92.6%); mp 179.9 C; HRMS-ESI (m/z) calc. for C29H42N [M ´ BF4]+ 404.3312, found 404.3311;
[α]2D3 = +2.28 (c 1.0, CHCl3); H-NMR (500 MHz, CDCl3) δ ppm 1.206 (d, J = 6.86 Hz, 6H, 2ˆ CH3),
1
1.209 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.33 (m, 1H, CH), 1.39 (m, 1H, CHH), 1.54 (m, 1H, CHH), 1.70 (m,
2H, CH2), 1.82 (m, 2H, CH2), 1.98 (dt, J = ´12.28 Hz, 1H, CHH), 2.28 (dt, J = ´12.77 Hz, 1H, CHH),
2.81 (sep, J = 6.86 Hz, 1H, CH), 2.83 (m, 1H, CHH), 2.92 (m, 1H, CHH), 3.14 (s, 3H, CH3), 3.17 (d,
J = ´12.75 Hz, 1H, CHH), 3.21 (s, 3H, CH3), 3.71 (d, J = ´12.75 Hz, 1H, CHH), 4.69 (d, J = ´12.75 Hz,
1H, CHH), 4.73 (d, J = ´12.75 Hz, 1H, CHH), 6.86 (d, J = 1.87 Hz, 1H, CHAr), 6.97 (dd, J = 8.17, 1.87
Hz, 1H, CHAr), 7.08 (d, J = 8.17 Hz, 1H, CHAr), 7.39 (m, 1H, CHAr), 7.42 (m, 1H, CHAr), 7.55 (m, 1H,
CHAr); 13C-NMR (75 MHz, CDCl3) δ ppm 18.5 (CH2), 19.7 (CH2), 19.8 (CH3), 24.08 (CH3), 24.11 (CH3),
25.6 (CH3), 29.8 (CH2), 33.6 (CH), 37.6 (CH2), 38.1 (C), 39.2 (CH2), 40.6 (C), 48.4 (CH), 51.3 (CH3), 51.6
(CH3), 73.1 (CH2), 76.2 (CH2), 123.7 (CHAr), 124.1 (CHAr), 127.0 (CHAr), 127.4 (CAr), 129.3 (CHAr),
130.9 (CHAr), 133.6 (CHAr), 134.3 (CAr), 146.2 (CAr), 146.8 (CAr).
N-Benzyl-1-(+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethanesulfonimide) (8c). Colorless
˝
glass (0.27 g, 89.9%); mp 48.8 C; HRMS-ESI (m/z) calc. for C29H42N [M ´ NTf2]+ 404.3312 found
404.3323 calc. for C2F6NO4S2 [NTf2] 279.9167, found 279.9166; [α]2D3 = +1.70 (c 1.0, CHCl3); 1H-NMR
(500 MHz, CDCl3) δ ppm 1.22 (d, J = 6.93 Hz, 6H, 2ˆ CH3), 1.24 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.37
20882

Molecules 2015, 20, 20873–20886
(m, 1H, CH), 1.41 (m, 1H, CHH), 1.53 (m, 1H, CHH), 1.74 (m, 2H, CH2), 1.84 (m, 2H, CH2), 2.00 (dt,
J = ´12.37, 3.29 Hz, 1H, CHH), 2.31 (dt, J = ´12.83, 2.82 Hz, 1H, CHH), 2.82 (m, 1H, CHH), 2.83 (sep,
J = 6.93 Hz, 1H, CH), 2.97 (dd, J = ´17.75, 6.68 Hz, 1H, CHH), 3.10 (d, J = ´14.00 Hz, 1H, CHH),
3.11 (s, 3H, CH3), 3.17 (s, 3H, CH3), 3.59 (d, J = ´14.00 Hz, 1H, CHH), 4.50 (d, J = ´12.54 Hz, 1H,
CHH), 4.56 (d, J = ´12.54 Hz, 1H, CHH), 6.89 (d, J = 2.05 Hz, 1H, CHAr), 6.99 (dd, J = 8.16, 2.05 Hz,
1H, CHAr), 7.11 (d, J = 8.16 Hz, 1H, CHAr), 7.469 (m, 1H, CHAr), 7.472 (m, 1H, CHAr), 7.51 (m, 1H,
CHAr); 13C-NMR (75 MHz, CDCl3) δ ppm 18.4 (CH2), 19.7 (CH2), 19.8 (CH3), 24.06 (CH3), 24.09 (CH3),
25.6 (CH3), 29.6 (CH2), 33.6 (CH), 37.6 (CH2), 38.2 (C), 39.3 (CH2), 40.8 (C), 48.3 (CH), 51.6 (CH3), 51.9
(CH3), 73.6 (CH2), 76.8 (CH2), 119.9 (q, J = 320.36, CF3), 123.7 (CHAr), 124.3 (CHAr), 126.7 (CAr), 127.0
(CHAr), 129.6 (CHAr), 131.4 (CHAr), 133.3 (CHAr), 134.0 (CAr), 146.3 (CAr), 146.6 (CAr).
2-Hydroxy-N-(+)-dehydroabietyl-N,N-dimethylethanaminium tetrafluoroborate (9b). White solid (0.093 g,
˝
91.3%); mp 188.5 C; HRMS-ESI (m/z) calc. for C24H40NO [M ´ BF4]+ 358.3104, found 358.3117;
[α]2D3 = +18.73 (c 1.0, CHCl3); H-NMR (500 MHz, CDCl3) δ ppm 1.20 (d, J = 6.93 Hz, 6H, 2ˆ CH3),
1
1.24 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.38 (m, 1H, CH), 1.42 (m, 1H, CHH), 1.60 (m, 1H, CHH), 1.73 (m,
2H, CH2), 1.85 (m, 2H, CH2), 2.01 (dt, J = ´12.20 Hz, 1H, CHH), 2.29 (dt, J = ´13.03 Hz, 1H, CHH),
2.80 (sep, J = 6.93 Hz, 1H, CH), 2.93 (m, 2H, CH2), 3.18 (d, J = ´14.31 Hz, 1H, CHH), 3.24 (s, 3H, CH3),
3.25 (s, 3H, CH3), 3.60 (br s, 2H, CH2), 3.64 (d, J = ´14.31 Hz, 1H, CHH), 4.07 (br s, 2H, CH2), 6.88
(d, J = 1.75 Hz, 1H, CHAr), 6.97 (dd, J = 8.11, 1.75 Hz, 1H, CHAr), 7.09 (d, J = 8.11 Hz, 1H, CHAr);
13C-NMR (75 MHz, CDCl3) δ ppm 18.5 (CH2), 19.62 (CH2), 19.64 (CH3), 24.08 (CH3), 24.11 (CH3),
25.7 (CH3), 29.7 (CH2), 33.6 (CH), 37.7 (C), 38.2 (CH2), 39.1 (CH2), 40.7 (C), 48.2 (CH), 53.7 (CH3), 53.9
(CH3), 56.8 (CH2), 69.3 (CH2), 78.3 (CH2), 123.7 (CHAr), 124.1 (CHAr), 127.0 (CHAr), 134.3 (CAr), 146.2
(CAr), 146.8 (CAr).
2-Hydroxy-N-(+)-dehydroabietyl-N,N-dimethylethanaminium bis(trifluoromethanesulfonimide) (9c). Viscous
colorless liquid (0.14 g, 97.8%); HRMS-ESI (m/z) Calc. for C24H40NO [M ´ NTf2]+ 358.3104, found
358.3105; calc. for C2F6NO4S2 [NTf2] 279.9167, found 279.9164; [α]2D3 = +6.56 (c 1.0, CHCl3); 1H-NMR
(500 MHz, CDCl3) δ ppm 1.21 (d, J = 6.80 Hz, 6H, 2ˆ CH3), 1.26 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.39
(m, 1H, CH), 1.43 (m, 1H, CHH), 1.59 (m, 1H, CHH), 1.82 (m, 2H, CH2), 2.01 (dt, J = ´12.52, 2.59 Hz,
1H, CHH), 2.33 (dt, J = ´12.93, 2.99 Hz, 1H, CHH), 2.82 (sep, J = 6.80 Hz, 1H, CH), 2.87 (m, 1H, CHH),
2.97 (ddd, J = ´17.65, 6.80, 1.81 Hz, 1H, CHH), 3.18 (d, J = ´14.05 Hz, 1H, CHH), 3.26 (s, 3H, CH3),
3.27 (s, 3H, CH3), 3.61 (br s, 2H, CH2), 3.62 (d, J = ´14.05 Hz, 1H, CHH), 4.09 (br s, 2H, CH2), 6.89
(d, J = 1.87 Hz, 1H, CHAr), 6.99 (dd, J = 8.15, 1.87 Hz, 1H, CHAr), 7.11 (d, J = 8.15 Hz, 1H, CHAr);
13C-NMR (75 MHz, CDCl3) δ ppm 18.4 (CH2), 19.66 (CH2), 19.70 (CH3), 24.05 (CH3), 24.11 (CH3),
25.6 (CH3), 29.5 (CH2), 33.6 (CH), 37.6 (CH2), 38.2 (C), 39.3 (CH2), 40.8 (C), 48.2 (CH), 54.0 (CH3), 54.2
(CH3), 56.8 (CH2), 69.6 (CH2), 78.7 (CH2), 119.9 (q, J = 320.27, CF3), 123.7 (CHAr), 124.3 (CHAr), 127.0
(CHAr), 134.0 (CAr), 146.3 (CAr), 146.6 (CAr).
3.2.8. Synthesis of Guests
N-Acetylation of phenylalanine was performed according to the literature [45]. n-Bu4N salts
were prepared by adding tetrabutylammonium hydroxide (1.0 M in MeOH, 1.0 eq) to the racemic
acid (1.0 eq) in MeOH. After stirring for 1–3 h, the solvent was evaporated and the product was dried
under vacuum.
4. Conclusions
A number of new chiral tertiary and quaternary amine solvating agents (CSAs) based on
(+)-dehydroabietylamine were synthesized and found to resolve racemic Mosher’s acid and its
n-Bu4N salt by 1H-NMR and 19F-NMR spectrocopy. Optimum conditions for the enantiomeric
resolution with the CSAs were determined by titration. The CSAs are also useful in the determination
of ee values of enantiomerically enriched mixtures. Both non-ionic and ionic CSAs resolve racemic
carboxylic acids equally well. Best results were obtained with racemic carboxylic acids containing
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Molecules 2015, 20, 20873–20886
a large electronegative group at the α-position. A modification of the RES-TOCSY NMR pulse
sequence was used, allowing the enhancement of enantiomeric discrimination when the resolution
of multiplets is insufficient. In future work, the development of different 2-based CSAs will
be continued.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/
11/19732/s1.
Acknowledgments: T.L. is grateful for the University of Helsinki and the Finnish Concordia Fund for
the support.
Author Contributions: T.L. conceived and designed the experiments; T.L. performed the experiments, except
the modification of RES-TOCSY pulse sequence and measurement of RES-TOCSY experiments which were done
by S.H.; T.L. analyzed the data, except the data from RES-TOCSY which was analysed by S.H.; T.L., S.H. and
K.W. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open
access article distributed under the terms and conditions of the Creative Commons by
Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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