Microwave-assisted synthesis of mono- And disubstituted 4-hydroxyacetophenone derivatives via Mannich reaction: Synthesis, XRD and HS-analysis

Article abstract of DOI:10.3390/molecules24030590

An efficient microwave-assisted one-step synthetic route toward Mannich bases is developed from 4-hydroxyacetophenone and different secondary amines in quantitative yields, via a regioselective substitution reaction. The reaction takes a short time and is

Full text of DOI:10.3390/molecules24030590

molecules
Article
Microwave-Assisted Synthesis of Mono- and
Disubstituted 4-Hydroxyacetophenone Derivatives
via Mannich Reaction: Synthesis, XRD
and HS-Analysis
Ghadah Aljohani 1,3, Musa A. Said 1,*, Dieter Lentz 2, Norazah Basar 3, Arwa Albar 4
,
Shaya Y. Alraqa 1 and Adeeb Al-Sheikh Ali 1,
*
1
Chemistry Department, College of Science, Taibah University, P.O. Box 30002,
Al-Madinah Al-Munawarah 14177, Saudi Arabia; musa_said04@yahoo.co.uk (G.A.);
shaya97@hotmail.com (S.Y.A.)
2
3
4
Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universität Berlin, Fabeckstr. 34-36,
14195 Berlin, Germany; dlentz@zedat.fu-berlin.de
Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, Johor Bahru 81310, Malaysia;
norazahb@utm.my
Department of Physics, College of Science, Jeddah University, P.O. BOX 80327, Jeddah 21589, Saudi Arabia;
arwa.albar@kaust.edu.sa
*
Correspondence: musa_said04@yahoo.co.uk (M.A.S.); AdeebAli@Dal.Ca (A.A.-S.A.);
Tel.: +966-595-883-585 (M.A.S.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: John Spencer
Received: 23 December 2018; Accepted: 2 February 2019; Published: 7 February 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: An efficient microwave-assisted one-step synthetic route toward Mannich bases is
developed from 4-hydroxyacetophenone and different secondary amines in quantitative yields,
via a regioselective substitution reaction. The reaction takes a short time and is non-catalyzed and
reproducible on a gram scale. The environmentally benign methodology provides a novel alternative,
to the conventional methodologies, for the synthesis of mono- and disubstituted Mannich bases of
4-hydroxyacetophenone. All compounds were well-characterized by FT-IR, 1H NMR, 13C NMR, and
mass spectrometry. The structures of 1-{4-hydroxy-3-[(morpholin-4-yl)methyl]phenyl}ethan-1-one
(
2a) and 1-{4-hydroxy-3-[(pyrrolidin-1-yl)methyl]phenyl}ethan-1-one (3a) were determined by
single crystal X-ray crystallography. Compound 2a and 3a crystallize in monoclinic, P21/n, and
orthorhombic, Pbca, respectively. The most characteristic features of the molecular structure
of 2a is that the morpholine fragment adopts a chair conformation with strong intramolecular
hydrogen bonding. Compound 3a exhibits intermolecular hydrogen bonding, too. Furthermore, the
computed Hirshfeld surface analysis confirms H-bonds and
packing analyses.
π–π stack interactions obtained by XRD
Keywords: Mannich bases; 4-hydroxyacetophenone; microwave irradiation; regioselectivity;
X-ray; HSA
1. Introduction
Mannich bases can be easily transformed into numerous compounds due to their high reactivity.
Several Mannich bases are of particular interest due to their importance as precursors of valuable
pharmaceuticals products and their use as synthetic building blocks [
attracted more and more attention from chemists due to their specific biological activities, such as
antiviral [ ], acetylcholinesterase inhibitory [ ], antioxidant [ ], and antiproliferative [10,11]
1,2]. Mannich bases have
3,4
5–
7
8,
9
Molecules 2019, 24, 590; doi:10.3390/molecules24030590
www.mdpi.com/journal/molecules

Molecules 2019, 24, 590
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activity. Mannich bases are also key precursors to accessing amino alcohols, peptides, lactams, and
optically active amino acids [12 13]. Consequently, many researchers were attracted to investigating
green protocols for the Mannich reaction during the last period [ ]. The Mannich reaction is an
essential reaction for the direct formation of new C–C and C–N bonds [10 14]. The products of
Mannich reaction of 4-hydroxyacetophenone as substrate vary depending on the reaction conditions.
Using classical conditions, such as low pH, the acetyl group undergoes reaction, producing -amino
,
2
,
β
alkyl ketone. In this case, the substrate is converted into the corresponding Mannich base through
an aminomethylation process. On the other hand, under an alkaline medium, the Mannich
reaction is selectively undergoes electrophilic aromatic substitution in the ortho position to the
hydroxyl group (Scheme 1) [1]. The conventional multicomponent Mannich reactions are found
to have drawbacks such as a long reaction time, harsh reaction conditions, and toxic vapor and
byproducts [15]. As a consequence, different reaction conditions have been widely described for
Mannich reaction in the presence of a variety of catalysts [16
for the synthetic methodologies of cleaner Mannich reactions seeking green chemistry principles
includes the use of protocols in water [14], biodegradable and reusable catalysts [18 19], ionic
liquids [12 19 20], and solvent-free and/or catalyst-free media reaction conditions under microwave
(MW) and ultrasound irradiation [21 27]. Microwave irradiation has been used to synthesize a
,17]. Additionally, a continuous search
,
,
,
–
lot of organic compounds. In fact, the use of microwave irradiation offers a higher reaction rate
and better product in chemical synthesis [28], however, few studies have been done utilizing
microwave irradiation in the synthesis of Mannich bases [21,25]. These studies were done under
acidic conditions using substituted acetophenones whereas the regioselectivity of the reaction was
studied on the 2-hydroxy-chalcone backbone [29]. Hence, we describe, herein, the first efficient,
gram-scale, non-catalyzed and microwave-assisted synthetic approach of mono- and disubstituted
Mannich bases of para-hydroxyacetophenone with various secondary amines.
R
R
H
H
N
H
O
O
+
CH3
Alkaline
medium
Acidic
medium
-H2O
-H2O
OH
NR2
O
CH3
CH3
O
NR2
OH
OH
Scheme 1. Possible products of Mannich-type reaction using classical conditions.

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2. Results and Discussion
2.1. General Synthesis
Firstly, the reactions were run in small scales (2 mmol) of 4-hydroxyacetophenone with different
ratios of morpholine as a model reaction, to find out the optimal conditions in terms of solvent, time,
reactant ratio, and temperature. Four different solvents, namely, water, ethanol, ethylene glycol, and
1,4-dioxane, at fixed power (300 W) were used for optimization. The temperature ranged between
100 and 120 ◦C, higher than the boiling points of the chosen solvent as the experiments were done
in a sealed vessel. When water was used as a solvent, the corresponding product was not observed
based on the TLC monitoring and the reaction led to the formation of an insoluble product in classical
organic solvents. On the other hand, using polar protic solvents (ethanol or ethylene glycol) gave the
corresponding monosubstituted Mannich product 2a at a very low yield. Interestingly, an excellent
yield was obtained when 1,4-dioxane was used as a solvent. The TLC showed complete consumption
of 4-hydroxyacetophenone after 30 min by disappearance of the starting material spot, and two new
main spots were observed using 1.5 equivalents of formaldehyde and morpholine as a model for
optimization (Scheme 2).
Scheme 2. Synthetic approach for synthesis of mono- and disubstituted Mannich bases of
4-hydroxyacetophenone (1).
The resulting mixture was purified via column chromatography. The first eluted compound
1
was characterized using spectroscopic analysis. The H NMR analysis of compound 2a showed
the disappearance of one of the aromatic protons, revealing regioselective monosubstitution on the
aromatic ring. 1H NMR exhibits a broad singlet at 3.78 ppm integrated to six protons related to
the benzylic protons which overlapped with four protons in (OCH2) related to morpholine moiety.
A multiplet peak, between 2.54 and 2.59 ppm, was assigned to the protons in (NCH2) in the morpholine
moiety and the methyl group. The 13C spectrum verified the formation of Mannich base 2a due to the
presence of three peaks of CH2 group related to (NCH2) at 52.74 ppm, benzylic (CH2) at 61.24 ppm, and
(OCH2) of morpholine moiety at 66.52 ppm. Moreover, the presence of only three resonances for the
aromatic CH at 116.07, 129.75, and 130.56 ppm confirmed the formation of monosubstituted Mannich
base. On the other hand, the 1H NMR spectral analysis of the second compound showed the formation
of disubstituted Mannich product 2b. As a result, two protons disappeared in the aromatic region and
the integration of two morpholine moieties to the other protons confirmed the formation of 2b. The
13C exhibit a single resonance of two equivalent aromatic CH at 130.24m confirming the occurrence of

Molecules 2019, 24, 590
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disubstitution reaction at the benzene ring. Meanwhile, the mass spectral data are in agreement with
the molecular formula of 2a and 2b. Due to the successful results, a gram-scale (16 mmol) experiment
was run for morpholine to determine the overall yield of both 2a and 2b.
Comparing the conventional method to the microwave radiation, it was found that the reaction
time decreased considerably from 22 h, using thermal heating, to 30 min in order to furnish mono-
and/or disubstituted Mannich bases 2a and 2b in quantitative yield [30]. Using the same optimized
conditions (power, solvent, temperature, and reactant ratio) for the formation of mono- or disubstituted
Mannich bases, compounds 3a–5a and 3b–4b were synthesized after 15 min in overall yields of 64% to
77% (Table 1, Supplementary Materials). The time was monitored for each amine based on TLC results.
◦
Table 1. Mannich bases derivatives 2a
/b
–
5a under microwave irradiation (300 W, 120 C using dioxane
as solvent).
Microwave Yield %
Reactant Ratio 1:1.5:1.5
Microwave Yield %
Reactant Ratio 1:2:2
Time
(min)
Compound
2
a
b
a
b
a
b
quantitative
yield
80
20
-
30
15
3
49
15
-
86
4
5
58
77
14
-
-
94
-
15
15
-
quantitative yield
In order to improve the product ratios, different reactant ratios were used in 1,4-dioxane at
◦
120 C (which was found to be the optimal reaction temperature) and 300 W. It was found that
the monosubstituted Mannich base 2a was obtained as a major product (80% after column) when
1.5 equivalent of the secondary amine and formaldehyde were used. However, the disubstituted
Mannich base 2b was formed quantitively as the only product when 2 equivalents of the secondary
amine and formaldehyde were used (Table 1, Supplementary Materials). The product yield was greatly
increased in quantitative yield, compared to the 60% that had been obtained before [30]. For the novel
compounds 3b and 4b, the yield under the same conditions was 86% and 94%, respectively. It should
be noted that the diethylamine used did not undergo disubstituted Mannich reaction under the same
conditions and only monosubstituted 5a was obtained but in nearly quantitative yield. This may be
due to the free rotation of diethyl groups that might sterically prevent the occurrence of disubstituted
reaction in comparison to the rigid cyclic secondary amines.
2.2. Crystal Structure Description
The structures of the monosubstituted compounds 2a and 3a were proposed on the basis of
1H and 13C NMR, and IR spectroscopic analyses. In order to gain information on their structural
characteristics, X-ray crystallographic analyses were carried out for both 2a and 3a [31–37]. The
molecular structures and some atom-numbering schemes are depicted in Figures 1 and 2 for 2a
and 3a respectively. Crystallographic data and structure refinement parameters for 2a and 3a are
listed in Table 2. Selected bond lengths, angles, and torsion angles are listed in Tables 3 and 4.

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The most characteristic feature of the molecular structure of 2a is that the morpholine fragment
adopts a chair conformation with strong intramolecular hydrogen bonding. One carbon atom of the
chair conformation deviates from the main plane by only 0.015 Å, indicating an almost perfect chair
conformation for the morpholine fragment. The acetyl substituent is located almost in the plane of
the aromatic with a torsion C5–C4–C12–O3 of 1.6◦. However, the morpholino substituent is turned
out of the ring plane resulting in C1–C2–C7–N1 of
hydrogen bond of H1 to the nitrogen atom N1 (O1 . . . N1 2.634 (2) with a normalized [38
0.938 Å, resulting in a N . . . H distance of 1.801 and an O1–H1–N1 angle of 146.5 ). No intermolecular
−
45.7◦. There exists only one intramolecular
,39] O–H of
◦
hydrogen bonds can be detected for 2a.
Figure 1. An ORTEP [34
,35] drawing of 2a with an atom-numbering scheme. The thermal ellipsoids
are drawn at the 50% probability level.
Figure 2. ORTEP [34,35] and numbering scheme of 3a, thermal ellipsoids are drawn at the 50%
probability level.

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Table 2. Crystallographic data and structure refinement parameters for 2a and 3a.
Compound
2a
3a
Chemical formula
Mr
Crystal system, space group
Temperature (K)
C13H17NO3
235.27
Monoclinic, P21/n
C13H17NO2
219.27
Orthorhombic, Pbca
100 (2)
100 (2)
10.8735 (8), 10.9988 (9), 19.0645
7.297 (6), 11.375 (8), 14.571 (12)
a, b, c (Å)
(15)
◦
β ( )
93.79 (3)
1206.9 (16)
4
Mo Kα
0.09
V (Å3)
2280.0 (3)
8
Mo Kα
Z
Radiation type
−1
0.09
µ (mm
)
Crystal size (mm)
Data collection
Diffractometer
0.50 × 0.40 × 0.35
0.44 × 0.18 × 0.17
Bruker D8 Venture Photon
Multi-scan SADABS2016/2
(Bruker AXS)
Bruker D8 Venture Photon
Multi-scan SADABS2016/2
(Bruker AXS)
Absorption correction
Tmin, Tmax
0.879, 0.928
0.879, 0.928
No. Of measured, independent
28902, 3719, 3447
86662, 3500, 3186
and observed [I > 2
σ
(I)] reflections
Rint
0.025
0.717
0.034
0.650
−1
(sin θ/λ)max (Å
)
Refinement
R[F2 > 4σ(F2)], wR(F2), S
No. Of reflection
0.034, 0.095, 1.03
0.037, 0105, 1.054
3719
157
3500
147
No. Of parameters
H-atom treatment
H-atom parameters constrained
H-atom parameters constrained
∆ρmax, ∆ρmin (e·−3
)
0.41, −0.20
0.39 and −0.308
Computer programs: Bruker APEX3, Bruker SAINT [31], SHELXT 2014/5, [32,33].
◦
Table 3. Geometric parameters (Å, ) for compound 2a.
O1–C1
O1–H1
O2–C10
O2–C9
O3–C12
1.3539 (13)
0.8400
C11–C10
N1–C11
N1–C7
C1–C6
C1–C2
1.5160 (14)
1.4675 (15)
1.4759 (13)
1.3959 (14)
1.4048 (13)
1.5031 (15)
120.84 (8)
120.05 (9)
119.09 (8)
119.33 (8)
121.58 (8)
119.27 (7)
109.34 (7)
111.10 (7)
1.4209 (12)
1.4241 (15)
1.2208 (13)
1.4633 (12)
110.06 (7)
109.45 (7)
110.34 (7)
111.90 (7)
119.13 (7)
120.61 (7)
109.95 (7)
111.38 (6)
N1–C8
C12–C13
C10–O2–C9
C8–N1–C11
C8–N1–C7
C11–N1–C7
O1–C1–C6
O1–C1–C2
N1–C8–C9
N1–C7–C2
O3–C12–C4
O3–C12–C13
C4–C12–C13
C5–C6–C1
C6–C5–C4
C3–C2–C1
N1–C11–C10
O2–C9–C8
◦
Table 4. Geometric parameters (Å, ) for compound 3a.
O1–C1
O1–H1
1.3381 (9)
0.8400
C6–H6
C5–H5
0.9500
0.9500
N1–C7
N1–C11
N1–C8
1.4777 (10)
1.4781 (10)
1.4817 (10)
112.43 (6)
113.93 (6)
103.46 (6)
118.31 (7)
177.70 (7)
−169.16 (6)
73.55 (8)
C8–C9
O2–C12
C3–C2
1.5386 (12)
1.2226 (12)
1.3924 (10)
102.67 (6)
120.57 (8)
120.09 (8)
112.27 (6)
−1.46 (11)
162.59 (7)
−46.12 (7)
173.05 (9)
−6.28 (13)
C7–N1–C11
C7–N1–C8
C11–N1–C8
O1–C1–C2
C3–C2–C1–O1
C11–N1–C7–C2
C8–N1–C7–C2
C3–C2–C7–N1
C1–C2–C7–N1
N1–C11–C10
O2–C12–C4
O2–C12–C13
N1–C7–C2
C7–C2–C1–O1
C7–N1–C8–C9
C8–N1–C11–C10
C3–C4–C12–O2
C5–C4–C12–O2
80.26 (9)
−100.58 (8)

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By contrast, compound 3a exhibits intermolecular hydrogen bonding. Another interesting
structural aspect in 3a is related to the molecular packing stability. It is documented that intermolecular
hydrogen bonding plays a significant role in the assembling of molecules into a well-ordered crystal
packing structure. This is because intermolecular hydrogen bonding helps to form a network
(Figure 3) [40,41]. It is worth mentioning that heterocycles containing a pyrrolidine moiety are
frequently found in many bioactive compounds [42]. The pyrrolidine ring in 3a has a slightly twisted
envelop conformation with a deviation of the C11 atom from the main plane of C8, C9 and C10 by
0.234 Å (Figure 2), indicating that the pyrrolidine ring has some ring strain [42]. The N1 atom is
◦
found above this main plane by 0.444 Å (Figure 2). On the other side, the angles around N1 of 114.80 ,
103.19◦, and 112.90◦ indicating a distorted tetrahedral geometry around the central atom N1.
Figure 3. Intermolecular hydrogen bond network of 3a (Diamond [36]). View along the a-axis.
2.3. Hirshfeld Analysis
The Hirshfeld surface analysis (HSA), mapped over dnorm and shape index plots, are illustrated
in Figure 4a,b for compounds 2a and 3a, respectively. Table 5 summarizes the relative contributions
of different atomic contacts to the HSs. The dnorm surface of 2a compound (ranging from –0.259 Å to
1.364 Å) shows two deep red spots related to H . . . O (2.267 Å) and H . . . H (2.767 Å), indicating strong
short contacts. The H . . . H interaction is found to be dominating for the 2a compound, accounting
for 55.8% of HS area, whereas H . . . O/O . . . H contact accounted for 12.6% and 14.8% of HS area.
The white spots on HS are mainly due to H . . . H contact. Shape index plot for 2a compound shows
adjacent red and blue triangle (red-dash circle) indicating the presence of π–π stacking. The dnorm
surface of 3a (ranging from –0.758 Å to 1.239 Å) shows two deep red spots related to O–H . . . N/N
. . . H–O strong short contacts (due to distances of 1.657 Å/2.132 Å), which accounted for only 1.6%
of HS area. Most of the white spots on the shape index surface are due to H . . . H contacts, which
contribute with 60.7% to HS area. The zero contribution of C . . . C interaction to HS for 3a compound
indicates the absence of π–π stacking. This is in agreement with that shown by XRD. The π–π stacking
distance, in 3a, is measured as the distance between the aromatic centroids. The X-ray structure of
3a shows a separation of 6.183 Å between the aromatic centroids. Shape index plots for 2a and 3a
show red concave and blue convex areas, which characterize the packing mode with nearby molecules
(Figure 4).

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Figure 4. Hirshfeld surfaces mapped with dnorm (left) and sharp index (right) for (
a) 2a and
(b) 3a compounds.
Table 5. Relative contributions of internal and external atomic contacts to the Hirshfeld surface for 2a
and 3a compounds.
Contact
Percentage in 2a
Percentage in 3a
H . . . H
H . . . O
O . . . H
55.8%
12.6%
14.8%
0.9%
0.0%
6.7%
8.8%
0.0%
60.7%
7.9%
9.4%
0.0%
1.6%
10.3%
8.3%
0.1%
C . . . C
N . . . H/H . . . N
H . . . C
C . . . H
O . . . C/C . . . O
Figure 5 shows the 2D fingerprint plots for the overall compounds, as well as for specific contacts.
The H . . . H interaction is indeed the dominating one for 2a and 3a compounds. The comparable wings
of 2a and 3a fingerprint plots, which are due to C . . . H/H . . . C contacts, indicate similarity between
the two compounds. C . . . H/H . . . C contact acts as a secondary interaction with no significant
peaks. For 2a, the red-dash circle indicates the 0.9% contribution of π–π stacking. While O–H . . .
N/N . . . H–O contact plays a critical role in 3a compound, it is completely absent in the 2a compound.
The two small side peaks obtained for 2a compound are due to O . . . H/H . . . O contact with tips
at di + de =2.25 Å. However, the shortest contact is obtained by the middle peaks (with tips at di +
de =2.2 Å), which are due to H . . . H contact, indicating strong H . . . H interaction. Interestingly,
two distinct sharp spikes are obtained for 3a, which are due to considerably short O–H . . . N/N . . .
H–O contacts, indicating strong molecular interaction. The corresponding di and de combination are
0.65 Å and 1.05 Å with tips at di + de =1.7 Å. Consequently, HAS findings are in agreement with XRD
packing analyses.

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Figure 5. 2D fingerprint plots for (a) 2a and (b) 3a: full (left) and then resolved into H . . . H, O . . .
H/H . . . O, and O–H . . . N/N . . . H–O contacts.
3. Materials and Methods
All solvents and reagents were purchased from Sigma-Aldrich (Deisenhofen, Germany) and used
without further purification. 4-Hydroxyacetophenone was purchased from Acros (Thermo Fisher
Scientific Geel–Belgium). The monitoring of reaction was done by the utilization of pre-coated silica gel
plates (60 F254) and thin layer chromatography (TLC). The normal phase silica gel (Merck, 70–230 mesh)
was used to perform column chromatography purification, while the Merck silica gel (230–400 mesh)
was utilized to perform the vacuum liquid chromatography.
A controllable single-mode microwave reactor, CEM Discover Microwave™ designed for synthetic
utilization, was used. The reactor consists of power and pressure controls in addition to a magnetic
stirrer. The temperature is controlled by an IR sensor. Melting points were measured using Sanyo
MPD350 apparatus (Gallenkamp, Osaka, Japan) with digital display, and they were not corrected.
A Perkin Elmer ATR spectrophotometer (Waltham, MA, USA) was used to record the infrared (IR)
spectra. A Bruker Advance 400 MHz spectrometer (Fällanden, Switzerland) was used to record 1H
NMR and 13C NMR spectra. NMR samples were separately measured in DMSO, CDCl3, and MeOD
at room temperature. Mass spectra were recorded on Finnigan MAT95XL (ThermoFisher Scientific,
Bremen, Germany) using (EI), at 70 eV.
3.1. General Synthesis of Mannich Bases (2–5)
To a solution of 4-hydroxy-acetophenone (
32 mmol) in 1,4-dioxane (15 mL), the corresponding secondary amine (morpholine (
piperidine ( ) or diethylamine ( )) was added using the same ratio of formaldehyde. This mixture was
1) (16 mmol, 2.18 g) and formaldehyde (24 mmol or
2
), pyrrolidine ( ),
3
4
5
placed in the MW sealed vessel with stirring. The reaction mixture was irradiated for 15–30 min at
120 ◦C (power 300 W). TLC was used to monitor the progress of the reaction. After consumption of
the starting materials, the vessel was removed and cooled down to room temperature. The reaction
mixture was concentrated under reduced pressure and purified using column chromatography.
3.1.1. 1-{4-Hydroxy-3-[(morpholin-4-yl)methyl]phenyl}ethan-1-one (2a)
The purification of the crude product, which has been synthesized in the respective ratio of
1:1.5:1.5 of compound 1, formaldehyde, and morpholine, was done using column chromatography
with hexanes/EtOAc (8:2) as eluent to yield 2a as colorless crystals (3.02 g; 80%), mp 69–70 ◦C. IR
1
spectrum (
ν
max/cm−1): 1110 (C–N), 1246 (C–O), 1581 (C=C), 1666 (C=O), 2978 (CH3, sp3). H NMR
(ppm/
δ
, 400 MHz, CDCl3): 2.59–2.54 (m, 7H), 3.77 (br s, 6H), 6.85 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.82

Molecules 2019, 24, 590
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(d, J = 8.5 Hz, 1H), 11.32 (br s, 1H, –OH). 13C NMR (ppm/
δ
, 100 MHz, CDCl3)
δ
26.24, 52.74, 61.24,
66.52, 116.07, 120.23, 129.20, 129.75, 130.56, 162.43, 196.77. EIMS, m/z (% rel. intensity): 235(100) [M+,
C13H17NO3], 204 (16), 188 (38), 176 (12), 162 (20), 149 (76), 133 (18), 106 (10), 100 (10), 86 (45), 77 (21),
57 (22).
3.1.2. 1-{4-Hydroxy-3,5-bis[(morpholin-4-yl) methyl]phenyl}ethan-1-one (2b)
The purification of the crude product which has been synthesized in the respective ratio of
1:2:2 of compound
1, formaldehyde, and morpholine was done using column chromatography with
EtOAc/MeOH (9:1) as eluent to yield 2b as colorless needles (5.32 g; quantitative yield) mp 88–90 ◦C
after removing the solvent. IR spectrum (
ν
max/cm−1): 1113 (C–N), 1304 (C–O), 1597(C=C), 1669(C=O),
1
2958 (CH3, sp3). H NMR (ppm/
δ, 400 MHz, MeOD): 2.59–2.55 (m, 11H), 3.74–3.72 (m, 12H), 7.83 (s,
2H), 7.92 (s, 1H). 13C NMR (ppm/
δ, 100 MHz, MeOD): 24.90, 52.78, 58.18, 66.32, 121.97, 128.25, 130.24,
161.44, 197.94. EIMS, m/z (% rel. intensity): 334(14) [M+, C18H26N2O4], 276 (6), 247 (100), 217 (12), 189
(14), 162 (8), 133 (34), 119 (11), 86 (24), 56 (14).
3.1.3. 1-{4-Hydroxy-3-[(pyrrolidin-1-yl) methyl]phenyl}ethan-1-one (3a)
A ratio of 1:1.5:1.5 of compound 1, formaldehyde, and pyrrolidine, respectively, were used to
synthesize 3a. Eluting system of hexanes/EtOAc (6:4), was used to purify the crude product to yield
pale-yellow crystals, (1.72 g; 49%), mp 92–95 ◦C. IR spectrum (
ν
max/cm−1): 1191 (C–N), 1284 (C–O),
1
1595 (C=C), 1661 (C=O), 2965 (CH3, sp3). H NMR (ppm/
δ
, 400 MHz, MeOD): 1.99–1.94 (m, 4H), 2.51
(s, 3H), 2.92 (t, J = 7.0 Hz, 4H), 4.03 (s, 2H), 6.72 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.83 (dd,
J = 8.7 and 2.4 Hz, 1H). 13C NMR (ppm/
δ, 100 MHz, MeOD): 23.02, 24.67, 52.88, 57.13, 116.53, 121.21,
126.14, 130.22, 130.73, 167.15, 197.75. EIMS, m/z (% rel. intensity): 219 (13) [M+, C13H17NO2], 149 (5),
133 (3), 106 (2), 91 (2), 84 (9), 77 (4), 70(100), 51 (2).
3.1.4. 1-{4-Hydroxy-3,5-bis[(pyrrolidin-1-yl) methyl] phenyl} ethan-1-one (3b)
The purification of the crude product which has been synthesized in the respective ratio of
1:2:2 of compound 1, formaldehyde and pyrrolidine was done using column chromatography with
EtOAc/MeOH (9:1) as eluent to yield 3b as dark red oily liquid (4.2 g; 86%). IR spectrum (
ν
max/cm−1):
δ, 400 MHz,
1302 (C–O), 1356 (C–N), 1597 (C=C), 1665 (C=O), 2963 (CH3, sp3). 1H NMR (ppm/
DMSO-d6): 1.76 (br s, 8H), 2.47 (s, 3H), 2.57 (br s, 8H), 3.77 (s, 4H), 7.69 (s, 2H). 13C NMR (100 MHz,
DMSO) ppm:
δ 23.66, 26.67, 53.54, 55.59, 123.68, 127.57, 128.98, 162.09, 196.56. EIMS, m/z (% rel.
intensity): 302 (14) [M+, C18H26N2O2], 231 (100), 216 (9), 188 (12), 159 (14), 147 (7), 133 (20), 119 (11),
84 (11), 70 (43), 55 (4).
3.1.5. 1-{4-Hydroxy-3-[(piperidin-1-yl) methyl] phenyl} ethan-1-one (4a)
The crude product of 4a was obtained from the reaction of the respective ratio 1:1.5:1.5
of compound
1
, formaldehyde, and piperidine. The obtained product was purified by ◦using
hexanes/EtOAc (6:4) as an eluent to yield 4a as colorless crystals (2.15 g, 58%), mp 82–83 C. IR
1
spectrum (
(ppm/
(s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 11.41 (br s, 1H). 13C NMR (ppm/
ν
max/cm−1): 1256 (C–N), 1287 (C–O), 1594 (C=C), 1661 (C=O), 2946 (CH3, sp3). H NMR
δ
, 400 MHz, CDCl3): 1.67–1.52 (m, 6H), 2.53 (br s, 7H), 3.75 (s, 2H), 6.84 (d, J = 8.4 Hz, 1H), 7.68
, 100 MHz, CDCl3): 23.71, 25.6, 26.22,
δ
53.73, 61.51, 115.93, 121.06, 128.73, 129.35, 130.24, 163.32, 196.86. EIMS, m/z (% rel. intensity): 233 (10)
[M+, C14H19NO2], 149 (4), 133 (2), 106 (1), 98 (5), 84 (100), 77 (3), 56 (2).
3.1.6. 1-{4-Hydroxy-3,5-bis[(piperidin-1-yl) methyl] phenyl} ethan-1-one (4b)
The crude product resulted from the reaction of the respective ratio 1:2:2 of compound
formaldehyde, and piperidine was purified using hexanes/EtOAc (3:7) as eluent to yield 4b as
pale-yellow crystals mp 93–96 ◦C (5 g, 94%). IR spectrum ( max/cm−1): 1300 (C–O), 1349 (C–N), 1594
1,
ν

Molecules 2019, 24, 590
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1
(C=C), 1669 (C=O), 2925 (CH3, sp3). H NMR (ppm/
δ
, 400 MHz, DMSO): 1.53–1.42(m, 12H), 2.46–2.43
(m, 11H), 3.6 (s, 4H), 5.51 (br s, 1H), 7.68 (s, 2H). 13C NMR (ppm/
δ, 100 MHz, DMSO): 24. 13, 25.90,
26.65, 53.84, 58.65, 123.01, 127.92, 129.27, 161.97, 196.59. EIMS, m/z (% rel. intensity): 330 (14) [M+,
C20H30N2O2], 245 (100), 228 (4), 202 (10), 147 (4), 133 (13), 119 (4), 98 (4), 84 (24), 55 (3).
3.1.7. 1-{3-[(Diethylamino) methyl]-4-hydroxyphenyl} ethan-1-one (5a)
The crude product of 5a was obtained from the reaction of the respective ratio 1:2:2. of compound
1
, formaldehyde, and diethylamine. The product was purified by column chromatography using
hexanes/EtOAc (6:4) to yield 5a as a yellow oily liquid (3.53 g, quantitative yield). IR spectrum
1
(ν
max/cm−1): 1280 (C–N), 1357 (C–O), 1589(C=C), 1667(C=O), 2972 (CH3, sp3). H NMR (ppm/
δ,
400 MHz, CDCl3): 1.07 (t, J = 7.0 Hz, 6H), 2.46 (s, 3H), 2.59 (q, J = 7.0 Hz, 4H), 3.77 (s, 2H), 6.74 (d,
J = 8.4 Hz, 1H), 7.60 (s,1H), 7.73 (d, J = 8.4 Hz, 1H), 11.47 (br s, 1H). 13C NMR (ppm/
δ, 100 MHz,
CDCl3): 10.99, 26.08, 46.22, 56.61, 115.87, 121.68, 128.51, 128.95, 130.06, 163.77, 196.74. EIMS, m/z (% rel.
intensity): 221 (5) [M+, C13H19NO2], 206 (6), 149 (8), 132 (2), 106 (1), 77 (2), 58 (100).
3.2. X-ray Structure Determination
Crystal data, data collection, and structure refinement details are summarized in Table 2.
Crystallographic data for 2a and 3a were collected on Bruker D8 Venture diffractometer; cell
refinement—Bruker SAINT, data reduction—Bruker SAINT [31]; program(s) used to solve and refine
structures—SHELXT 2014/5 and SHELXL2014/7 [32,33]; molecular graphics—ORTEP [34,35]; and
software used to prepare material for publication—WinGX [37]. All non-hydrogen atoms were refined
anisotropically. The hydrogen atoms at the oxygen atoms were located from Fourier map, at carbon
and nitrogen atoms placed in calculated positions and refined as rigid atoms. All calculations were
performed on PC using WinGX program. Data collection: images were indexed, integrated, and scaled
using the APEX3 data reduction package [31]. All figures were made using the program ORTEP and
Diamond program [32–36].
3.3. Computations
Hirshfeld surface analysis (HSA) and 2D fingerprint plots calculations were carried via dnorm
surface property with rescale using CRYSTAL EXPLORER 3.0 program [43]. Normalized distances,
dnorm, based on di and de, are calculated for each point on the surface. HSA mapped over dnorm
generates a surface with red, blue, and white areas—red spots correspond to closer contacts (the sum
of van der Waals radii and dnorm is negative), blue spots correspond to longer contacts (the sum of
van der Waals radii and dnorm is positive) and white spots correspond to dnorm values around van der
Waals separations. The 2D fingerprint plots provide information about the frequency of each di and de
combination across all points on HS. The green, blue, and gray colors correspond to interactions with
large contribution, with moderate contribution, and without contribution to HS area, respectively. The
identical features along 2D plots diagonal correspond to mirrored internal–external atomic contacts
(e.g., O . . . H and H . . . O contacts).
4. Conclusions
It can be concluded that this novel alternative methodology offers significantly less synthesis time
with competitive product yield of Mannich bases in the absence of any catalyst. The X-ray crystal
structure of 2a shows an intramolecular hydrogen bonding and displays a chair conformation for the
morpholine fragment and, unlike 3a, exhibits intermolecular hydrogen bonding. The HAS shows that
the intermolecular interactions are dominated by H . . . H interaction for both compounds, though for
2a it is stronger. Moreover, 2D fingerprint plots confirm that π–π stacking is only present for 2a.

Molecules 2019, 24, 590
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Supplementary Materials: Supplementary Materials are available online.
Author Contributions: Conceptualization, A.A.A., S.Y.A. and N.B., Supervision; G.A.; Methodology, All authors,
mainly, G.A.; Writing-Review & Editing; D.L. and M.A.S; X-ray work, A.A.; HSA work.
Funding: This research received no external funding.
Acknowledgments: Ghadah Aljohani and Norazah Basar gratefully acknowledge support by Taibah University
and Universiti Teknologi. Musa A. Said thanks the Alexander von Humboldt foundation for the valuable and
continuous support.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Atomic coordinates, bond lengths, bond angles and thermal parameters have been deposited
at the Cambridge Crystallographic Data Centre (CCDC). These data can be obtained free of charge via www.ccdc.
cam.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336
033; or deposit@ ccdc.cam.ac.uk). Any requests to the CCDC for data should quote the full literature citation and
CCDC reference numbers for 2a and 3a 1832359, 1832328 respectively.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).