Synthesis and evaluation of D-gluconamides as green mineral scales

Article abstract of DOI:10.1016/j.carres.2012.01.027

A series of 13 d-gluconamides were synthesized in moderate to good yields and evaluated as green scale inhibitors. The crystal structures of two compounds were determined by X-ray crystallography. The compounds 6c and 6d showed a reasonable inhibition of BaSO₄ precipitation from aqueous solution (47% and 51%, respectively) that indicated the potential for these derivatives of δ-gluconolactone.

Full text of DOI:10.1016/j.carres.2012.01.027

Carbohydrate Research 353 (2012) 6–12
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis and evaluation of D-gluconamides as green mineral scales
Marcelo I.P. Reis a, Aline D. Gonçalves b, Fernando de C. da Silva a, Alessandro K. Jordão a, Ricardo J. Alves d,
Saulo Fernandes de Andrade d, Jackson A.L.C. Resende c, Anderson A. Rocha b, Vitor F. Ferreira a,
⇑
a Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Outeiro de S. João Batista, s/n°, Centro, 24020-150 Niterói, RJ, Brazil
b Universidade Federal Fluminense, Instituto de Química, Departamento de Química Analítica, Outeiro de S. João Batista, s/n°, Centro, 24020-150 Niterói, RJ, Brazil
c Universidade Federal Fluminense, Departamento de Química Inorgânica, Outeiro de São João Batista, s/n°, Centro, 24020-141 Niterói, RJ, Brazil
d Universidade Federal de Minas Gerais, Faculdade de Farmácia, Departamento de Produtos Farmacêuticos, 31270-901 Belo Horizonte, MG, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 13 D-gluconamides were synthesized in moderate to good yields and evaluated as green scale
Received 16 November 2011
Received in revised form 25 January 2012
Accepted 31 January 2012
inhibitors. The crystal structures of two compounds were determined by X-ray crystallography. The
compounds 6c and 6d showed a reasonable inhibition of BaSO4 precipitation from aqueous solution
(47% and 51%, respectively) that indicated the potential for these derivatives of d-gluconolactone.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 10 February 2012
Keywords:
Carbohydrate
D-Gluconamides
Scale inhibitors
Green scale
1. Introduction
anti-fouling. Inhibitors prevent the deposition of inorganic salts
on the pipe walls along the production system. They disrupt the
Water is an abundant resource that has different impurities or
additives depending on the natural source: seas, rivers, lakes,
groundwater aquifers, sewage, and so forth. Its use as a refrigerant,
the generation of vapor in reactions, and distillations, among other
applications, are problematic because of the presence of ions.
Depending on the thermodynamic conditions, water can become
a supersaturated solution of calcium carbonate, calcium phos-
phate, calcium oxalate, barium sulfate, strontium and magnesium
silicates, and others. These salts can promote corrosion and min-
eral scale and can cause microbiological fouling.1 Mineral or inor-
ganic scale is caused by the accumulation of inorganic salts with
low aqueous solubility on the surface of several materials. This
phenomenon occurs in many types of industrial water pipes, sew-
age treatment equipment,2 pipelines, oil wells at sea, surfaces of
membranes used in water filtration, reactor stirrers and water
evaporators.3,4 This scale can cause serious damage to the flow
assurance in production and processing facilities, such as the clo-
sure of flow devices (control valves, flow restrictions in pipes and
ducts) in the vicinity of the producing wells. In addition, lost pro-
ductivity and increased costs of repair and maintenance operations
can result from this scale.
thermodynamic stability during the maturation of the nuclei,
which causes dissolution of nucleated embryos and/or interferes
with the process of crystal growth. Both circumstances block crys-
tal growth.5 Notably, scale inhibitors should not harm the environ-
ment if they possess the following properties: biodegradability,
low toxicity and a lack of bioaccumulation.6
Mineral anti-scale agents belong to different classes of sub-
stances that possess functional groups that form complexes with
salts. The most important property of these agents is the interac-
tion of the functional groups while the cation is being sequestered.
Most of them have a combination of functional groups, such as
hydroxyl with carboxylic, sulfonic, and phosphonic acids (Fig. 1).
Examples of such agents are aminotrismethylene phosphonic acid
(DTPMPA, 1), poly(sulfonic-acrylic acid) (2), and the natural poly-
saccharide inulin (3).7–9
Aldono-1,5-lactones have been used extensively as starting
materials in organic synthesis,10 including for ecologically recom-
mended scale inhibitors and chelating agents.11 These carbohy-
drates are capable of chelating metals and may also sequester free
radicals, thus protecting the skin from the harmful effects of ultravi-
olet radiation.12 The salts obtained from these sugars are widely
used in the fine chemical, cosmetic, medicine and pharmaceutical
industries. The mechanism of action of these amide–lactones is
based on their ability to form complexes or compounds with polyva-
The most economical and practical way to prevent or minimize
scale formation is the use of chemical inhibitors or inorganic
lent metal ions. Indeed,
D-gluconamides have been synthesized and
⇑
Corresponding author. Tel.: +55 21 26292345; fax: +55 21 26292136.
E-mail address: cegvito@vm.uff.br (V.F. Ferreira).
tested as chelating agents for the Fe3+ ion.13,14
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2012.01.027

M. I. P. Reis et al. / Carbohydrate Research 353 (2012) 6–12
HO
7
O
HO
O
P
OH
P OH
OH
O
OH
OH
OH
O
N
HO
OH
O
HO
m
N
N
P
HO
n
OH
HO
HO
HO2C
SO3H
P
O
P
O
HO
HO
2
OH
n
1
O
O
HO
HO
O
HO
OH
O
OH
3, Inulin
Figure 1. Examples of some classes of anti-scaling compounds.
OH
We describe the synthesis of
D
-gluconamides derived from
(v/v) solution of absolute ethyl alcohol/ethyl ether, and the obtained
solid was recrystallized from 95% ethanol.
d-gluconolactone and evaluate them as potential anti-scaling inhib-
itors as outlined in Scheme 1, with the goal of developing anti-scal-
ing substances from renewable biomass that are ecologically benign
for the oil industry.
All of the compounds were obtained in moderate to good yields
and were fully characterized by 1H nuclear magnetic resonance
spectroscopy (1H NMR), 13C NMR (APT type), infrared spectroscopy
(FT-IR), mass spectroscopy and elemental analysis (CHN). The C1
carbonyl groups were an important feature in the 13C NMR spectra,
and this signal was generally observed at about 172 ppm.
2. Results and discussion
The mono-, di-, tri- and tetra-substituted derivatives were
obtained by adjusting the number of amine equivalents reacted
with d-gluconolactone (4). The product 6a was obtained in a 65%
yield using an equivalent ratio of reagents. However, the prepara-
tion of 7a was carried out using different reagent ratios. For
example, 2 equiv of d-gluconolactone (4) with 1 equiv of ethylene-
diamine gave the disubstituted product 7a in a 70% yield. Its 13C
NMR spectrum showed only one signal for a carbonyl (C1) at
170.0 ppm and a signal for both methylenes at 38.2 ppm. The same
trend was observed for 7b in the 13C NMR spectrum, with a signal at
172.1 ppm for the C-1 carbonyl and the methylene signals at 38.1,
28.9, 28.4, and 26.2 ppm. In the reactions to synthesize products
8a–c, variable amounts of 4e and the triamine were used. The
Since these products may have future applications in the oil
industry, their preparation needs to be simple and adaptable to
large-scale synthesis. More specifically, we synthesized compounds
containing different amounts of D-gluconoyl groups bonded with
mono- to tetramines (Scheme 1). In general, the products were ob-
tained via nucleophilic addition of amines to the carbonyl group of
d-gluconolactone (4) by employing a method in the literature with
slightly modified conditions, as described in Scheme 2.15–21 The
reactions were processed at room temperature or at reflux with
magnetic stirring for a period of 6–24 h. The reactions were moni-
tored by TLC, and the excess amine and solvent were removed by
reducing the pressure. The residues were then washed with a 1:1
R1
H
OH OH
N
N
R2
HO
n
OH OH
O
R1, R2 = H, Me or Et
NHR2
NHR3
OH OH
H
N
R1HN
N
HO
R
OH OH
O
R = Bn or Bu
R1, R2 = H or D-gluconoyl
O
O
HO
HO
OH
OH
δ-Gluconolactone
RHN
NHR
H
N
H
N
n
R
R
RHN
NHR
OH OH
R = D-gluconoyl
R = D-gluconoyl
HO
OH OH
O
D-gluconoyl
Scheme 1. Substituted D-gluconamides obtained from d-gluconolactone.

8
M. I. P. Reis et al. / Carbohydrate Research 353 (2012) 6–12
OH OH
R1 6a
, R1 = R2 = H, n = 2, 65%
H
N
N
6b, R1 = R2 = Me, n = 2, 73%
, R1 = R2 = Et, n = 2, 81%
R2
HO
6c
OH OH
O
n
6d, R1 = R2 = Me, n = 3, 70%
6e, R1 = R2 = Et, n = 3, 77%
NHR2
OH OH
H
N
R1HN
N
ii
HO
R
OH OH
O
i
NHR3
iii
5a, R = Bn, 96%
8a, R1 = R2 = H, R3
= -gluconoyl, 75%
D
O
O
5b
, R = Bu, 98%
8b, R1 = H, R2 = R3 = D-gluconoyl, 68%
HO
HO
8c
, R1 = R2 = R3 = D-gluconoyl, 65%
OH
iv
v
OH
δ-Gluconolactone
RHN
NHR
H
N
H
N
n
R
R
RHN
NHR
7a, n = 2, R = D-gluconoyl, 70%
7b %
, n = 7 R = D-gluconoyl 75
OH OH
9, R = D-gluconoyl, 60%
,
,
HO
OH OH
O
D-gluconoyl
Scheme 2. Products and reaction conditions for the synthesis of compounds 5-9. Reagents and conditions: (i) RNH2, pyridine, rt, 24 h; (ii) H2N–(CH2)n–NR1R2, MeOH, reflux,
6 h; (iii) N(CH2CH2NH2)3, MeOH, reflux, 12 h; (iv) C(CH2CH2NH2)4, MeOH, reflux, 12 h; (v) H2N–(CH2)n–NH2, MeOH, reflux, 6 h.
compounds 8a–c showed only one signal in the 13C NMR spectra
from the C1 carbonyl, but 8a and 8b had different integrations in
the 1H NMR spectra for the methylene peak close to the amide
and free amine. The structure of 8c was confirmed by mass spectra
using ESIMS, which showed the mass of the protonated species
(M+H)+ m/z 681 (100%). The reaction of 4 and the tetramine (4:1 ra-
tio) provided the tetrasubstituted derivative 9. Only eight signals
were observed in 13C NMR spectrum for this compound, which is
consistent with its structure.
In addition, compound 5a had its crystal structure determined
by X-ray crystallography. The crystalline structure of 7a was deter-
mined in an indirect way; we were able to obtain crystals of the
peracetylated derivative 10. The acetylation reaction of 7a is de-
scribed in Section 4.
Commercially available DETPMP [diethylenetriamine penta
(meth ylene phosphonic acid)] was used as positive control to indi-
cate the barium sulfate inhibition. Both the scale inhibitors were
used as a reference and the synthesized molecules were tested at a
concentration of 50 mg Lꢀ1. To evaluate the extent of maximum pre-
cipitation in the system, a negative control was performed (blank
test) without scale inhibitor. The calculation of the inhibition
efficiency was performed using the following equation:
2þ
2þ
2þ
2þ
%E ¼ 100 ꢁ ð½Ba
where [Ba2+
ꢂ
ꢀ ½Ba
ꢂ
Þ=ð½Ba
ꢂ
ꢀ ½Ba
ꢂ
Þ
test
blank
original
blank
]
is the concentration (mg Lꢀ1) of Ba2+ for the test
test
with scale inhibitor or new molecules, [Ba2+
]
is the concentra-
blank
tion (mg Lꢀ1) of Ba2+ for the test without scale inhibitor, [Ba2+
]
original
is the concentration (mg Lꢀ1) of Ba2+ in the formation water.
Compound 5a crystallizes in space group P1. In this compound,
the phenyl group is disordered over two positions, as illustrated in
Figure 2. The compound 10 crystallizes in space group C2. The
C(7)–C(7)i bond is situated over a twofold rotation axis. The crystal
packing is stabilized by hydrogen bonds along the [100] and [010]
directions to compound 5a and along [010] direction to compound
10 (Table 1, Fig. 3).
The assays were performed in triplicate and the results are
reported in Table 3 as the averages of these analyses.The results
in Table 3 for compounds 5–9 indicate that they can be divided
into groups. The compounds without the terminal amide group
(5a and 5b, entries 1 and 2) had the lowest efficiencies, which indi-
cate that the amide group is not important for the complexation
process. The second group (entries 3–7), represented by substances
6a and 6b, had an increased efficiency in inhibiting BaSO4 precipi-
tation. Substance 6b performed much better than 6a, and this dif-
ference may be due to the increased availability of the electron pair
of N,N-dimethylamine for the formation of a stable complex. Com-
pounds 6c and 6d have one more carbon in the structure and can
form a more stable complex. Therefore, compound 6d is the best
ligand and shows 51.1% efficiency of inhibition. The low result
from compound 6e may be due to substitution of the methyl with
an ethyl group, resulting in no gain in electronic effect but a loss in
steric hindrance. The introduction of a further gluconamide group
at the end of the diamine, as in 7a (entry 8), did not increase the
efficiency of inhibition, even in longer chains such as 7b. In reality,
the formation of the bis-amides greatly reduces the availability of
the electron pair for chelation.Among the substances derived from
The selected torsion angles of skeleton
D-gluconamide are
showed in Table 2. The main differences are observed in the hydro-
xyl group due to hydrogen bonds.
The synthesized molecules were tested as inhibitors of barium
sulfate precipitation. Static tests for efficiency of inhibition were
conducted following the standard NACE TM 0197-2002 with some
modifications. The tests were carried out by simulating the mixture
of formation water (Ba2+, 46 mg Lꢀ1) and injection water (SO4
,
2ꢀ
2834 mg Lꢀ1) at a ratio of 1:1 with the pH adjusted to 7–8. The
recipients containing the mixture were left standing for 1 h at
25 °C. Then, the aliquots of the supernatant were removed and
filtered (0.45 l). After dilution, the amount of barium was deter-
mined with Inductively Coupled Plasma Mass Spectroscopy
(ICPMS).

M. I. P. Reis et al. / Carbohydrate Research 353 (2012) 6–12
9
Figure 2. Atom numbering scheme and atom arrangements for 5a and 10. Probability ellipsoids are drawn at the 30% and 30% levels, respectively. Hydrogen atoms are drawn
as spheres of arbitrary radius.
showed reasonable performances of 47% and 51.1%, respectively,
Table 1
which indicate the potential utility of these derivatives of
Hydrogen bonds for compound 5a and 10
d-gluconolactone.
D–Hꢃ ꢃ ꢃA
D–H(Å)
Hꢃ ꢃ ꢃA(Å)
Dꢃ ꢃ ꢃA(Å)
D–Hꢃ ꢃ ꢃA(°)
Compound 5a
N1–H1ꢃ ꢃ ꢃO1i
O2–H2ꢃ ꢃ ꢃO4
O3–H3ꢃ ꢃ ꢃO5i
O4–H4ꢃ ꢃ ꢃO3ii
O5–H5ꢃ ꢃ ꢃO6iii
O6–H6ꢃ ꢃ ꢃO4iv
4. Experimental
0.86
0.82
0.82
0.82
0.82
0.82
2.17
2.34
1.96
1.91
1.90
1.95
2.856 (5)
2.992 (4)
2.709 (3)
2.715 (3)
2.708 (4)
2.721 (4)
137
137
151
169
168
156
4.1. General procedures
Melting points were determined with a Fischer-Johns instru-
ment and are uncorrected. Analytical grade solvents were used.
Solvents were distilled before being used. Reagents were
purchased from Aldrich or Acros Chemical. Column chromatogra-
phy was performed on Silica Gel 60; 0.063–0.200 mm (Ref.
1.05554 Merck). Yields refer to chromatographically and spectro-
scopically homogeneous materials. Reactions were routinely mon-
itored by thin-layer chromatography (TLC) on pre-coated F254 silica
gel plates from Merck and using UV light or an ethanolic solution of
sulfate as the visualizing agent. Infrared (IR) spectra were recorded
on an ABB FTLA2000-100 spectrophotometer and calibrated rela-
tive to the 1601.8 cmꢀ1 absorbance of polystyrene in KBr pellets.
Compound 10
N1–H1ꢃ ꢃ ꢃO1i
0.86
2.61
3.374 (9)
149
Symmetry codes: (i) x, y + 1, z; (ii) x + 1, y, z; (iii) x ꢀ 1, y, z; (iv) x, y ꢀ 1, z.
the triamine (entries 10–12) and tetramine (entry 13), the bis-
gluconamide 8b was the most efficient. This finding shows that
the amino group of 8a and 8b may be placing the two gluconamide
moieties sufficiently close to effect complexation and chelation
with the barium ion.
NMR spectra were obtained on
a Varian Unity Plus VXR
3. Conclusion
(300 MHz and 500 MHz) in either DMSO-d6 or CDCl3 solutions,
and tetramethylsilane was used as the internal standard (d 0 ppm).
In this work, we synthesized 13 compounds (5a–b, 6a–e, 7a–b,
8a–c and 9) derived from d-gluconolactone that contained differ-
ent amino groups bound to the D-gluconoyl moiety in moderate
4.2. General procedure for the synthesis of 5a and 5b
to good yields. Two compounds (5a and 10) had their crystal struc-
tures determined by X-ray crystallography. The efficiency of these
potential scale inhibitors were evaluated by measuring BaSO4
precipitation from an aqueous solution. Compounds 6c and 6d
In a round bottomed flask (50 mL) were added d-gluconolactone
(4, 5.6 mmols), 0.06 mmol of the desired amine (butylamine or
benzylamine) and pyridine (0.06 mmol). After the addition of

10
M. I. P. Reis et al. / Carbohydrate Research 353 (2012) 6–12
Figure 3. Molecular packing of 5a and 10 showing an infinite chain of hydrogen bonds.
Table 2
Table 3
Torsion angles of 5a and 10
Inhibition of precipitation of BaSO4 by compounds 5–9
5a
10
Entry
Compounds
Efficiencya (%)
O1–C1–N1–C7
C2–C1–N1–C7
C3–C2–C1–N1
C4–C3–C2–C1
C5–C4–C3–C2
C6–C5–C4–C3
O2–C2–C1–N1
C3–C2–C1–O1
O3–C3–C2–C1
C4–C3–C2–O2
O4–C4–C3–C2
C5–C4–C3–O3
O5–C5–C4–C3
C6–C5–C4–O4
O6–C6–C5–C4
ꢀ3.3 (6)
ꢀ3.2 (8)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5b
6a
6b
6c
6d
6e
7a
7b
8a
8b
8c
9
19.2
16.9
21.7
34.6
47.0
51.1
27.8
17.6
26.0
24.5
38.0
23.2
17.8
90.0
173.8 (4)
ꢀ114.5 (4)
ꢀ165.8 (3)
179.7 (3)
ꢀ179.3 (3)
6.3 (4)
179.5 (4)
89.4 (5)
176.1 (5)
ꢀ174.5 (4)
ꢀ177.6 (4)
ꢀ31.9 (6)
ꢀ88.2 (6)
ꢀ60.9 (5)
ꢀ62.3 (5)
68.2 (5)
62.8 (5)
67.7 (3)
74.7 (4)
ꢀ61.9 (4)
ꢀ55.2 (4)
ꢀ57.9 (3)
58.1 (3)
62.0 (4)
60.3 (5)
ꢀ56.3 (5)
DETPMP
53.7 (4)
ꢀ50.9 (5)
a
Inhibition of BaSO4 precipitation.
amine, the flask was closed, and the reaction mixture was kept at
room temperature under constant magnetic stirring for 24 h. The
reaction was followed by TLC. The solvent was evaporated under
reduced pressure, and the crude solid formed was washed with
100 mL of a mixture of ethanol and diethyl ether (1:1 v/v). The
solid was purified by recrystallization from 95% ethanol to give

M. I. P. Reis et al. / Carbohydrate Research 353 (2012) 6–12
11
Table 4
4.3.1. N-(2-Aminoethyl)-D-gluconamide (6a)
Crystal data and structure refinement
Obtained in a 65% yield as a white solid. Mp: 121–123 °C (mp
lit. 123 °C recrystallized in 95% ethanol).15 Optical rotation and
Spectroscopic data were the same as that reported in the
literature.15,20
Compound
5a
10
Chemical formula
Mr
Cell setting, space
group
Temperature (K)
a (Å)
C
13H19N1O6
C34H48N2O22
836.74
Monoclinic, C2
285.29
Triclinic, P1
4.3.2. N,N-(2-(Dimethylamino)ethyl)-D-gluconamide (6b)
293 (2)
293 (2)
18.444 (4)
5.5567 (11)
20.538 (4)
90
101.62 (3)
90
2061.8 (7)
2
Obtained in a 73% yield as yellow oil. Optical rotation ½a 2D0
ꢂ
+72°
4.8087 (10)
5.0732 (10)
14.272 (3)
83.10 (3)
82.85 (3)
82.86 (3)
340.84 (12)
1
(c, 1, H2O). IR m
max (cmꢀ1, thin film): 3500, 3343, 1653,1093, 1038.
b (Å)
c (Å)
1H NMR (300 MHz, DMSO-d6) d: 2.12 (6H, s, H-100); 2.28–2.33 (2H,
m, H-10 or H- 20); 3.14–3.21 (2H, m, H-10 or H-20); 3.38–3.40 (2H, m,
H-4 and H-5), 3.46–3.48 (2H, m, H-6); 3.87 (1H, d, J = 2.4, H-3), 3.98
(1H, d, J = 3.5 Hz, H-2), 7.53 (1H, t, J = 5.6 Hz, N–H); 13C NMR was
the same as that reported in the literature.22
a
(°)
b (°)
c
(°)
V (Å3)
Z
Radiation type
Mo K
0.11
a
Mo Ka
0.11
l
(mmꢀ1
)
Crystal size (mm)
Diffractometer
0.31 ꢄ 0.18 ꢄ 0.15 mm
0.21 ꢄ 0.13 ꢄ 0.1 mm
4.3.3. N,N-(2-(Diethylamino)ethyl)-D-gluconamide (6c)
KappaCCD
KappaCCD
Obtained in a 85% yield as yellow oil. Optical rotation ½a 2D0
ꢂ
diffractometer
0.066
diffractometer
0.058
0.051, 0.134, 1.01
6897/2010
+13.4° (c, 1, H2O). IR mmax (cmꢀ1, film): 3399, 3343, 3283, 1644,
Rint
1
1092, 1034; H NMR (DMSO-d6) d: 0.94 (6H, t, H-200, J = 7.2 Hz);
R[F2 > 2
r
(F2)], wR(F2), S 0.060, 0.177, 1.08
2.38–2.48 (6H, m, H-20
e
H-100); 3.11–3.18 (2H, m, H-10);
No. of reflections/
unique
8409/2293
3.47–3.48 (2H, m, H-6); 3.55–3.60 (2H, m, H-4 and H-5),
3.88–3.91 (1H, m, H-3); 3.97 (1H, d, J = 3.8 Hz, H-2), 7.52 (1H, t,
J = 5.7 Hz, N–H); 13C NMR was the same as that reported in the
literature.22
No. of parameters
216
0.37, ꢀ0.28
267
0.30, ꢀ0.16
D
qmax
,
D
qmin (e Åꢀ3
)
the amides 5a and 5b. The structures were confirmed by 1H NRM,
13C-APT NMR and FTIR.
4.3.4. N,N-(3-(Dimethylamino)propyl)-D-gluconamide (6d)
Obtained in a 70% yield as yellow oil. Optical rotation ½a 2D0
ꢂ
+96°
4.2.1. N-Benzyl-D-gluconamide (5a)
(c, 1, H2O). IR mmax (cmꢀ1, film): 3391, 1647, 1084, 1041. 1H NMR
(DMSO-d6) d: 1.51–1.56 (2H, m, H-20); 2.01 (6H, s, H-100); 3.07–
3.14 (2H, m, H-30); 3.32–3.41 (4H, m, H-10 and H-6); 3.46–3.48
(2H, m, H-4 and H-5); 3.55 (1H, d, J = 2.6 Hz, H-3), 3.96 (1H, d,
J = 3.5 Hz, H-2), 7.70 (1H, t, J = 5.9 Hz, N–H); 13C NMR is in agree-
ment with the data available in the literature.22
Obtained in a 96% yield as a white solid. Mp: 177–178 °C (mp
lit.23 175–177 °C). The optical rotation was the same as that re-
ported in the literature.23 IR mmax (cmꢀ1, KBr pellet) 3502, 3370,
3321, 1648, 1099); 1H NMR (300 MHz, DMSO-d6) d: 3.49–3.50
(m, 2H); 4.07 (dd, 1H, J = 4.8 Hz and J = 3.6 Hz); 4.30–4.38 (m,
2H); 4.46 (t, 1H, J = 6.9 Hz); 5.45 (d, 1H, J = 5.1 Hz); 7.19–7.30 (m,
5H); 8.15 (t, 1H, J = 6.3 Hz); 13C NMR (APT, 75 MHz, DMSO-d6) d
41.7 (C-10); 63.3 (C-6); 70.1 (C-5); 71.5 (C-4); 72.5 (C-3); 73.8 (C-
2); 126.5 (C-400); 127.1 (C-200 and C-600); 128.1 (C-300 and C-500);
139.5 (C-100); 172.6 (C-1).
4.3.5. N,N-(3-(Diethylamino)propyl)-D-gluconamide (6e)
Obtained in a 77% yield as a yellow oil. Optical rotation ½a 2D0
ꢂ
+72° (c, 1, H2O). IR mmax (cmꢀ1, film): 3347, 2967, 2935, 1647,
1
1083. H NMR (DMSO-d6) d: 1.06 (6H, t, J = 7.2 Hz, H-200); 1.55–
1.69 (2H, m, H-20); 2.42–2.58 (8H, m, H-10or H-30 or H-100); 3.20–
3.26 (2H, m, H-6); 3.59 (2H, m, H-4 and H-5) 3.68 (1H, m, H-3);
4.09 (1H, d, J = 3.8 Hz, H-2), 7.83 (1H, t, J = 5.2 Hz, N–H); 13C NMR
was the same as that reported in the literature.22
4.2.2. N-Butyl-D-gluconamide (5b)
Obtained in a 94% yield as a white solid. Mp: 146–149 °C. Opti-
cal rotation ½a D20
ꢂ
+13.6° (c 1, H2O). IR m
max (cmꢀ1, KBr pellet): 3510,
3367 1649, 1097, 1037; 1H NMR (300 MHz, DMSO-d6) d: 0.86 (t,
3H, J = 7.2 Hz); 1.20–1.44 (m, 4H); 3.04–3.14 (m, 2H); 3.90 (d,
1H, J = 4.7 Hz); 3.97 (t, 1H, J = 3.9 Hz); 4.32–4.40 (m, 2H); 4.53(d,
1H, J = 3.4 Hz); 5.36 (d, 1H, J = 4.8 Hz); 7.59 (t, 1H, J = 6.0 Hz). 13C
NMR (75 MHz, DMSO-d6) d: 13.6 (C-40); 19.4 (C-30); 31.1 (C-20);
37.8 (C-10); 63.3 (C-6); 70.0 (C-5); 71.4 (C-4); 72.3 (C-3); 73.5 (C-
2); 172.1 (C-1).
4.3.6. N,N0-(Ethane-1,2-diyl)bis-
D-gluconamide (7a)
Obtained in a 70% yield as a white solid. Mp: 187–189 °C (mp
lit.15 188 °C recrystallized in 95% ethanol). The optical rotation
was the same as that reported in the literature.15 IR mmax (cmꢀ1
,
film): 3540, 3390, 3318, 1661, 1097. 1H NMR (DMSO-d6) d: 3.18–
3.19 (2H, m, H-10); 3.49 (2H, m, H-6); 3.99 (1H, s, H-5), 4.29 (1H,
t, J = 4.9 Hz, H-4), 4.38 (1H, d, J = 5.9 Hz, H-3), 5.33 (1H, s, H-2),
4.3. General procedure for the synthesis of 6a–e, 7a–b, 8a–c and 9
13
7.77 (1H, s, N–H). C NMR (75 MHz, DMSO-d6) d: 38.2 (C-10);
63.3 (C-6); 70.1 (C-5); 71.4 (C-4); 72.1 (C-3); 73.3 (C-2); 172.9 (C-1).
In a round bottomed flask (125 mL) fitted with a reflux condenser
were added d-gluconolactone (4, 5.6 mmols), anhydrous methanol
(50 mL) and the appropriate amine (5.6 mmols for N,N-dimethyl-
ethylenediamine, N,N-diethylethylenediamine, N,N-dimethylpro-
pylamine, N,N-diethylpropylamine, ethylenediamine; 11.2 mmol
for ethylenediamine or heptane-1,7-diamine; 1.86 mmol or
2.3 mmol or 5.6 mmol for tris(2-aminoethyl)amine; 1.4 mmol for
2,2,-bis(aminomethyl)propane-1,3-diamine). The reaction was kept
at reflux and stirred for 6–12 h and was followed by TLC. The solvent
was then evaporated under reduced pressure on a rotary evaporator.
The obtained product was washed with 200 mL of a solution of eth-
anol and diethyl ether (1:1 v/v), and its structure was confirmed by
1H NMR, 13C NMR, and infrared.
4.3.7. N,N0-(Heptane-1,7-diyl)bis-
D-gluconamide (7b)
Obtained in a 75% yield as a white solid. Mp: 183–185 °C (mp
lit. 186 °C recrystallized in 95% ethanol), and optical rotation ½a 2D0
ꢂ
+204° (c, 1, H2O). IR mmax (cmꢀ1, film): 3530, 3326, 2923, 1654,
1097. Spectroscopic data were the same as that reported in the
literature.24
4.3.8. N-(Bis(2-aminoethyl)-D-gluconamide (8a)
Obtained in a 85% yield as an oil and measurement of specific
optical rotation ½a 2D0
ꢂ
+109° (c, 1, H2O). IR mmax (cmꢀ1, film): 3349,
NMR
3285, 3188, 2938, 2870, 2812, 1654, 1086, 1038.13
C

12
M. I. P. Reis et al. / Carbohydrate Research 353 (2012) 6–12
(DMSO-d6) d: 36.6 (C-200 and C-2000; 38.4 (C-10); 53.1 (C-20); 57.2 (C-
1000 or C-100); 57.5 (C-1000 or C-100); 63.1 (C-6); 69.7 (C-5); 71.2 (C-4);
72.0 (C-3); 73.3 (C-2); 172.2 (C-1).
(C-2), 69.5 (C-3), 69.2 (C-4), 68.9 (C-5), 61.7 (C-6), 39.1 (C10),
20.7, 20.6, 20.5, 20.4 (CH3).
4.5. X-ray crystallography
4.3.9. N,N0-2,2-(2-Aminoethyl)-bis-(ethane)-
D-gluconamide (8b)
Obtained in a 68% yield as a yellow oil. Optical rotation ½a 2D0
ꢂ
4.5.1. Data and refinement of crystal structures for substances
5a and 10
Crystallographic X-ray data were collected for compounds 5a
and 10 with MoKa radiation (k = 0.71069 Å) at 293(2)K on a Bruker
KAPPA CCD diffractometer using a graphite crystal monochroma-
tor. The data reduction and integration were performed using the
DIRAX25 and EVALCCD26 program. The structures were solved by
direct methods using the SHELXS-9727 program, and refinement
was performed with the SHELXL-9727 program with the full-matrix
least-squares method. All atoms except hydrogen were refined
anisotropically. Hydrogen atoms were geometrically added to the
structure and then refined by the riding model.
+176° (c, 1, H2O). IR mmax (cmꢀ1, film): 3352, 2884 1645, 1084,
1040. 1H NMR (DMSO-d6) d: 2.36–2.42 (6H, m), 2.53–2.57 (6H,
m), 3.47–3.49 (2H, m), 3.80–3.91 (2H, m), 3.97–4.00 (2H, m),
13
8.28 (1H, s, N–H); C NMR (DMSO-d6) d: 37.0 (C-200 and C-2000);
36.8 (C-10); 53.5 (C-20); 53.3 (C-2000); 57.2 (C-1000 or C-100); 57.5 (C-
1000 or C-100); 63.4 (C-6); 70.2 (C-5); 71.6 (C-4); 72.4 (C-3); 73.7
(C-2); 172.6 (C-1).
4.3.10. N,N,N-Tris-(ethane)-D-gluconamide (8c)
Obtained in a 65% yield as a white solid, (mp 119–121 °C recrys-
tallized in 95% ethanol). Optical rotation ½a 2D0
ꢂ
+81.1° (c, 1, H2O). IR
mmax (cmꢀ1, thin film): 3413, 1646, 1085. 1H NMR (DMSO-d6) d:
2.54 (6H, t, J = 6.9 Hz, H-20); 3.14–3.19 (6H, m, H-10), 3.38–3.40
(6H, m, H-6), 3.48–3.49 (6H, m, H-5 and H-4), 3.59 (3H, d,
J = 3.4 Hz, H-3), 4.00 (3H, d, J = 3.4 Hz, H-2), 7.59 (3H, t, J = 5.4 Hz,
4.5.2. Details of data collection and structure refinement for the
compounds 5a and 10 given in Table 4
Crystallographic data for the structures reported have been
deposited at the Cambridge Crystallographic Data Center. This
information may be obtained freely from the Director, CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: +44-1223-336033;
e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
13
N–H); C NMR (75 MHz, DMSO-d6) d: 36.5 (C-10); 52.9 (C-20);
63.2 (C-6); 70.0 (C-5); 71.4 (C-4); 72.3 (C-3); 73.5 (C-2); 172.4 (C-1).
4.3.11. N,N0-(2,20,200,2000-Tetra-(methyl)-
D-gluconamide) (9)
Obtained in a 60% yield as a white solid, mp = 179 °C, with
decomposition and measurement of specific optical rotation ½a 2D0
ꢂ
References
+4.8° (c, 1, H2O). IR mmax (cmꢀ1, thin film): 3460, 3327, 1637,
1
1602, 695. H NMR (D2O) d: 2.59 (8H, d, J = 6.4 Hz, H-10), 3.21
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(4H, d, J = 14.7 Hz, H-6), 3.56–3.62 (4H, m, H-60), 3.56–3.80 (4H,
m, H-3), 3.56–3.80 (4H, m, H-4), 3.56–3.80 (4H, m, H-5), 3.56–
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4.4.1. 2,3,4,5,6-Penta-O-acetyl-N,N-bis-ethane-D-gluconamide
(10)
Obtained in a 97% yield as a white solid. Mp: 176–177 °C (mp
lit. 176–177 °C).15 The optical rotation was the same as that re-
ported in the literature.15 IR mmax (cmꢀ1, KBr pallet): 3462, 3367,
1747, 1677, 1538, 1377, 1224, 1076, 1051, 963.1H NNR
(300 MHz, CDCl3) d: 8.15 (t, 1H, J = 6.4 Hz); 7.29–7.18 (m, 5H),
5.45 (d, 1H, J = 5.0 Hz), 4.34 (t, 1H, J = 5.0 Hz), 4.07 (dd, 1H),
3.98–3.94 (m, 1H), 3.59–3.49 (m, 2H); 13C NMR (75 MHz, CDCl3)
d: 170.6; 170.0; 169.9; 169.8; 169.8 COCH3; 166.8 (C-1), 71.3
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