Kinetic study on the esterification of hexanoic acid with N,N-dialkylamino alcohols: Evidence for an activation by hydrogen bonding

Article abstract of DOI:10.1515/znb-2006-0513

The pseudo-first order rate constant for the esterification of hexanoic acid (1) and five different N,N-dialkylamino alcohols (2) was determined in comparison to 1-hexanol (k = 0.67 · 10^-5 s^-1). The values range from 0.60 · 10^-5 s^-1 to 9.3 · 10^-5 s^-1. The data suggest a differing reactivity for structurally related compounds, which is directly correlated to the ability of the corresponding amino alcohol to activate the carboxylic acid by hydrogen bonding. A seven-membered transition state C≠ is postulated for reactions of 2-amino alcohols. The fastest reaction was observed for trans-2-(N,N- dimethylamino)cyclohexanol (2e), in which the amino and the hydroxyl groups are in an almost perfect synperiplanar 1,2-position. Attempts to further enhance the rate of the esterification by the addition of potential catalysts failed. Only Cu(OTf)₂ (2.5 mol-%) allowed for a moderate rate increase from 7.5 · 10^-5 s^-1 (uncatalyzed) to 14.8 · 10 ^-5 s^-1 (catalyzed) in the esterification of hexanoic acid (1) with 2-(N,N-dimethylamino)ethanol (2a).

Full text of DOI:10.1515/znb-2006-0513

Kinetic Study on the Esterification of Hexanoic Acid with
N,N-Dialkylamino Alcohols: Evidence for an Activation by
Hydrogen Bonding
Stefan Breitenlechner and Thorsten Bach
Lehrstuhl fu¨r Organische Chemie I, Technische Universita¨t Mu¨nchen, Lichtenbergstraße 4,
D-85747 Garching, Germany
Reprint requests to Prof. Dr. Th. Bach. Fax: +49 89 / 289 13315. E-mail: thorsten.bach@ch.tum.de
Z. Naturforsch. 61b, 583 – 588 (2006); received January 27, 2006
The pseudo-first order rate constant for the esterification of hexanoic acid (1) and five different
N,N-dialkylamino alcohols (2) was determined in comparison to 1-hexanol (k = 0.67 · 10−5
s
−1).
The values range from 0.60 · 10−5 s−1 to 9.3 · 10−5
s
−1. The data suggest a differing reactivity for
structurally related compounds, which is directly correlated to the ability of the corresponding amino
alcohol to activate the carboxylic acid by hydrogen bonding. A seven-membered transition state C= is
postulated for reactions of 2-amino alcohols. The fastest reaction was observed for trans-2-(N,N-di-
methylamino)cyclohexanol (2e), in which the amino and the hydroxyl groups are in an almost perfect
synperiplanar 1,2-position. Attempts to further enhance the rate of the esterification by the addition
of potential catalysts failed. Only Cu(OTf)2 (2.5 mol-%) allowed for a moderate rate increase from
7.5 · 10−5 s−1 (uncatalyzed) to 14.8 · 10−5 s−1 (catalyzed) in the esterification of hexanoic acid (1)
with 2-(N,N-dimethylamino)ethanol (2a).
Key words: Acylation, Amino Alcohols, Hydrogen Bonds, Kinetics, Transition States
Introduction
The esterification of an alcohol with a carboxylic
acid is one of the best known and probably one of
the oldest chemical reactions [1]. It proceeds most
commonly by a nucleophilic attack of the alcohol
at the carboxylic group of the ester (AAc2 mecha-
nism) [2]. While plenty of data has been amassed
over the decades on this reaction, some mechanis-
tic details still remain unravelled. We became inter-
ested in the reaction of the title compounds with car-
boxylic acids in connection with the industrially im-
portant cross-linking of polycarboxylic acids and tri-
ethanolamine◦[3]. This process is routinely carried out
at 180– 200 C and it was our goal to elucidate the
mechanism of this reaction more closely and to eval-
uate possible catalysts. The test reaction which we
established is depicted in Scheme 1. Hexanoic acid
(1) and 2-(N,N-dimethylamino)ethanol(2a) were con-
verted into the correspondingester 3a. For comparison,
the kinetics of the esterification of hexanoic acid with
1-hexanol were also recorded. Remarkably◦, it turned
out that the former reaction proceeds at 111 C (reflux-
ing toluene) in the absence of a catalyst ten times faster
Scheme 1. Esterification of hexanoic acid (1) with amino al-
cohol 2a and 1-hexanol.
amino alcohol that the rate of the esterification is heav-
ily dependent on its ability to activate the carboxylic
acid by intermolecular hydrogen bonding. In this pa-
per we provide full details of our work in this area and
discuss the mechanism of the process. The rate of the
esterification of amino alcohol 2a was shown to be not
significantly influenced by acidic catalysts.
Results
Kinetic studies
The alcohol 2a (or 1-hexanol) (c = 0.125 M) was
than the latter reaction. It was shown by varying the converted into the corresponding ester 3a (or 4) under
c
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S. Breitenlechner – T. Bach · Kinetic Study on the Esterification of Hexanoic Acid
Table 1. The effect of potentially active catalytic additives in
the reaction 2a → 3a.
Catalysta
Amount
[mol-%]
r2b
k3a
a
Entry
[s−1
]
1
2
3
4
5
6
7
8
NaH2PO2
H3PO2
2.5
2.5
2.5
2.5
1.0
2.5
2.5
5.0
0.983
0.999
0.995
0.992
0.991
0.995
0.990
0.994
7.3·10−5
8.7·10−5
6.8·10−5
14.8·10−5
9.5·10−5
10.5·10−5
9.3·10−5
10.0·10−5
Yb(OTf)3
Cu(OTf)2
Fe2(SO4)3
P(C6F5)3
PPh3
c
imidazole
9
2.5
0.986
8.0·10−5
a
b
For experimental details, see the Experimental Section; the co-
efficient of determination is provided as square of Pearson‘s correla-
Fig. 1. Uncatalyzed conversion of 1-hexanol and 2-(N,N-
dimethylamino)ethanol (2a) to the corresponding hex-
anoates 3a and 4.
c
tion coefficient r; the experiment was carried out in a Dean-Stark
trap apparatus without the addition of Na SO4.
2
of the corresponding hexanoates are given. The rate
constants vary by a factor of 15. The fastest reac-
tion was observed with the conformationally restricted
trans-amino alcohol 2e. A small induction period (up
to 10 min) was noticed in almost all esterification reac-
tions of the amino alcohols. This period was subtracted
from the elapsed time and it was not taken into account
when fitting the curve to the monoexponential regres-
sion. In general, 10 – 12 data points were obtained (see
Fig. 1) and the coefficient of determination r2 varied
in all measurements between 0.991 and 0.997. Several
of the measurements were repeated for accuracy. The
variation of the data was within the experimental error
(∆k = 5%). It was shown that the reaction 2a → 3a
proceeded to full conversion.
Fig. 2. Pseudo-first order rate constants for the esterifica-
tion of hexanoic acid with amino alcohols 2b – 2e in toluene
at 111 ◦C to the corresponding esters 3b – 3e.
pseudo-first order reaction conditions. A tenfold ex-
cess of the carboxylic acid was used and the kinetics
were studied by GLC analysis using an internal stan-
dard (see Experimental Section). The water was re-
moved to guarantee an irreversible reaction. In prelim-
inary experiments it was shown that Na2SO4 is best
˚
suited for this purpose while the water removal by 4 A
Catalysis experiments were carried out under the
conditions specified above. The well established acid
catalysis was nicely corroborated by the esterifica-
tion of 1-hexanol. Upon addition of 1 mol-% of para-
toluenesulfonic acid (p-TsOH) the pseudo-first order
rate constant increased from k4 = 0.67 · 10−5 s−1 (un-
catalyzed) to k4 = 4.5·10−5 s−1. With 2.5 mol-% of p-
molecular sieves or by a Dean-Stark trap was incom-
plete. Fig. 1 depicts the product development (conver-
sion) for compounds 3a and 4 with respect to time
in an uncatalyzed esterification. The conversion was
recorded upon addition of the amino alcohol to the
◦
acid in refluxing toluene (111 C). From these data
TsOH the value k4 increased further to 13.8·10−5 s−1
.
the pseudo-first order rate constants were calculated
as k3a = 7.5 · 10−5 s−1 and k4 = 0.67 · 10−5
s
−1. In
Contrary to these results, p-TsOH did not influence
the rate of the esterification with amino alcohol 2a.
The rate constant k3a remained unchanged within the
range of error. Other catalysts were screened. Support
other words, the reaction of amino alcohol 2a occurs
ten times faster than the reaction of an aliphatic pri-
mary alcohol such as 1-hexanol.
For comparison other amino alcohols 2 were stud- for the claimed catalytic effect of phosphinic acid [5]
ied. While amino alcohols 2b – 2d are commercially was not obtained (entries 1, 2). Among the Lewis acids
available, trans-2-(N,N-dimethylamino)cyclohexanol screened, most of them had no or only a small effect.
(2e) was prepared from trans-2-aminocyclohexanol by As examples the data for ytterbium trifluoromethane-
reductive amination [4]. The compounds are listed sulfonate (Yb(OTf)3, entry 3), iron(III) sulfate (en-
in Fig. 2 and the rate constants for the formation try 5), and tris(pentafluorophenyl)phosphane (entry 6)
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S. Breitenlechner – T. Bach · Kinetic Study on the Esterification of Hexanoic Acid
585
are provided in Table 1. Only the twofold rate increase
observed with Cu(OTf)2 was significant. Other nucle-
ophilic catalysts (entries 7 – 9) had a limited influence,
the rate constant k3a barely exceeding the value for the
uncatalyzed reaction (k3a = 7.5·10−5 s−1).
Fig. 3. Structure of the aminocyclitols 6 and 7, the hydrolyses
of which was studied by Holland et al. [7a].
Discussion
Kinetic data for the esterification of carboxylic acids
with 2-amino alcohols are rare [6]. The reverse reac-
tion, however, i.e. the saponification and hydrolysis of
2-aminoalkyl esters, has been intensively studied [7].
An example for an early kinetic study concerns the
aminocyclitol derivatives depicted in Fig. 3. Hydrol-
Fig. 4. Structure of the two transition states A= (ester hydrol-
ysis) and C= (esterification) leading to the presumed tetrahe-
dral intermediate B.
◦
yses of these compounds were carried out at 25 C in a
supporting aqueous medium containing 0.088 M NaCl
as electrolyte and 12.5% v/v methanol at pH = 7.7.
The first-order rate constant for the hydrolysis of
the scyllo-diastereoisomer 6 was determined as 2.2 ·
sition state nicely explains the rate difference observed
for 1-hexanol and compound 2a. If the formation of
a cyclic transition state is restricted or even impossi-
ble the rate constants for the esterification decrease.
Amino alcohol 2b served as a model for a conforma-
tionally locked 2-(N,N-dialkylamino)ethanol with the
hydroxyl group and the amino group in an antiperi-
planar arrangement, which cannot react via transition
state C=. The rate of the esterification is consequently
10−5 −1. The myo-diastereoisomer 7 was hydrolyzed
s
more slowly with a rate constant of 1.0·10−5 s−1 [7a].
Hansen summarized previous work in the field [7b]
and concluded that “the mechanism of the hydroly-
sis of tertiary aminoalkyl esters in alkaline solution is
better explained in terms of an intramolecular hydro-
gen bonding than by any other mechanism.” The sug-
gested transition state leading to the tetrahedral inter-
mediate B can be written as A= with either a water
molecule (as in A=) or a hydroxide ion as the nucle-
ophile (Fig. 4). For the given example in Fig. 3 the
scyllo-diastereoisomer 6 can adopt such a transition
state more readily than the myo-diastereoisomer 7. In 6
the all-equatorial arrangement of the substituents facil-
itates the approach of the oxygen nucleophile. Hansen
ended his account with the words “In order to confirm
this result it would be interesting to study some com-
pounds in which the hydrogen bond for steric reasons
is very unlikely”.
as low (k3b = 0.60 · 10−5
s
−1) as for 1-hexanol (k4 =
0.67·10−5 s−1). For 3-(N,N-dimethylamino)propanol
(2c) a cyclic transition state is feasible but the eight-
membered ring transition state is disfavoured (k3c
=
2.7 · 10−5
s
−1) compared to the transition state of its
nor-analogue 2a (k3a = 7.5 · 10−5
s
−1). Similar ar-
guments hold for the formation of esters 3d and 3e.
The slightly lower rate constant for 2d (k3d = 6.3 ·
10−5 −1) suggests that the gem-dimethyl substitu-
s
tion and the increased steric strain induced by the ad-
ditional methyl groups cancel out each other while
amino alcohol 2e as a model for a conformationally
locked synperiplanar 2-(N,N-dialkylamino)ethanol re-
acted fastest (k3e = 9.3·10−5 s−1).
The results we collected in the esterification of hex-
anoic acid with amino alcohols 2 lend support to a re-
The results obtained with the various additives (Ta-
lated transition state C= in the rate-determining step ble 1) are subtle and more difficult to explain. Their
of this transformation. The intermediate B is formed influence was apparently not very pronounced, only
by attack of the amino alcohol at the carboxyl group, Cu(OTf)2 leading to a significant rate increase (en-
which is in turn activated by hydrogen bonding to the try 4). In this instance, the Lewis acidic copper cation
protonated amino group of 2. Based on the pKa val- presumably coordinates to the oxygen of the carboxyl
ues tabulated for hexanoic acid (pKa = 4.89) [8] and group and further enhances its electrophilicity. Nucle-
N,N-dialkylamino alcohols [e. g. 2-(N,N-dimethyl- ophilic catalysis was suspected to be responsible for
amino)ethanol: pKa = 9.42] [9] the amino alcohols the rate increase observed with imidazole (Table 1, en-
are almost quantitatively protonated under the reaction try 8). However, an attempt to further increase the re-
conditions. The activation via a seven-membered tran- action rate by introducing an amino methyl group into
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586
S. Breitenlechner – T. Bach · Kinetic Study on the Esterification of Hexanoic Acid
the imidazole (5, entry 9) disappointingly failed. We 15 : 1). Average yields were around 70 – 75% after chro-
matography.
therefore conclude that an efficient catalyst for the es-
terification of N,N-dialkylamino alcohols has not been
found.
2-(N,N-Dimethylamino)ethyl hexanoate (3a)
In summary, our study has proven that the activa-
tion of carboxylic acid derivatives by hydrogen bond-
ing, which has been earlier postulated for the saponifi-
cation of 2-aminoalkyl esters, is responsible for a rate
increase in the esterification of 2-(N,N-dialkylamino)
alcohols. It was shown by variation of the amino alco-
hols that the esterification rate constant is high for sub-
The reaction was carried out according to the general pro-
cedure with 2-(N,N-dimethylamino)ethanol (2a) (502 µl,
496 mg, 5.00 mmol). – Rf = 0.34 (DCM/MeOH, 12 : 1). –
1H NMR (360 MHz, CDCl3): δ = 0.83 (t, 3J = 6.9 Hz, 3 H,
CH3CH2), 1.18 – 1.32 (m, 4 H, CH3CH2CH2), 1.56 (virt. qu,
3
∼
J
7.5 Hz, 2 H, CH CH CO), 2.23 (s, 6 H, N(CH ) ),
2 2 3 2
=
2.27 (t, 3J = 7.5 Hz, 2 H, CH2CO), 2.50 (t, 3J = 5.7 Hz,
strates which favor an intermolecular hydrogen bond- 2 H, CH2O), 4.11 (t, 3J = 5.7 Hz, 2 H, CH2N) ppm. –
13C NMR (90.6 MHz, CDCl3): δ = 14.0 (q, CH3CH2), 22.4
ing. Contrary to this, 2-(N,N-dialkylamino) alcohols
(t, CH3CH2), 24.6 (t, CH2CH2CO), 31.3 (t, CH3CH2CH2),
34.2 (t, CH2CO), 45.8 (s, N(CH3)2), 57.9 (t, CH2N), 62.0−(t1,
(vs, C-H), 2861 (s, C-H), 2821 (s, C-H), 2770 (s, C-H),
1737 (vs, C=O), 1456 (s), 1377 (m), 1244 (s), 1171 (vs,
C-O), 1100 (s), 1042 (s), 968 (m), 850 (m), 782 (m), 734
(m). – GC-MS (EI, 70 eV, tR = 10.5 min): m/z(%) = 99
(1) [C6H11O+], 72 (6) [C4H10N+], 58 (100) [C3H8N+]. –
C10H21NO2 (187.28): calcd. C 64.13, H 11.30, N 7.48; found
C 64.00, H 11.42, N 7.43.
which for steric reasons cannot form an intermolecu-
lar hydrogen bond (e. g. substrate 2b) react with the
same rate constant as normal aliphatic alcohols such as
1-hexanol.
˜
CH2CO), 174.0 (s, CO) ppm. – IR (NaCl): ν = 2957 cm
Experimental Section
General remarks
2-(N,N-Dimethylamino)-2-methyl-1-propanol and com-
mon solvents [ethyl acetate, toluene, methanol (MeOH)
and dichloromethane (DCM)], were distilled prior to use.
All other amino alcohols, 1-hexanol, hexanoic acid and all
other reagents were used as received. IR: Perkin Elmer 241
FT-IR. GC-MS: Agilent 6890 (GC system, flow: 1.3 ml/min,
column: HP 5MS (30 m), temperature: 50 → 250 ◦C
at 10 ◦C/min, 10 min at 250 ◦C), Agilent 5973 (Mass selective
detector). 1H and 13C NMR: Bruker AV-360 and AV-500.
Chemical shifts are reported relative to tetramethylsilane as
internal reference. Apparent multiplets that occur as a result
of accidental equality of coupling constants to magnetically
non-equivalent protons are marked as virtual (virt.). The mul-
tiplicities of the 13C NMR signals were determined by DEPT
experiments. TLC: Merck glass sheets 0.25 mm silica gel 60-
F254. Detection by coloration with Bromocresol Green. Flash
chromatography: Merck silica gel 60 (230 – 400 mesh) (ca.
50 g for 1 g of material to be separated), eluent given in
brackets.
1-Methyl-3-piperidyl hexanoate (3b)
The reaction was carried out according to the general
procedure with 3-hydroxy-1-methylpiperidine (2b) (576 µl,
576 mg, 5.00 mmol). – Rf = 0.48 (DCM/MeOH, 12 : 1). –
1H NMR (360 MHz, CDCl3): δ = 0.87 (t, 3J = 6.3 Hz,
3 H, CH3CH2), 1.26 – 1.32 (m, 4 H, CH3CH2CH2), 1.40 –
1.47 (m, 1 H, CHCHHN), 1.55 – 1.64 (m, 3 H, CH2CH2CO /
CH2CHHN), 1.73 – 1.79 (m, 2 H, CHHNCHH), 2.24 – 2.33
(m, 7 H, CH2CO / CHHCHHN / NCH3), 2.38 – 2.43 (m,
1 H, CHHCHHN), 2.60 – 2.65 (m, 1 H, CH2CHHCHO),
4.85 – 4.90 (m, 1 H, CHO) ppm. – 13C NMR (90.6 MHz,
CDCl3): δ = 14.0 (q, CH3CH2), 22.4 (t, CH3CH2), 22.6 (t,
CH2CH2N), 24.8 (t, CH2CH2CO), 28.9 (t, CHCH2N), 31.4
(t, CH3CH2CH2), 34.6 (t, CH2CO), 46.5 (q, NCH3), 55.5 (t,
CH2CH2N), 59.3 (t, CH2CH2CHO), 69.−21(d, CHO), 173.5
˜
(s, CO) ppm. – IR (NaCl): ν = 2941 cm (vs, C-H), 2860
(s, C-H), 2783 (s, C-H), 1732 (vs, C=O), 1467 (s), 1245
(s), 1172 (vs, C-O), 1013 (s), 978 (m), 914 (w), 872, (m),
787 (w), 734 (w). – GC-MS (EI, 70 eV, tR = 13.2 min):
m/z(%) = 114 (1) [C6H12NO+], 99 (5) [C6H11O+], 97
(100) [C6H11N+]. – C12H23NO2 (213.32): calcd. C 67.57,
H 10.87, N 6.57; found C 67.21, H 11.03, N 6.57.
General procedure for preparation of esters 3
Amino alcohol 2 (5.0 mmol) was added to a refluxing so-
lution of hexanoic acid (6.31 ml, 5.81 g, 50.0 mmol), do-
decane (100 µl, 75.3 mg, 442 µmol) and Na2SO4 (6.0 g)
in toluene (40 ml). The corresponding ester 3 was obtained
from the reaction mixture of the kinetic experiment after
complete data collection (5 h). At ambient temperature the
reaction mixture was washed with saturated Na2CO3 (3 ×
50 ml), brine (50 ml) and was dried with Na2SO4. After fil-
3-(N,N-Dimethylamino)-1-propyl hexanoate (3c)
The reaction was carried out according to the general pro-
tration, the solvent was removed in vacuo and the residue cedure with 3-(N,N-dimethylamino)propanol (2c) (592 µl,
was purified by flash chromatography (silica, DCM/MeOH = 516 mg, 5.00 mmol). – Rf = 0.15 (DCM/MeOH, 12 : 1). –
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587
1H NMR (360 MHz, CDCl3): δ = 0.87 (t, 3J = 6.9 Hz, CHHCHHCHHCHHCH), 1.61 (virt. qu, J 7.4 Hz, 2 H,
3
∼
=
3 H, CH33CH2), 1.23 – 1.36 (m, 4 H, CH3CH2CH2), 1.60 CH2CH2CO), 1.66 – 1.74 (m, 2 H, CHHCHHCH2CHN),
∼
(virt. qu,
J
7.5 Hz, 2 H, CH CH CO), 1.78 (virt. qu, 1.80 – 1.83 (m, 1 H, CHHCHN), 1.96 – 2.00 (m, 1 H,
=
2
2
3
∼
J
6.7 Hz, 2 H, CH CH N), 2.21 (s, 6 H, (CH ) N), CHHCHO), 2.27 – 2.31 (m, 2 H, CH2CO), 2.28 (s, 6 H,
=
2
2
3 2
2.27 (t, 3J = 7.5 Hz, 2 H, CH2CO), 2.32 (t, 3J = 7.5 Hz, N(CH3)2), 2.45 (dt, 3J = 3.6 Hz , 3J = 10.1 Hz , 1 H, CHN),
2 H, CH2N), 4.09 (t, 3J = 6.5 Hz, 2 H, CH2O) ppm. – 4.83 (dt, 3J = 4.5 Hz, 3J = 10.1 Hz, 1 H, CHO) ppm. –
13C NMR (90.6 MHz, CDCl3): δ = 14.0 (q, CH3CH2), 22.4 13C NMR (90.6 MHz, CDCl3): δ = 14.1 (q, CH3CH2), 22.5
(t, CH3CH2), 24.8 (t,CH2CH2CO), 27.1 (t,CH2CH2N), 31.4
(t, CH3CH2CH2), 34.4 (t, CH2CO), 45.5 (s, (CH3)2N), 56.4
(t, CH2N), 62.−71(t, CH2O), 174.0 (s, CO) ppm. – IR (NaCl):
2765 (s, C-H), 1737 (vs, C=O), 1462 (s), 1387 (m), 1246 (s),
1173 (vs, C-O), 1099 (s), 1042 (s), 902 (w), 839 (w), 734
(w). – GC-MS (EI, 70 eV, tR = 12.0 min): m/z(%) = 201
(1) [M+], 99 (1) [C6H11O+], 84 (3) [C5H10N+], 58 (100)
[C3H8N+]. – C11H23NO2 (201.31): calcd. C 65.63, H 11.52,
N 6.96; found C 65.53, H 11.68, N 7.01.
(t, CH3CH2), 24.3 (t, CH2CH2CHO), 24.8 (t, CH2CHN*),
24.8 (t, CH2CH2CO*), 24.9 (t, CH2CH2CHN*), 31.4 (t,
CH3CH2CH2), 31.8 (t, CH2CHO), 35.0 (t, CH2CO), 41.2 (q,
˜
ν = 2957 cm (vs, C-H), 2860 (s, C-H), 2816 (s, C-H),
(CH3)2N), 66.0 (d, CHN), 72.5 (d, CHO), 173.5 (s, CO) ppm.
−1
˜
– IR (NaCl): ν = 2932 cm (vs, C-H), 2860 (s, C-H), 2827
(m, C-H), 2780 (m, C-H), 1732 (vs, C=O), 1452 (m), 1378
(m), 1245 (m), 1176 (s, C-O), 1048 (m), 953 (m), 871 (m). –
GC-MS (EI, 70 eV, tR = 14.8 min): m/z(%) = 241 (6) [M+],
142 (22) [(M – C6H11O)+], 125 (35) [C8H15N+], 99 (11)
[C6H11O+], 84 (100) [C5H10N+]. – C14H27NO2 (241.37):
calcd. C 69.66, H 11.27, N 5.80; found C 69.33, H 11.34,
N 5.95.
2-(N,N-Dimethylamino)-2-methylpropyl hexanoate (3d)
The reaction was carried out according to the general pro-
cedure with 2-(N,N-dimethylamino)-2-methyl-1-propanol
(2d) (586 mg, 5.0 mmol). – Rf = 0.23 (DCM/MeOH, 12 : 1).
Kinetic studies
All reactions were carried out according to the general
procedure and data collection started with the addition of
the alcohol (t = 0 min). A sample (0.3 ml) was taken every
ten minutes in the first hour of the esterification and subse-
quently every 30 min. The data collection was stopped af-
ter four hours. The samples were filtered over basic alumina
with ethyl acetate as eluent and analyzed by gas chromatog-
raphy. Dodecane was used as the internal standard. Calibra-
tion curves for dodecane and the esters were constructed
with concentrations injected into the GLC ranging from 0.1
to 3.0 µl/ml ethyl acetate (r2 = 0.995 – 0.999 in all cases).
Dodecane and the esters were calibrated to correlate area
percentage and concentration of each compound. With the
knowledge of the theoretical concentration of dodecane in
the reaction mixture and its measured concentration after fil-
tration, a dilution factor can be calculated which allows to
work back to the concentration of the ester in the reaction
mixture from the measured concentration of the ester after
filtration.
–
1H NMR (360 MHz, CDCl3): δ = 0.87 (t, 3J = 7.0 Hz,
3 H, CH3CH2), 1.05 (s, 6 H, (CH3)2C), 1.24 – 1.33 (m,
4 H, CH3CH2CH2), 1.61 (virt. qu, 3J
7.5 Hz , 2 H,
∼
=
CH2CH2CO), 2.28 (s, 6 H, (CH3)2N), 2.32 (t, 3J = 7.5 Hz,
2 H, CH2CO), 3.97 (s, 2 H, CH2O) ppm. – 13C NMR
(90.6 MHz, CDCl3): δ = 14.0 (q, CH3CH2), 20.8 (q,
(CH3)2C), 22.4 (t, CH3CH2), 24.8 (t, CH2CH2CO), 31.4 (t,
CH3CH2CH2), 34.5 (t, CH2CO), 39.0 (q, (CH3)2N), 56.1 (s,
(CH3)2C), 69.−01(t, CH2O), 174.0 (s, CO) ppm. – IR (NaCl):
˜
ν = 2957 cm (vs, C-H), 2872 (s, C-H), 2825 (s, C-H),
2783 (s, C-H), 1740 (vs, C=O), 1465 (m), 1462 (m), 1244
(m), 1170 (vs, C-O), 1097 (m), 1017 (m). – GC-MS (EI,
70 eV, tR = 12.4 min): m/z(%) = 100 (8) [C6H14N+], 99 (3)
[C6H11O+], 86 (100) [C5H12N+]. – C12H25NO2 (215.33):
calcd. C 66.93, H 11.70, N 6.50; found C 66.60, H 11.92,
N 6.43.
trans-2-(N,N-Dimethylamino)cyclohexyl hexanoate (3e)
Acknowledgements
The reaction was carried out according to the general
procedure with trans-2-(N,N-dimethylamino)cyclohexanol
This work has been generously supported by the BASF
(2e) (716 mg, 5.00 mmol). – Rf = 0.35 (DCM/MeOH, AG (Ludwigshafen). We thank Drs. M. Gerst, K. Michl, and
12 : 1). – 1H NMR (360 MHz, CDCl3): δ = 0.88 (t, 3 H,
B. Reck for valuable discussions and their continuing interest
in this research.
3J = 6.9 Hz, CH3CH2), 1.16 – 1.36 (m, 8 H, CH3CH2CH2 /
[1] J. Otera, Esterification, Wiley-VCH, Weinheim (2003).
[2] C. K. Ingold, Structure and Mechanism in Organic
Chemistry, p. 1129 – 1131, 2nd ed., Cornell University
Press, New York (1969).
[3] R. Fuessl, B. Meyer-Roscher, M. Gerst, E. Smink
(BASF AG, Germany), Ger. Offen. 10253498 (2003);
Chem. Abstr. 139, 70148 (2003).
Unauthenticated
Download Date | 2/11/16 2:20 AM

588
S. Breitenlechner – T. Bach · Kinetic Study on the Esterification of Hexanoic Acid
[4] S. Miyano, L. D.-L. Lu, S. M. Viti, K. B. Sharpless,
J. Org. Chem. 50, 4350 (1985).
[7] a) G. F. Holland, R. C. Durant, S. L. Friess, B. Witkop,
J. Am. Chem. Soc. 80, 6031 (1958); b) B. Hansen,
Acta Chem. Scand. 16, 1927 (1962); c) M. M.
Werber, Y. Shalitin, Bioorg. Chem. 2, 202 (1973);
d) E. Scha¨tzle, M. Rottenberg, M. Thu¨rkauf, Helv.
[5] R. A. Wanat, C. C. Crabb (Rohm & Haas Co.), U.S. Pat.
5063259 (1991). Chem. Abstr. 116, 7571 (1992).
[6] Uncatalyzed esterification reactions employing 2-
amino alcohols: a) R. Stevens, J. Org. Chem. 23, 301
(1958); b) J. H. Billmann, J. L. Rendall, J. Am. Chem.
Soc. 66, 745 (1944); c) G. Bouilloux, Bull. Soc. Chim.
Fr. 547 (1957); d) G. Bouilloux, Bull. Soc. Chim. Fr.
1446 (1958); e) E. D. Petrov, O. P. Blinkova, J. Gen.
Chem. USSR 34, 3963 (1964).
¨
Chim. Acta 42, 1708 (1959); e) A. Agren, U. Hed-
sten, B. Jonsson, Acta Chem. Scand. 15, 1532 (1961);
f) E. R. Garrett, J. Am. Chem. Soc. 80, 4049 (1958).
[8] Y. Kiso, T. Hirokawa, Chem. Lett. 323 (1980).
[9] F. Wang, L. M. Sayre, J. Am. Chem. Soc. 114, 248
(1992).
Unauthenticated
Download Date | 2/11/16 2:20 AM