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Kinetic Investigation of Peptide Coupling.

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Kinetic Investigation of Peptide Coupling[**]
By Manfred Mutter and Hanspaul HagenmaierC'1
Very little has so far been published on the kinetics of individual peptide coupling reactions['], though a knowledge of
such is always essential in the optimization of peptide syntheses. To the best of our knowledge IR spectroscopy has
not previously been used for such investigations. The principle
can be illustrated with a few examples. In peptide syntheses
with symmetric anhydrides"] the anhydride band at 18101820cm-' becomes weaker, while an amide band appears
between 1640 and 1700cm
_ _ - _- _ _ _ b
e. g . peptide syntheses on solid supports131. The simplicity
of the procedure would suggest far reaching possibilities for
the application of IR spectroscopy to kinetic investigations.
Received: October 29, 1973 [Z 968 IE]
German version: Angew. Chem. 86. 163 (1974)
113 J . J . Maher, M . E. Furry, and L. J .
Greenberg, Tetrahedron Lett. 1971.
27; R. H . Andreatta and H . Rink, Helv. Chim. Acta 56, 1205 (1973); E.
Bayer, M . Mutter, R. Uhmann, J . Polster and H . Mausrr, J. Amer. Chem.
SOC.,in press.
[2] H . Schiissler and H . Zahn, Chem. Ber. 95, 1076 (1962); H . Hagrnmairr
and H . Frank, Hoppe-Seylers Z. Physiol. Chem. 353, 1973 (1972).
[3] R. B. M e r r i j d d , Advan. Enzymol. 32, 221 (1969).
[4] M . Mutter. H . Hagrnmaier, and E . Bayrr, Angew. Chem. 83, 883 (1971):
Angew. Chem. internat. Edit. 10,81 I (1971); M . Muzter and E . Bayer, Nature
237, 512 (1972): Angew. Chem. 86, 101 (1974); Angew. Chem. internat. Edit.
13, 88 ( 1974).
Novel Ligand Systems for Complexing Alkali Metal
t [ S I A
Fig. I . Trace of coupling reactions by the "stop-flow" method in the region
of theamide band (1635--1645cm-'). Total concentration of reagents: lo-'
mol/l in methylene chloride. PEG = polyethylene glycol. In brackets: relative
reaction rate u,., . a ) Dibutylamine+Boc-Pro-anhydride (1.00); b) H-GIyOC2H5+Ac2O (1.64); c) H-Pro-PEG [4] + A c 2 0 (2 57); d) Dibutylamine +Ac,O (1.36). Equal volumes of the reaction solutions were fed together
by means of a dual-piston pump into an an arrow-shaped mixing block
and pumped through the flow cuvette (layer thickness 0.2mm, NaCI).
Figures 1 and 2 show the kinetic course of a few coupling
(N-acylation) reactions. The change in the amide and anhydride band, respectively, for each reaction is plotted against
t Is1
Fig. 2. Kinetic course of the coupling reaction H-Gly-Ala-Pro-PEG ( l o - '
mol/l). Trace of the anhydride band at 1820cm-'. tirc]
(referred to reaction a in Fig. I ) = 1.1 1.
time. As expected, both curves yield the same rate constants.
For the determination of relative coupling rates firel., measurements can be performed in a concentration range from 10- '
mol/l. For absolute rate constants a calibration curve
must be recorded and the measurements carried out at higher
The change in the absorption bands can be measured directly
in the reaction solution by a flow technique. This method
is thus also suitable for monitoring heterogeneous reactions
Dr. M. Mutter and Prof. Dr. H. Hagenmaier
Chemisches Institut der Universitat
74 Tiibingen. Auf der Morgenstelle (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
Angew. Chem. internat. Edit. 1 Vol. 13 (1974) / No. 2
By Fritz Vogtle and Edwin Weberyl
Two fundamental types of neutral ligand systems for the specific complexing of alkali metal and alkaline earth metal salts
have been described in the last few years: crown ethers['.21
and cryptating agentsC3.1' . In the continuation of our studies
on medio- and macrocyclic pol yet her^^^] we have discovered
a series of novel ligand systems ( J ) - ( 4 ) , which specifically
complex alkali metal ions. The new ligand systems are readily
accessible under dilution-principle conditions without use of
the "template effect"['].
While sodium permanganate is instantaneously solubilized by
(2) (m.p. 90-91'C;
S=3.96) and (3) (m.p. 58-59'C;
6 = 3.87)[5.61, remarkably, KMnO, remains completely undissolved. In contrast to (2), (3) also renders NaMn04 soluble
in benzene. Lithium, rubidium, cesium, ammonium, and silver
salts are not solubilized by (2) and (3) in organic solvents.
Addition of sodium iodide to solutions of (3) in CDC13
leads to a down-field shift of the characteristic r-CHl singlet
by about 0.15ppm; an intense band appears at 1640cm-'
in the IR spectrum, and in the UV region a new band is
observed at 243nm, apart from the ligand absorption at
h= 273 nm.
In view of the observed Na+-specificity of compounds (2)
and (3) it is interesting to note the structural characteristics
that deviate from those of the usual crown ethers and cryptate
ligands; a) the metu-bridged aromatic ring, b) the spz nitrogen
as potential donor atom, and c) the heteroatom beta to the
aromatic ring. Highly informative is a comparison of the
18-membered cycles ( 3 ) , ( 5 ) (colorless viscous oil, S=4.25)
and (6) (colorless viscous oil; S=4.01) with [18]crown-6,
dibenzo[ 181crown-6; and dicyclohexyl[ 18]crown-6~"'1, which
[*] Prof Dr. F. Vogtle and DiplLChem. E. Weber
Institut fur Organische Chemie der Unlversitat
87 Wiirzburg, Am Hubland (Germany)
[**I This work was supported by the Fonds der Chemischen lndustrie
and the Deutsche Forschungsgemeinschaft.
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investigation, couplings, kinetics, peptide
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