Christopher Cox

Harald Wack

Thomas Lectka

CiteSeerX

COMMUNICATIONS
798  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 1433-7851/99/3806-0798 $ 17.50+.50/0 Angew. Chem. Int. Ed. 1999, 38, No. 6
Strong Hydrogen Bonding to the Amide
Nitrogen Atom in an ªAmide Proton Spongeº:
Consequences for Structure and Reactivity**
Christopher Cox, Harald Wack, and Thomas Lectka*
The carbonyl oxygen atom of the amide functional group is
universally believed to be the thermodynamically preferred
site of protonation in amides;[1] however, N protonation has
been proposed to play a key role in biologically important
reactions of peptides and proteins such as acid-catalyzed
peptide hydrolysis[2] and cis ± trans isomerization about the
CÿN bond.[3] Extensive research into the mechanism of acid-
catalyzed amide hydrolysis has led to the belief that the
O-protonated form is generally the important intermediate on
the pathway to hydrolysis.[4] Still, evidence supporting N
protonation in certain cases,[2] as well as in the related thiol-
catalyzed amide hydrolysis reactions important in cysteine
proteases,[5] has also been reported. N-Protonated amides
have thus far eluded characterization, probably because they
are disfavored thermodynamically relative to the O-proto-
nated form by about 7 pKa units in aqueous solution.[6] Even
species showing strong hydrogen bonding between a donor
and the amide N atom are unknown.[7] Herein we present the
first spectroscopic and crystallographic characterization of a
strong hydrogen bond between a charged donor (a protonated
amine) and an amide nitrogen atom in a model system, and
also disclose unusual reactivity of the amide functionality that
stems from this interaction.
We designed system 1 in which a protonated amine group
can act as a donor suitably positioned to engage in a strong
intramolecular hydrogen bond with the amide nitrogen atom
rather than with the carbonyl oxygen atom [Eq. (1)].[8]
Compound 1 is based on the venerable ªproton spongeº 2
NN
H3C
CH3
CH3
R
O
N
H
N
H3C
CH3
CH3
R
O
HOTf
+
TfO
+1 1-H
(1)
whose exceptional basicity arises from destabilization in the
free base due to electron ± electron repulsion and also from
formation of a strong intramolecular hydrogen bond upon
protonation.[9] ªAmide proton spongeº 1 is available in two
steps from 1,8-diaminonaphthalene,[10] and we propose the
isomeric 1,5-naphthalene 3 as a control compound to factor
out through-bond inductive effects of the electron-withdraw-
ing protonated amine.
The 1H NMR spectrum of 1 a in [D3]acetonitrile in the
presence of one equivalent of trifluoromethanesulfonic acid
(HOTf) displayed a broad signal due to one proton at d 11.0,
whereas the analogous signal in control 3 a under the same
conditions appeared at d 9.4, a difference that hints at the
presence of an intramolecular hydrogen bond between the
protonated amine group and the amide N atom in 1 a-H
[Eq. (1)].[11] Additional support for N coordination of a
proton is provided by 13C NMR spectroscopy of 1 a-H in
which the carbonyl carbon atom is 13C-labeled. Before
addition of acid, labeled 1 a shows amide carbonyl peaks at
d 170.2 and 171.3 corresponding to both the cis and trans
forms of the amide; however, upon protonation the peaks
coalesced and shifted downfield to d 175.0,[12] consistent
with the formation of a more ketone-like carbonyl group. The
fact that both 1 a and 3 a are fully protonated by one
equivalent of HOTf in acetonitrile is confirmed by UV/Vis
spectroscopy.[10]
NNH3C
H3C
CH3
CH3
N
N(CH3)2
R
CH3
O
NN
H3C
CH3
CH3
R
O
3a  R = Ph
3b  R = 2-FC6H4
2 31
1a  R = Ph
1b  R = 2-FC6H4
Evidence supporting hydrogen bonding to the amide N
atom under these conditions was also obtained by means of IR
spectroscopy. Upon protonation of 1 a in [D3]acetonitrile, the
amide CO stretch shifts47 cmÿ1 from 1637 to 1684 cmÿ1. It
has been previously proposed that a shift of this so-called
amide I stretch to higher wavenumber is strong evidence for N
coordination, if it could be validated that the peaks are
correctly assigned.[13] To support our interpretation, we
investigated 13C-labeled 1 a under identical conditions and
found that the 13CO peak moves from 1597 to 1644 cmÿ1,
again a difference of 47 cmÿ1, confirming our assignment.
Upon protonation of 3 a, the CO stretch undergoes a small
shift of <5 cmÿ1, indicating that the 47 cmÿ1 shift observed
for 1 a-H is not due to inductive effects.
We also obtained the single-crystal X-ray structure of 1 b-
H (Figure 1) that clearly shows the hydrogen atom (H1A)
placed between the amine nitrogen atom (N1A) and the
amide nitrogen atom (N2A).[14] The N2A ± H1A distance of
2.17  and the N2A-H1A-N1A angle of 1368 in 1 b-H (as
determined by isotropic refinement of H1A's position)
classifies the interaction as a moderately strong hydrogen
bond by Jeffreys criteria.[15] Further evidence supporting the
strong hydrogen bond was obtained by examination of the
pyramidalization of the amide nitrogen atom (N2A) upon
protonation and comparison to that of the free base 1 b, whose
X-ray structure was also solved.[16] As expected, 1 b contains a
planar amide unit, as characterized by summation of the three
[*] Prof. Dr. T. Lectka, C. Cox, H. Wack
Department of Chemistry, Johns Hopkins University
Baltimore, Maryland 21218 (USA)
Fax: (1) 410-516-8420
E-mail : lectka@jhunix.hcf.jhu.edu
[**] T.L. thanks the National Institutes of Health (R29 GM54348) and the
American Cancer Society for support of this work, and Eli Lilly for a
Young Faculty Grantee Award. C.C. thanks the Organic Division of
the ACS for a Graduate Fellowship sponsored by Organic Reactions,
Inc. (1997 ± 98) and JHU for a Kilpatrick Fellowship (1998 ± 99). The
authors thank Professor John Toscano for use of his FTIR and UV/Vis
spectrometers and Dr. Victor G. Young, Jr., director of the X-ray
Crystallographic Laboratory at the University of Minnesota, for
solving the structures of 1 b and 1b-H.
COMMUNICATIONS
Angew. Chem. Int. Ed. 1999, 38, No. 6  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 1433-7851/99/3806-0799 $ 17.50+.50/0 799
Figure 1. X-ray structure of the triflate salt of 1 b-H (50 % ellipsoids).[14]
The unit cell consists of two molecules of 1b-H, two triflate counterions,
and one molecule of water. All hydrogen atoms, except for H1A, have been
excluded for clarity. The dashed line indicates the proposed hydrogen bond
between H1A and N2A. Selected bond lengths [] and angles [8]: N2A ±
H1A 2.17(4), N1A ± N2A 2.869(5), C14A ± N2A 1.369(5); N2A-H1A-N1A,
136(3)8.
valence angles around N2, V 359.98 (perfectly planar
3608), and the out-of-plane angle, a 7.58 (perfectly
planar 08).[17] On the other hand, 1 b-H displays V
349.48 and a 36.08, values that correspond very closely to
pyramidalized amides based on strained bicyclic systems.[17]
Thus, 1 b-H is a rare case of a highly distorted amide whose
pyramidalization is not the result of a strained backbone.
The first clue to the interesting reactivity of 1-H was
discovered while we were attempting to obtain diffractable
crystals of the hydrochloride salt of 1 a. After bubbling
anhydrous HCl through a solution of 1 a in CH2Cl2 for one
minute and storing the test tube in the dark for three days, we
did not observe crystallization but instead noted the presence
of benzoyl chloride [Eq. (2)]. The conversion in this process
NN
H3C
CH3
CH3
Ph
O
N
H
N H
H3C
CH3
CH3
COCl
Cl
+
+
1a
(2)
 HCl
CH2Cl2 or THF
4-H
was low, but when we performed the reaction in THF with
gentle heating to 50 8C for 30 h, the reaction became
quantitative based on recovery of 8-methylamino-1-dimethyl-
aminonaphthalene hydrochloride 4-H.[18] Under the same
conditions control 3 a is inert, underscoring the importance of
the strategically placed hydrogen bond in 1 a-H. To our
knowledge, this is the only case where HCl reverts an amide to
an acid chloride and amine salt, a transformation that can be
thought of as the ªreverseº of normal peptide bond formation.
A second novel reaction of 1 is the PhSH-mediated
conversion to 4 and thioester 5 [Eq. (3)]. Upon heating 1 a
with 10 equivalents of PhSH in a thoroughly degassed 50/50
mixture of tBuOH/water under a nitrogen atmosphere in a
pressure tube at 125 8C for 48 h, we observed 55 % conversion
of 1 a to 4, as indicated by HPLC analysis of the crude
reaction.
NN
H3C
CH3
CH3
Ph
O
NN H
H3C
CH3
CH3
COSPh
5
+ (3)
1a 4
PhSH
tBuOH/H2O
The following control reactions were also run under
identical conditions: 1) one equivalent of HOTf was added
along with 1 a and PhSH; and 2) control 3 a was used instead
as the substrate, both with 10 mol % triethylamine and
without. In each control there was no indication of any
reaction, which suggests a mechanism in which a small
amount of PhSH is deprotonated by 1 a and the PhSÿ
subsequently attacks the amide carbonyl group to yield
products. To our knowledge, this is the first example of the
thiolysis of an unstrained, nonactivated amide under neutral
conditions by a monofunctional thiol, and supports Browns
mechanistic hypothesis that the thiol-mediated cleavage of
amides is subject to rate-limiting proton transfer to a
tetrahedral intermediate from a properly aligned general
base.[19] The 1-PhSH system therefore appears to be a mimetic
for the active site of cysteine proteases in which Cys 25 and
His 159 form a highly nucleophilic thiolate/imidazolium ion
pair that is proposed to be the active species in these
enzymes.[20]
In contrast to the results with HCl in organic solvents, the
triflate salt of protonated amide 1 a-H in aqueous solution
showed a surprising lack of reactivity. In the presence of one
equivalent of HOTf in a 50/50 mixture of EtOH/H2O, 1 a
underwent no reaction, even when heated to 150 8C for 24 h in
a pressure tube. The lack of reactivity in this case supports the
hypothesis that the O-protonated form is the intermediate on
the pathway to acid-catalyzed amide hydrolysis.[4] Further
studies on the protonation of amide nitrogen atoms and the
novel reactivity of amide sponges 1 are currently underway.[21]
Received: October 21, 1998 [Z 12556 IE]
German version: Angew. Chem. 1999, 111, 864 ± 867
Keywords: amides ´ hydrogen bonding ´ naphthalenes ´
proton sponges
[1] R. B. Homer, C. D. Johnson in The Chemistry of Amides (Ed.: J.
Zabicky), Wiley, New York, 1970, chap. 3.
[2] a) C. J. Giffney, C. J. OConnor, Aust. J. Chem. 1976, 29, 307 ± 314;
b) L. M. Jackman, T. E. Kavanagh, R. C. Haddon, Org. Magn. Reson.
1969, 1, 109 ± 123. c) Brown et al. have also shown that for some highly
distorted amides at low pH, attack by H2O on an N-protonated amide
is likely: Q.-P. Wang, A. J. Bennet, R. S. Brown, B. D. Santarsiero, J.
Am. Chem. Soc. 1991, 113, 5757 ± 5765, and references therein.
[3] a) R. L. Stein, Adv. Protein Chem. 1993, 44, 1 ± 24; b) J. T. Gerig,
Biopolymers 1971, 10, 2435 ± 2443; c) I. Z. Steinberg, W. F. Harring-
ton, A. Berger, M. Sela, E. Katchalski, J. Am. Chem. Soc. 1960, 82,
5263 ± 5279.
[4] R. S. Brown, A. J. Bennet, H. Slebocka-Tilk, Acc. Chem. Res. 1992, 25,
481 ± 488.
[5] a) B. A. Kellogg, A. A. Neverov, A. M. Aman, R. S. Brown, J. Am.
Chem. Soc. 1996, 118, 10829 ± 10837; b) G. A. Dafforn, D. E.
Koshland, Jr., J. Am. Chem. Soc. 1977, 99, 7246 ± 7257.
[6] The pKa value of an O-protonated amide is close to zero, whereas an
N-protonated amide has a pKa value of about ÿ7; see: A. J. Williams,
J. Am. Chem. Soc. 1976, 98, 5645 ± 5651.
COMMUNICATIONS
800  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 1433-7851/99/3806-0800 $ 17.50+.50/0 Angew. Chem. Int. Ed. 1999, 38, No. 6
A Novel Phenylene Topology: Total Syntheses
of Zigzag [4]- and [5]Phenylene**
Christian Eickmeier, Daniel Holmes, Heiko Junga,
Adam J. Matzger, Frank Scherhag, Moonsub Shim, and
K. Peter C. Vollhardt*
Missing from the phenylene topologies hitherto synthe-
sizedÐlinear, angular, and trigonal[1]Ðis the zigzag variant,
exemplified by the title compounds 1 a and 2 a. These
molecules are important as substructure models for the one-
dimensional, zigzag phenylene polymer,[2] the two-dimen-
sional all-carbon net based on the anti-kekulene motif,[1c, 2a, 3]
and the three-dimensional carbon allotropes Oh-C48[4] and Ih-
C120 (archimedene).[5] They are also interesting as members of
a family of phenylene isomers with different topologies, in
particular in comparison to their angular relatives in which
[7] Texter et al. examined hydrogen bonding in the crystal structures of 42
proteins solved at high resolution provided eight examples where
there are strongly basic residues (Lys, Arg, His) within 4  of a proline
nitrogen atom that could result in hydrogen bonding to amide
nitrogen atoms; see: F. L. Texter, D. B. Spencer, R. Rosenstein, C. R.
Matthews, Biochemistry 1992, 31, 5687 ± 5691.
[8] Related 1,8-disubstituted naphthalenes have been reported by Kirby
to undergo intramolecular proton transfer catalysis in acetal and
enol ether hydrolysis; see: A. J. Kirby, Acc. Chem. Res. 1997, 30, 290 ±
296.
[9] a) F. Hibbert, J. Emsley, Adv. Phys. Org. Chem. 1990, 26, 255 ± 379;
b) R. W. Alder, Chem. Rev. 1989, 89, 1215 ± 1223; c) H. A. Staab, T.
Saupe, Angew. Chem. 1988, 100, 895 ± 909; Angew. Chem. Int. Ed.
Engl. 1988, 27, 865 ± 879. For the orignal report describing the
exceptional properties of 2, see: d) R. W. Alder, P. S. Bowman,
W. R. S. Steele, D. R. Winterman, J. Chem. Soc. Chem. Commun.
1968, 723 ± 724.
[10] See the Supporting Information for details.
[11] The magnitude of the downfield shift of a hydrogen-bound proton is
related to the strength of the bond; see: J. Emsley, J. Chem. Soc. Rev.
1980, 9, 91 ± 125. No coupling was observed in 1 a-H between the N-H
proton and the methyl protons of the dimethylamino group, as is often
noted for the protonated proton sponge 2.[9]
[12] The observation that the resonances for the cis and trans isomers
coalesce to one upon protonation is consistent with previous reports
that predict a lower barrier to rotation about the C ± N bond when an
amide is N-coordinated to a Lewis acid. See, for example: a) C. Cox, T.
Lectka, J. Am. Chem. Soc. 1998, 120, 10660 ± 10668; b) C. Cox, V. G.
Young, Jr., T. Lectka, J. Am. Chem. Soc. 1997, 119, 2307 ± 2308; c) C.
Cox, D. Ferraris, N. N. Murthy, T. Lectka, J. Am. Chem. Soc. 1996, 118,
5332 ± 5333.
[13] a) G. A. Olah, A. M. White, D. H. OBrien, Chem. Rev. 1970, 70, 561 ±
591. b) The amide I band is primarily a CO stretch, and a relationship
between CO bond length and uCO has been found; see A. J. Bennet,
V. Somayaji, R. S. Brown, B. D. Santarsiero, J. Am. Chem. Soc. 1991,
113, 7563 ± 7571.
[14] a) The unit cell consists of two molecules of 1 b-H, two triflate
counterions, and one molecule of water. X-ray crystal data for
compound 1 b-H, grown by slow diffusion of Et2O into a solution of
1b-H in acetone: C21H21F4N2O4.50S, Mr 481.46, yellow block (0.30
0.26 0.21 mm), triclinic, P1Å, a 12.5179(2), b 12.9868(1), c
14.3698(2) , a 87.722(1), b 66.638(1), g 89.306(1)8, V
2142.84(5) 3, Z 4, 1calcd 1.492 Mgmÿ3, F(000) 996, Siemens
SMART Platform CCD, MoKa radiation, l 0.71073 , T
173(2) K, 10567 reflections collected, 7152 independent reflections,
structure solved by direct methods, difference Fourier synthesis, and
full-matrix least-squares on F 2 (SHELXTL-V5.0). R1 0.0704,
wR2 0.1688 for 4744 reflections; the hydrogen atoms on N1A and
N1B were located in the Fourier difference map and refined isotropi-
cally, all other hydrogens were placed in ideal positions and refined as
riding atoms; one of the triflate anions has significant disorder caused
by a rocking motion. b) Crystallographic data (excluding structure
factors) for the structures reported in this paper have been deposited
with the Cambridge Crystallographic Data Center as supplementary
publication no. CCDC-104129 (1b-H) and CCDC-104130 (1b).
Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (44) 1223-
336-033; e-mail : deposit@ccdc.cam.ac.uk).
[15] Jeffreys definition of a ªmoderately strong hydrogen bondº is
inclusive of most biologically relevant interactions, such as the more
common hydrogen bonding mode available to amides wherein the
oxygen atom is the acceptor; see: G. A. Jeffrey, An Introduction to
Hydrogen Bonding, Oxford, New York, 1997, chap. 2.
[16] X-ray crystal data for compound 1b, grown by slow evaporation of
Et2O: C20H19FN2O, Mr 322.37, colorless block (0.33 0.24
0.20 mm), monoclinic, P21/c, a 8.1527(2), b 10.2495(3), c
19.5690(6) , b 90.305(1)8, V 1635.18(8) 3, Z 4, 1calcd
1.309 Mg mÿ3, F(000) 680, Siemens SMART Platform CCD, MoKa
radiation, l 0.71073 , T 173(2) K, 7755 reflections collected,
2819 independent reflections, structure solved by direct methods,
difference Fourier synthesis, and full-matrix least-squares on F 2
(SHELXTL-V5.0). R1 0.0554, wR2 0.1196 for 2063 reflections;
all hydrogen atoms were placed in ideal positions and refined as riding
atoms; disorder was found in the position of the fluorine atom.[14b]
[17] T. Ohwada, T. Achiwa, I. Okamoto, K. Shudo, K. Yamaguchi,
Tetrahedron Lett. 1998, 865 ± 868.
[18] No transesterification products attributable to ring-opened THF were
detected.
[19] a) J. W. Keillor, A. A. Neverov, R. S. Brown, J. Am. Chem. Soc. 1994,
116, 4669 ± 4673; b) J. W. Keillor, R. S. Brown, J. Am. Chem. Soc. 1992,
114, 7983 ± 7989; c) J. W. Keillor, R. S. Brown, J. Am. Chem. Soc. 1991,
113, 5114 ± 5116.
[20] H.-H. Otto, T. Schirmeister, Chem. Rev. 1997, 97, 133 ± 171.
[21] We have recently demonstrated that sponge 1 b-H undergoes
dramatic intramolecular catalysis of amide isomerization in aqueous
solution: C. Cox, H. Wack, T. Lectka, unpublished results.
[*] Prof. Dr. K. P. C. Vollhardt, Dr. C. Eickmeier, D. Holmes,
Dr. H. Junga, Dr. A. J. Matzger, Dr. F. Scherhag, M. Shim
Department of Chemistry, University of California at Berkeley
and
The Chemical Sciences Division, Lawrence Berkeley National
Laboratory
Berkeley, CA 94720 (USA)
Fax: (1) 510-643-5208
E-mail : vollhard@cchem.berkeley.edu
[**] This work was supported by the National Science Foundation (CHE-
9610430). C.E. and F.S. thank the Deutsche Forschungsgemeinschaft
for postdoctoral fellowships. A.J.M. was a Syntex predoctoral (1994 ±
1995) and an ACS Division of Organic Chemistry Graduate Fellow
(1995 ± 1996), the latter sponsored by Rohm and Haas Co. We are
indebted to Dr. K. Oertle (Ciba-Geigy AG) for a gift of chlorodi-
methyl(1,1,2-trimethylpropyl)silane and Professors J. M. Schulman
and P. von R. Schleyer for preprints of their work.


Strong hydrogen bonding to the amide nitrogen atom in an amide proton sponge. Consequence for structure and reactivity

http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=5183AC268C1F02F8ADC0F431AD247F72?doi=10.1.1.1049.6801&rep=rep1&type=pdf

Strong hydrogen bonding to the amide nitrogen atom in an amide proton sponge. Consequence for structure and reactivity

Abstract

Similar works

Full text

Available Versions

CiteSeerX