Stable and Persistent Acyclic Diaminocarbenes with Cycloalkyl Substituents and Their Transformation to β-Lactams by Uncatalysed Carbonylation with CO

Article abstract of DOI:10.1002/chem.201805307

Four new acyclic diaminocarbenes (ADACs), viz. [(cyclo-C_nH_2n?1)₂N]₂C (n=5–7) and iPr₂N-C-N(cyclo-C₆H₁₁)₂, were synthesised by reacting the corresponding formamidinium

Full text of DOI:10.1002/chem.201805307

A Journal of
Accepted Article
Title: Stable and Persistent Acyclic Diaminocarbenes with Cycloalkyl
Substituents and Their Transformation to β-Lactams by
Uncatalysed Carbonylation with CO
Authors: Ulrich Siemeling, Lars Wallbaum, Daniel Weismann, Dennis
Löber, Clemens Bruhn, Pascal Prochnow, and Julia E.
Bandow
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To be cited as: Chem. Eur. J. 10.1002/chem.201805307
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1
Stable and Persistent Acyclic Diaminocarbenes with Cycloalkyl Substituents and Their
Transformation to -Lactams by Uncatalysed Carbonylation with CO
Lars Wallbaum,[a] Daniel Weismann,[a] Dennis Löber,[a] Clemens Bruhn,[a] Pascal
Prochnow,[b] Julia E. Bandow,[b] and Ulrich Siemeling*[a]
[a]
Dr. L. Wallbaum, Dr. D. Weisman, D. Löber, Dr. M. Leibold, Dr. C. Bruhn, Prof. Dr.
U. Siemeling
Institute of Chemistry, University of Kassel
Heinrich-Plett-Straße 40, 34132 Kassel (Germany)
E-Mail: siemeling@uni-kassel.de
[b]
P. Prochnow, Prof. Dr. J. E. Bandow
Biology of Microorganisms, Ruhr University Bochum
Universitätsstraße 150, 44801 Bochum (Germany)
Dedicated to Prof. Dietmar Stalke on the occasion of his 60th birthday
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Abstract: Four new acyclic diaminocarbenes (ADACs), viz. [(cyclo-CnH2n 1)2N]2C (n = 5 –

7) and iPr2NCN(cyclo-C6H11)2, were synthesised by reacting the corresponding
formamidinium hexafluorophosphates with NaN(SiMe3)2. Their nucleophilicities and
electrophilicities were respectively judged from the 1JCH values determined for the N2CH unit
of the corresponding formamidinium cations and from the 77Se NMR chemical shifts of the
selenourea derivatives obtained from the reaction of elemental selenium with the
corresponding ADACs. An ambiphilic profile essentially identical to that of the “Alder
carbene” (iPr2N)2C was found in each case. Similar to the latter carbene, the new ADACs
undergo a well-defined thermal decomposition by -fragmentation, affording an alkene and a
formamidine. The stabilities of [(cyclo-CnH2n 1)2N]2C depend strongly on the value of n,

following the order 6 > 5 > 7, with the latter congener being too unstable for isolation.
[(cyclo-C6H11)2N]2C shows no thermal decomposition at room temperature in solution and is
thus significantly more stable than (iPr2N)2C. The stability of iPr2NCN(cyclo-C6H11)2 is
intermediate between that of (iPr2N)2C and [(cyclo-C6H11)2N]2C, its -fragmentation
selectively affording propene and iPrN=CHN(cyclo-C6H11)2. [(cyclo-CnH2n 1)2N]2C (n = 5 –

7) react readily with CO under mild conditions, selectively affording trisubstituted spirocyclic
-lactam derivatives with an antimicrobial activity spectrum similar to that of penicillin G.
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Introduction
Acyclic diaminocarbenes (ADACs) are currently attracting increased attention.[1, 2] This may
be surprising at first glance, because the number of ADACs which are sufficiently stable for
isolation is very limited and only four crystallographically characterised examples are known
to date.[3] However, even (Me2N)2C, which is the sterically least encumbered ADAC that can
be generated as a free carbene in solution, is sufficiently persistent for follow-up chemistry.[2k,
4] The attractiveness of ADACs lies in their special steric and electronic properties,[1] which
are substantially different from those of the more familiar N-heterocyclic carbenes (NHCs).[5]
ADACs exhibit comparatively wide NCN angles (ca. 121[3] vs. ca. 100  106 for
standard five-membered ring NHCs[6]). Consequently, their substituents are positioned closer
to the divalent carbon atom, which may be advantageous for catalytic applications.[1c,f] In
terms of electronics, ADACs exhibit a much higher electrophilicity and nucleophilicity than
NHCs. ADACs are superior even to cyclic (alkyl)(amino)carbenes (CAACs)[7] in this
respect.[4a] Owing to their ambiphilic profile, CAACs are suitable for the activation of
fundamentally important small molecules like ammonia and carbon monoxide at room
temperature or below.[8] We recently found that ADACs, too, react with CO under very mild
conditions.[4b, 9] This behaviour is perfectly plausible in view of the similar electronic profiles
of CAACs and ADACs.[4a, 10] The primary carbonylation product of an ADAC is the
corresponding diaminoketene (R2N)2C=C=O, which is a transient species too unstable for
isolation.[10, 11] It is usually trapped through nucleophilic addition of unreacted ADAC,
affording a betainic oxyallyl compound of the type [(R2N)2C]2CO.[4b] This process is
unfavourable in sterically encumbered cases such as, for example, the iconic “Alder carbene”
(iPr2N)2C,[3c] where instead a retro-Wolff rearrangement of the diaminoketene takes place.[4b,
9b] The resulting transient (amido)(amino)carbene R2NCC(O)NR2[12] subsequently
undergoes an intramolecular CH insertion, affording a -lactam derivative. In addition to the
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previously unrecognised high reactivity of the “Alder carbene” towards carbon monoxide, we
also uncovered that this long-known ADAC is not stable at room temperature in solution, but
undergoes a -fragmentation, cleanly affording propene and N,N,N’-
triisopropylformamidine.[13] In the same vein, the unsymmetrical ADAC (iPr2N)C(PipMe2)
(PipMe2 = cis-2,6-dimethylpiperidino) reported by Herrmann and co-workers[14] was found to
show a carbonylation and -fragmentation behaviour strictly analogous to that of the “Alder
carbene”.[9a] This similarity in chemical behaviour is not at all surprising because the cyclic
amino group (PipMe2) can be viewed as a conformationally constrained version of the iPr2N
group. In contrast to these two isolable, but still highly reactive, dialkylamino-substituted
acyclic carbenes, alkyl(aryl)amino-substituted congeners (ArMeN)2C (Ar = mesityl,[3b] 2,6-
diisopropylphenyl[15]) reported by Bielawski and co-workers are significantly less reactive.
They show perfect thermal stability at room temperature. Similar to the widely used and
highly popular NHCs, they are inert towards carbon monoxide.[16] This may be ascribed to
their comparatively low electrophilicity, as indicated by the 77Se NMR signal of the
corresponding selenium adducts[17] located at ca. 400 ppm.[3a] This value is already at the low-
field end of the region typical of selenium adducts of NHCs.[18] Selenium adducts of other
acyclic diaminocarbenes exclusively exhibit signals at significantly lower field ( ca. 450
ppm).[3a] According to the “selenium scale”, diamidocarbenes are considerably more
electrophilic than ADACs, since their selenium adducts show signals at extremely low field
(ca. 850 ppm).[17a] However, this enhanced electrophilicity coincides with attenuated
nucleophilicity lower than that of prototypical NHCs.[19] Note that these carbenes do not tend
to form stable carbonylation products and thus apparently lack the ambiphilic profile
necessary for this reaction.[10, 20, 21] We herein describe the synthesis and chemical properties
of three ADACs of the type [(cyclo-CnH2n 1)2N]2C (1a – c; n = 5, 6, 7). These compounds are

the first cycloalkyl-substituted ADACs. They are akin to the “Alder carbene”, since a
cycloalkyl substituent can be viewed as a conformationally constrained version of an
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isopropyl substituent (Figure 1). While the steric parameter of a cyclohexyl group is identical
to that of an isopropyl group on Beckhaus’ Sf scale (2.29), the steric impact of a cyclopentyl
(Sf = 1.81) and a cycloheptyl group (Sf = 2.94) is respectively lower and higher than that.[22]
C
C
N
N
N
N
1a - c
=
a
b
c
Figure 1. Analogy between the “Alder carbene” (iPr2N)2C and the ADACs of type 1 studied
in this work.
Results and Discussion
Synthesis
Free ADACs are usually generated by deprotonation of the corresponding formamidinium
salts,[23] which is also the most widely used method for the synthesis of NHCs.[24] The use of
hexafluorophosphate as counter anion is known to facilitate the purification of these most
popular diaminocarbene precursors.[25] The ADAC precursors of the type 1H[PF6] were
synthesised according to the protocol developed by Alder and co-workers (Scheme 1).[25]
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PF6
H
R
R
R
R
NH
N
R
N
R
R
1H[PF6]
O
Cl
a cyclopentyl
b cyclohexyl
c cycloheptyl
R
R
N
R
N
R
Cl
Scheme 1. Synthesis of the ADAC precursors of the type 1H[PF6].
The sequence starts from the secondary amines (cyclo-CnH2n 1)2NH (n = 5, 6, 7). The

respective amine was transformed to the formamide (cyclo-CnH2n 1)2NCHO with formic

acid. Subsequent activation of the formamide with oxalyl chloride afforded the Vilsmeyer
complex [(cyclo-CnH2n 1)2N=CHCl]Cl, which was then reacted with (cyclo-CnH2n 1)2NH to


afford the formamidinium chloride 1HCl. One equivalent of triethylamine was used to mop
up the hydrogen chloride produced in the latter step. Finally, an anion exchange was
performed with ammonium hexafluorophosphate. 1bH[PF6] and 1cH[PF6] were structurally
characterised by single-crystal X-ray diffraction (vide infra).
The target ADACs were generated by treatment of the respective formamidinium
hexafluorophosphate with sodium bis(trimethylsilyl)amide. The three carbenes show
markedly different thermal stabilities. Only 1b could be isolated in crystalline form and was
structurally characterised by single-crystal X-ray diffraction (vide infra). In view of the -
fragmentation observed for the “Alder carbene” already at room temperature (vide supra), we
were surprised to find that the cyclohexyl congener 1b is perfectly stable in C6D6 solution
even at elevated temperatures up to ca. 40 C. In contrast, 1a decomposes faster than the
“Alder carbene”. When the work-up was performed rapidly, only traces of the fragmentation
products N,N,N’-tricyclopentylformamidine and cyclopentene were apparent in the 1H NMR
spectrum; after several days at room temperature in C6D6, the 13C NMR signal at 266.0 ppm
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due to the divalent carbon atom was not observed any more, indicating quantitative
decomposition of 1a on this timescale (see Figures S16 – S21 in the Supporting Information).
The decomposition of 1c to cycloheptene and N,N,N’-tricycloheptylformamidine was
considerably faster and happened on a timescale of hours (see Figures S24 – S27 in the
Supporting Information). The diagnostic Ccarbene signal at 254.7 ppm could be observed only
when the carbene was subjected to 13C NMR spectroscopic analysis immediately after its
generation in C6D6. The corresponding signal of the stable ADAC 1b is located at 259.0 ppm,
which is approximately half-way in between the chemical shifts found for 1a and 1c. For
comparison, the ADACs (iPr2N)2C and (iPr2N)C(PipMe2) exhibit Ccarbene NMR signals at
255.5 and 258.9 ppm, respectively, in C6D6 solution.[3c, 14] In the case of 1c the chemical shift
was probably influenced by the presence of equimolar amounts of sodium
hexafluorophosphate. It is well documented that the interaction of diaminocarbenes with
alkali metal cations leads to noticeable high-field shifts of the Ccarbene NMR signal.[26, 27] For
example, in the case of (Me2N)2C this signal is shifted from 259.7 ppm in THF-d8[27a] to 253.1
ppm by the presence of 1.25 equivalents of lithium ions.[4b]
The thermal stabilities of the three new ADACs in solution follow the order 1b > 1a > 1c. The
decomposition of these carbenes leads to the formation of the corresponding cycloalkene
cyclo-CnH2n 2 (n = 5, 6, 7) and N,N,N’-tricycloalkylformamidine (cyclo-CnH2n


1)2NCH=N(cyclo-CnH2n 1). In each case this process involves the breaking of a methylene

CH bond. In the analogous reaction of the “Alder carbene”, it is a methyl CH bond which
is cleaved. As a rule, primary CH bonds are stronger than secondary ones by ca. 4
kcal/mol.[28] Consequently, it seems reasonable to expect that the thermal stability of the
“Alder carbene” is higher than that of the ADACs of type 1. This is indeed true for 1a and 1c.
In addition, there is a significant influence of the ring size on the CH bond strengths in
cycloalkanes. The CH bond dissociation enthalpy of cyclohexane (99.5 kcal/mol) is higher
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than that of cyclopentane (95.6 kcal/mol) and cycloheptane (94.0 kcal/mol).[29] These values
are fully in line with the order of the thermal stabilities of 1a – c.
In view of the higher stability of (Cy2N)2C (1b, Cy = cyclohexyl) in comparison to (iPr2N)2C,
we surmised that the stability of the corresponding “hybrid carbene” iPr2NCNCy2 (2,
synthesised according to the route outlined in Scheme 1 starting from Cy2NH and
iPr2NCHO) will be intermediate between that of the “Alder carbene” and 1b. This indeed
turned out to be the case. According to NMR-spectroscopic analysis, the decomposition of 2
by -fragmentation is more sluggish at room temperature than that of (iPr2N)2C and
exclusively involves the iPr2N unit.
We now come to the electronic properties of the new carbenes of this study.[30] The
nucleophilicity of ADACs 1a – c and 2 was judged from the 1JCH value determined for the
N2CH unit of the respective formamidinium cation. Ganter and Kunz have pointed out that
these 1JCH coupling constants correlate inversely with the -donor strength, and hence
nucleophilicity, of the corresponding carbenes, since the -donor strength decreases with
increasing s-character of the -orbital at the divalent carbon atom and large 1JCH coupling
constants reflect high s-character of the carbon valence orbital involved in the CH bond.[17a,
31] 1
J
coupling constants determined for the protonated standard NHCs IMes and SIMes are
CH
225 and 206 Hz, respectively.[17a] The protonated six-membered ring analogue of SIMes
exhibits a 1JCH coupling constant of only 200 Hz, in line with the enhanced donor capacity of
ring-expanded NHCs.[32] The 1JCH coupling constants determined for the three formamidinium
compounds of the type 1H[PF6] are much lower, viz. 183 Hz. The same value was obtained
for the “Alder carbene” precursor (iPr2N)2CH[PF6] and for 2H[PF6]. These 1JCH coupling
constants can be obtained from proton-coupled 13C NMR spectra or, more conveniently and
accurately, from the 13C satellite signals present in the 1H NMR spectra, because the
formamidinium N2CH signals generally show not overlap with other signals.
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The electrophilicity of ADACs 1a – c and 2 was probed by a 77Se NMR spectroscopic
investigation of the corresponding easily available (see Experimental Section) selenourea
derivatives of the type 1Se. This well-established method[33] was recently applied by us for a
broad range of ADAC-derived selenoureas.[3a] The chemical shifts of the 77Se NMR signals of
these compounds in CDCl3 lie in the range from 381 – 758 ppm. The signal of (iPr2N)2CSe is
located in the middle of this range, at 563 ppm. The signals of 1aSe, 1bSe and 1cSe were
observed at only marginally higher field (546, 539 and 550 ppm, respectively), which points
to an almost identical electrophilicity of the “Alder carbene” and its analogues of type 1. The
77Se NMR signal of 2Se at  = 559 ppm lies even closer to that of the “Alder carbene”. In the
case of selenoureas derived from standard five-membered ring NHCs the chemical shifts lie
between ca. 20 and 200 ppm,[17] in line with the comparatively low electrophilicity of these
widely used carbenes. In addition to their spectroscopic characterisation, the crystal structures
of 1aSe and 1bSe were determined by single-crystal X-ray diffraction (vide infra). 1cSe was
obtained as an oil that showed no tendency to crystallise, which is reminiscent of the
behaviour of (iPr2N)2CSe.[17e]
In view of the very similar steric and electronic properties of the “Alder carbene” and its
analogues of type 1, we expected the latter carbenes also to react readily with CO, cleanly
affording racemic -lactam derivatives. This indeed turned out to be the case (Scheme 2). The
spirocyclic products 3a – c were isolated as viscous oils, which slowly solidified upon
standing. However, crystals suitable for X-ray diffraction were obtained only in the case of 3a
and 3c. 3b was therefore treated with HCl in diethyl ether, which furnished single crystals of
the hydrochloride 3bHCl.
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R
O
N
N
C
R
R
CO
N
R
N
R
R
R
n
R =
2a - c
n
n = 1, 2, 3
Scheme 2. Reaction of 1a – c with carbon monoxide.
Metal-catalysed methods for the synthesis of -lactams using carbon monoxide as building
block have been known for almost four decades.[34, 35] Together with our previously reported
carbonylations of (iPr2N)2C and (iPr2N)C(PipMe2), the reactions shown in Scheme 2
represent the first metal-free method in this context. In view of the fact that secondary
aliphatic amines serve as our starting point (Scheme 1), our method is related to that reported
recently by Gaunt and co-workers, which affords -lactams by PdII-catalysed CH
carbonylation reactions using secondary aliphatic amines.[36] We note that Gaunt’s metal-
catalysed approach is based on the activation of methyl or methylene CH bonds and gives
access to mono- and disubstituted -lactams. Our metal-free method achieves the activation of
tertiary CH bonds and therefore opens the door to trisubstituted -lactams not available by
Gaunt’s method.
Crystal structures
The molecular structures of the cation of 1bH[PF6], the stable ADAC 1b and the
corresponding selenourea derivative 1bSe in the solid state are shown in Figures 2, 3 and 4
(see Figures S1, S2 and S3 in the Supporting Information for the molecular structures of
1cH[PF6], 2H[PF6]ꞏCHCl3 and 1aSe). Pertinent structural parameters are collected in Table 1.
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Structural data for the “Alder carbene” (iPr2N)2C and its precursor [(iPr2N)2CH](OTf) are
included in the Table for comparison.
Figure 2. Molecular structure of the cation of 1bH[PF6] in the crystal.
Figure 3. Molecular structure of 1b in the crystal.
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Figure 4. Molecular structure of 1bSe in the crystal.
Table 1. Selected bond lengths and angles for acyclic formamidinium salts, ADACs and
ADAC-based selenourea compounds.
NCN [Å] NCN [] Sum of angles at N [] Dihedral angle [][a]
1bH[PF6]
1.317(5)
1.324(5)
133.4(4)
359.9(3)
359.9(3)
360.0(7)
359.9(7)
359.5(2)[b]
359.9(2)[c]
359.8(2)
360.1(2)
359.7(5)
359.8(5)
357.93(15)
359.8(4)
343.2(4)
359.9(2)
5.6
10.0
0.0
1cH[PF6]
1.294(10) 131.2(8)
1.307(10)
0.0
2H[PF6]ꞏCHCl3
1.319(3)[b] 131.3(3)
1.317(3)[c]
18.3[b]
18.6[c]
9.7
[(iPr2N)2CH](OTf)[d] 1.316(4)
133.2(2)
1.317(4)
5.0
(iPr2N)2C[e]
1.362(9)
1.381(8)
1.353(2)
1.327(6)
1.431(6)
1.332(4)
121.0(5)
9.8
7.7
f]
1b[
120.7(2)
115.1(4)
20.5
4.5
1aSe
1bSe
78.9
5.7
115.2(2)
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1.435(3)
341.7(2)
85.4
[a] Angle of the N2C plane with the NC2 plane of each amino group. [b] Refers to the Cy2N
unit. [c] Refers to the iPr2N unit. [d] Ref.[24] [e] Ref.[3c] [f] Crystallographically imposed
molecular C2 symmetry.
We first turn our attention to the formamidinium salts and the ADACs listed in Table 1, since
these compounds exhibit rather similar structural features. Their nitrogen atoms are in a
trigonal planar bonding environment (sum of angles ca. 360), compatible with sp2
hybridisation. The dihedral angles formed by the N2C plane and the NC2 planes of the amino
units are fairly small, which can be ascribed to the -delocalisation in the central N2C unit.
These angles are largest for the cation of 2H[PF6]ꞏCHCl3 (18.3 and 18.6). It is not clear
whether this is mainly due to the presence of the solvent molecule. Closer inspection of the
structural parameters reveals that the degree of -delocalisation is higher for the
formamidinium cations than for the free diaminocarbenes, which is a long known
phenomenon already noted by Arduengo and co-workers in their seminal paper describing the
first stable diaminocarbene.[37] The C−N bond lengths of the central N2C unit of the
formamidinium cations listed in Table 1 are ca. 1.31 Å on average, which is significantly
shorter than the average value of 1.36 Å exhibited by the ADACs, both being in between the
values typical for C(sp2)−N(sp2) single (1.41 Å) and double bonds (1.28 Å).[38] A lesser
degree of -delocalisation in the ADACs is also indicated by their larger dihedral angles
between the N2C plane and the NC2 plane of each amino group in comparison to those of the
corresponding formamidinium cation. This effect is particularly pronounced for the pair
1bH[PF6]/1b, since 1b shows with a substantial margin the largest dihedral angles (20.5) of
all structurally characterised ADACs,[39] indicative of significant strain due to steric repulsion
between its two bis(cyclohexyl)amino groups. Closer inspection reveals that this twisting is
caused by the cyclohexyl substituents which are pointing away from the Ccarbene atom. The
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distance between their tertiary carbon atoms is 3.14 Å, which is substantially below the sum
of the van der Waals radii of two sp3 hybridised carbon atoms (3.54 Å).[40] For comparison,
the corresponding interatomic distance for the “Alder carbene” is 3.19 Å.[3c]
The structures of 1aSe and 1bSe are similar to those of other selenourea derivatives of
ADACs containing very bulky amino groups such as, for example, (iPr2N)C(PipMe2).[3a] The
most notable feature is the fact that one of the two amino group is in an almost perpendicular
orientation to the N2C plane (dihedral angle: 78.9 and 85.4 for 1aSe and 1bSe, respectively;
see Table 1). This conformation prevents an efficient participation of the lone pair of electrons
of this particular amino group in -delocalisation. Consequently, the N atom is pyramidalised
(sum of anglec ca. 342) and exhibits an NCSe bond length significantly larger than that of
the second amino group (ca. 1.43 vs. 1.33 Å) and compatible with a single bond. The CSe
bond lengths of 1aSe and 1bSe are ca. 1.85 Å, which compares well with values determined
for closely related selenourea derivatives.[3a] The distances are in between the values typical
of carbon−selenium single and double bonds, which has been rationalised in terms of a
significant contribution of zwitterionic structures that feature single N2C+−Se− dative
bonds.[41]
We finally come to the structures of the -lactam derivatives 3a (Figure 5) and 3c (see Figure
S4 in the Supporting Information) and to the structure of the hydrochloride 3bHCl (Figure 6).
For comparison, the structure of the hydrochloride of the -lactam derivative obtained by
carbonylation of the “Alder carbene” (AHCl) is shown in Figure S5 in the Supporting
Information.[16] Pertinent bond lengths and angles are collected in Table 2.
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Figure 5. Molecular structure of 3a in the crystal.
Figure 6. Molecular structure of 3bHCl in the crystal. The broken line indicates a hydrogen
bond between the chloride anion and the cationic (cyclo-C6H11)2HN substituent.
Table 2. Selected bond lengths an angles for -lactam derivatives.
C1O1 [Å] C1N1 [Å] C3N1 [Å] C1C2 [Å] C2C3 [Å] C2N2 [Å]
3a
1.220(5)
1.222(2)
1.213(6)
1.236(6)
1.211(6)
1.340(5)
1.351(3)
1.355(6)
1.332(6)
1.357(6)
1.474(6)
1.485(3)
1.495(6)
1.508(6)
1.510(6)
1.524(6)
1.544(3)
1.545(6)
1.540(7)
1.546(7)
1.587(5)
1.603(3)
1.582(6)
1.570(7)
1.580(7)
1.440(5)
1.434(3)
1.509(6)
1.531(6)
1.533(6)
3c
3bHCl
AHCl[a]
[a] Two independent molecules.
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The structural parameters of the compounds listed in Table 2 compare well with those of
related amino-substituted -lactam derivatives.[42] Not surprisingly, the C2N2 bond is
significantly longer in the hydrochloride compounds, where the former amino nitrogen atom
N2 is protonated and hence four-coordinate. Note that ordinary trialkylammonium cations
such as, for example, Me3NH+ exhibit CN bond lengths  1.50 Å, whereas values of ca. 1.53
Å, similar to those determined for AHCl, have been reported for sterically congested cases.[43]
Steric strain in the cation of AHCl is also indicated by the CN2C angles, which range from
110.2(4) to 114.0(4) (average value 112.6). For comparison, Me3NH+ exhibits an average
CNC angle of only 111.4.[43] In the same vein, the amino nitrogen atom N2 of the -
lactam derivatives 3a and 3c shows a tendency towards planarization in each case, the sum of
angles at nitrogen being 346.5(4) and 351.7(2), respectively. The difference between these
two values of ca. 5 indicates that the steric congestion due to the cycloheptyl substituents is
significantly more pronounced than that due to the cyclopentyl substituents, which is in line
with their substantially different steric parameters (see above). For comparison, in the case of
the bulky trialkylamine iPr3N the sum of angles at nitrogen is 348.6(1) at 84 K.[44]
Antimicrobial activity of 3a – c
We have investigated the antimicrobial activity of the new -lactam derivatives 3a – c against
Gram-positive and Gram-negative bacteria by determining their minimal inhibitory
concentrations (MICs). The results are summarised in Table 3.
Table 3. Minimal inhibitory concentrations.
Gram-negative
Gram-positive
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Escherichia Acinetobacter Pseudomonas Bacterium
Staphylococcus
Staphylococcus
coli
baumannii
no activity
no activity
no activity
no activity
no activity
aeruginosa
no activity
no activity
no activity
no activity
no activity
subtilis 168
aureus (type strain) aureus (MRSA)
1
1
1
256 g mL
512 g mL
3a
no activity
no activity
no activity
64 g mL
64 g mL
no activity
1
1
1
64 g mL
64 g mL
64 g mL
3b
1
1
256 g mL
256 g mL
256 g mL
3c
1
1
1
1
1
8 g mL
0.5 g mL
16 g mL
Penicillin G
Amoxicillin
1
1
1
2  4 g mL
2 g mL
48 g mL
All three compounds exhibit significant activities against the Gram-positive bacteria Bacillus
subtilis and Staphylococcus aureus. 3b has the most pronounced activity, with an MIC value
1
of 64 g mL for B. subtilis 168 as well as for the S. aureus type strain (DSM 20231) and a
methicillin-resistant S. aureus (MRSA) strain. Its antibiotic activity is four times higher than
that determined previously by us for the -lactam derivative A obtained by carbonylation of
the “Alder carbene” (MIC = 256 g mL ),[9a] the activity of which equals that of 3c. 3a
1
exhibits the same activity against B. subtilis 168 as 3c, but its activity against the S. aureus
type strain is lower by a factor of two and it is inactive against the S. aureus MRSA strain. All
these -lactam derivatives are inactive against Gram-negative bacteria. Their spectrum of
activity resembles that of penicillin G or amoxicillin, whose activities, however, are higher
than that of 3b by approximately two orders of magnitude.
Conclusion
The new ADACs [(cyclo-CnH2n 1)2N]2C (n = 5 – 7) and iPr2NCNCy2 exhibit the same

ambiphilic profile as the iconic “Alder carbene” (iPr2N)2C, which explains their ability to
activate fundamentally important small molecules like CO. Their carbonylation affords -
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lactam derivatives with a spirocyclic scaffold. Compounds of this type have emerged as
important candidates for biological evaluations.[45] The carbonylation of sterically
encumbered ADACs is the first metal-free method for the synthesis of -lactams using CO as
a building block. This method complements the metal-catalysed one recently published by
Gaunt,[36] which also uses secondary amines as starting point, but only allows the synthesis of
mono- and disubstituted -lactams, while our method provides facile access to trisubstituted
derivatives. The surprising thermal stability of (Cy2N)2C, which is significantly higher than
that of (iPr2N)2C, is currently under investigation by DFT methods. We surmise that the
pathway identified for the -fragmentation of (iPr2N)2C[13] is also operative in the case of
(Cy2N)2C, but is impeded by conformational restraints leading to higher barriers.
Experimental Section
All reactions involving air-sensitive compounds were performed in an inert atmosphere
(argon or dinitrogen) by using standard Schlenk techniques or a conventional glovebox.
Starting materials were procured from standard commercial sources and used as received. The
secondary amines (cyclo-CnH2n 1)2NH (n = 5, 7)[46] were synthesised by following adapted

versions of the published procedures. The formamides (cyclo-CnH2n 1)2NCHO (n = 5, 6)

were synthesised from formic acid and the respective secondary amine by using an
established method.[47] Their spectroscopic data were identical to those reported in the
literature.[48] 1H and 13C NMR spectra were recorded at ambient temperature with Varian
NMRS-500 and MR-400 spectrometers operating at 500 and 400 MHZ, respectively, for 1H.
77Se NMR spectra were recorded with a Varian NRMS-500 spectrometer with neat
dimethylselenide as external standard ( = 4 ppm).[49] High-resolution (HR) ESI and APCI
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mass spectra were obtained with a micrOTOF time-of-flight mass spectrometer (Bruker
Daltonics, Bremen, Germany) using an ApolloTM “ion funnel” ESI source. Mass calibration
was performed immediately prior to the measurement with ESI Tune Mix Standard (Agilent,
Waldbronn, Germany). IR spectra were obtained with a Bruker ALPHA FT-IR spectrometer
(ATR mode). A Mettler-Toledo ReactIR 15 instrument was used for monitoring carbonylation
reactions in situ and in real time. Elemental analyses were carried out with a HEKAtech Euro
EA-CHNS elemental analyser at the Institute of Chemistry, University of Kassel, Germany.
Synthesis of (cyclo-C7H13)2NCHO: Formic acid (1.10 g, 23.9 mmol) was added to a
solution of dicycloheptylamine (2.00 g, 9.6 mmol) in toluene (150 mL). The mixture was
refluxed for 4 d with continuous removal of water by means of a Dean-Stark apparatus. The
solution was allowed to cool down to ambient temperature. Volatile components were
removed under vacuum, leaving the product as a pale yellow crystalline solid. Yield 2.13 g
(93%). 1H NMR (CDCl3):  = 8.09 (s, 1H, CHO), 3.88, 3.22 (2 × br. m, 2 × 1H, NCHCH2),
2.1  1.3 ppm (m, 24H, CH2); 13C NMR (CDCl3):  = 166.7 (CHO), 56.4, 55.3 (2 ×
NCHCH2), 33.0, 31.0, 27.6, 27.3, 25.4, 24.2 ppm (6 × CH2); HRMS/APCI(+): m/z =
238.21654 [M + H]+, 238.21709 calcd for [C15H28NO]+.
General procedure for the synthesis of the formamidinium salts of the type 1H[PF6]: In a
typical experiment, freshly distilled oxalyl chloride (1.27 g, 10.0 mmol) was added dropwise
to a stirred solution of the formamide (cyclo-CnH2n 1)2NCHO (9.0 mmol) in

dichloromethane (50 mL) cooled to 20 C. The cooling bath was removed and stirring was
continued for 2 h. Volatile components were removed under vacuum, leaving the Vilsmeyer
complex [(cyclo-CnH2n 1)2N=CHCl]Cl as a colourless solid. Dichloromethane (40 mL) was

added and the suspension cooled to 20 C with stirring. A solution of the secondary amine
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(cyclo-CnH2n 1)2NH (9.0 mmol) and triethylamine (9.0 mmol) in dichloromethane (50 mL)

was cooled to 20 C and slowly added via cannula. The cooling bath was removed and
stirring was continued for 3 h. Volatile components were removed under vacuum. Acetone
(100 mL) was added and insoluble material removed by filtration. The filtrate was reduced to
dryness under vacuum. The residue was taken up in ice cold ethanol (50 mL). The product
was precipitated by addition of an ice cold saturated aqueous solution of ammonium
hexafluorophosphate (1.96 g, 12.0 mmol). The precipitate was filtered off, washed with ice
cold water (2 × 10 mL), followed by ice cold diethyl ether (2 × 10 mL) and subsequently
dried under vacuum. While this procedure afforded analytically pure 1aH[PF6] (3.16 g) and
1bH[PF6] (3.69 g) as ochre crystalline solids in 76% and 79% yield, respectively, further
purification was necessary in the case of 1cH[PF6]. This was achieved by placing the crude
product in a Soxhlet thimble containing silica gel (50 g) and subjecting it for 1 d each to
extraction with hexane, followed by extraction with toluene and finally with diethyl ether. The
hydrocarbon extracts were discarded. The ether extract was reduced to dryness under vacuum,
leaving 1cH[PF6] (2.86 g) as a pale yellow crystalline solid in 55% yield.
1aH[PF6]: 1H NMR (CDCl3):  = 7.43 (s, 1H, N2CH), 4.02 (br., 4H, NCHCH2), 2.15, 1.82 (2
× br., 2 × 8H, CH2), 1.68 ppm (br., 16H, CH2); 13C NMR (CDCl3):  = 153.3 (N2CH), 61.8
(br., NCHCH2), 33.3 (br., CH2), 24.6 ppm (CH2); HRMS/ESI(+): m/z = 317.29515 [M 
PF6]+, 317.29567 calcd for [C21H37N2]+; elemental analysis calcd (%) for C21H37N2F6P
(462.50): C 54.54, H 8.06, N 6.06; found: C 54.85, H 8.05, N 6.06. 1bH[PF6]: 1H NMR
(CDCl3):  = 7.33 (s, 1H, N2CH), 3.57, 3.40 (2 × br., 2 × 2H, NCHCH2), 1.94 (br., 16H, CH2),
1.72, 1.47 1.31 ppm (3 × br., 24H, CH2); 13C NMR (CDCl3):  = 151.6 (N2CH), 62.5, 59.0 (2
× br., NCHCH2), 34.5, 31.0 (2 × br., CH2), 25.7, 24.5 ppm (2 × CH2); HRMS/ESI(+): m/z =
373.35526 [M  PF6]+, 373.35827 calcd for [C25H45N2]+; elemental analysis calcd (%) for
C25H45N2F6P (518.60): C 57.90, H 8.75, N 5.40; found: C 58.02, H 8.73, N 5.47. 1cH[PF6]:
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1H NMR (acetone-d6):  = 7.27 (s, 1H, N2CH), 3.76, 3.53 (2 × br., 2 × 1H, NCHCH2) 3.42
(br., 2H, NCHCH2), 2.1  1.2 ppm (br., 48H, CH2); 13C NMR (acetone-d6):  = 151.0 (N2CH),
63.8, 61.9 (2 × br., NCHCH2), 57.3 (NCHCH2), 36.7, 32.6 (2 × br., CH2), 30.9, 27.4, 26.5 (3
× CH2), 24.7 (br., CH2), 23.5 ppm (CH2); HRMS/ESI(+): m/z = 429.41712 [M  PF6]+,
429.42087 calcd for [C29H53N2]+; elemental analysis calcd (%) for C29H53N2F6P (574.71): C
60.61, H 9.30, N 4.87; found: C 59.74, H 9.24, N 4.72.
Synthesis of 2H[PF6]: Freshly distilled oxalyl chloride (2.16 g, 17.0 mmol) was added
dropwise to a stirred solution of diisopropylformamide (2.00 g, 15.5 mmol) in
dichloromethane (50 mL) cooled to 20 C. The cooling bath was removed and stirring was
continued for 2 h. Volatile components were removed under vacuum. Dichloromethane (50
mL) was added to the remaining solid and the suspension cooled to 0 C with stirring. A
solution of dicyclohexylamine (2.81 g, 15.5 mmol) and triethylamine (1.57 g, 15.5 mmol) in
dichloromethane (50 mL) was slowly added via cannula. The cooling bath was removed and
stirring was continued for 3 h. Volatile components were removed under vacuum. Acetone
(100 mL) was added and insoluble material removed by filtration. The filtrate was reduced to
dryness under vacuum. The residue was taken up in ice cold ethanol (70 mL). The product
was precipitated by addition of an ice cold saturated aqueous solution of ammonium
hexafluorophosphate (3.00 g, 18.4 mmol). The precipitate was filtered off, washed with ice
cold water (2 × 20 mL), followed by ice cold diethyl ether (2 × 20 mL) and subsequently
dried under vacuum. Yield 5.57 g (82%). 1H NMR (acetone-d6):  = 7.74 (s, 1H, N2CH), 4.26,
3.82 (2 × br., 2  2H, NCHC), 1.97 (br., 4H, CH2), 1.84 (br., 8H, CH2), 1.63 (br., 2H, CH2),
1.48 (d, 3JHH = 6.7 Hz, 12H, Me), 1.43 (br., 4H, CH2), 1.25 (br., 2H, CH2); 13C NMR
(acetone-d6):  = 153.1 (N2CH), 26.3 (Me), 25.3 (CH2), signals due to the isopropyl and
cyclohexyl CH units could not be detected even with prolonged acquisition times;
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HRMS/ESI(+): m/z = 293.29404 [M  PF6]+, 293.29567 calcd for [C19H37N2]+; elemental
analysis calcd (%) for C19H37N2F6P (438.48): C 52.05, H 8.51, N 6.39; found: C 52.38, H
8.50, N 6.22.
1a: THF (3 mL) was cooled to 20 C and added to a mixture of sodium
bis(trimethylsilyl)amide (37 mg, 0.20 mmol) and 1aH[PF6] (94 mg, 0.20 mmol). The mixture
was stirred for 10 min. Volatile components were removed under vacuum. The residue was
extracted with hexane (3 × 3 mL). The combined extracts were passed through a glass filter to
remove traces of insoluble material. Volatile components were removed from the filtrate
under vacuum, leaving the crude product as a reddish brown oil. Due to the thermal
decomposition of the carbene and its extreme sensitivity towards air and moisture, further
purification was not possible. Yield: 25 mg (39%). 1H NMR (C6D6):  = 3.93 (quint, 3JHH
=
7.9 Hz, 4H, CH), 2.09 (br., 8H, CH2), 1.86 (br., 16H, CH2), 1.7  1.5 ppm (br., 8H, CH2); 13C
NMR (C6D6):  = 266.0 (Ccarbene), 61.1 (CH), 34.1, 25.3 ppm (2 × CH2).
1b: THF (5 mL) was cooled to 20 C and added to a mixture of sodium
bis(trimethylsilyl)amide (367 mg, 2.00 mmol) and 1aH[PF6] (1.037 g, 2.00 mmol). The
mixture was stirred for 10 min. Volatile components were removed under vacuum. The
residue was extracted with toluene (3 × 10 mL). The combined extracts were passed through a
glass filter to remove traces of insoluble material. The volume of the solution was reduced
under vacuum until crystallisation started. Subsequent storage at 80 C afforded the product
as colourless crystals. The mother liquor was decanted off and the crystals were dried under
vacuum. Yield 430 mg (58%). 1H NMR (C6D6):  = 3.25 (br., 4H, CH), 1.89 (br., 8H, CH2),
1.77 (br., 16H, CH2), 1.56 (br., 4H, CH2), 1.26 (br., 8H, CH2), 1.10 ppm (br., 4H, CH2); 13C
NMR (C6D6):  = 259.0 (Ccarbene), 59.8 (br., CH), 34.8 (br., CH2), 26.8, 25.7 ppm (2 × CH2).
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1c: Sodium bis(trimethylsilyl)amide (35 mg, 0.19 mmol) was added to a suspension of
1cH[PF6] (103 mg, 0.18 mmol) in C6D6 (0.5 mL). The mixture was stirred for 5 min.
Insoluble material was removed by filtration. The filtrate was placed in an NMR tube and
immediately subjected to NMR spectroscopic analysis. 1H NMR (C6D6):  = 3.8  3.2 (br.,
4H, CH), 2.9 – 1.1 (br., 48H, CH2); 13C NMR (C6D6):  = 254.7 (Ccarbene), 55.9 (CH), 36.5,
29.6, 27.0, 25.2 ppm (4 × CH2).
2: THF (10 mL) was cooled to 20 C and added to a mixture of sodium
bis(trimethylsilyl)amide (421 mg, 2.30 mmol) and 2H[PF6] (1.021 g, 2.33 mmol). The
mixture was stirred for 10 min. Insoluble material was removed by filtration. The filtrate was
reduced to dryness under vacuum, leaving the crude product as a grey solid. Yield: 552 mg
(84%). 1H NMR (C6D6):  = 3.66, 3.28 (2  br., 2  2H, CH), 1.76 (br., 10H, CH2), 1.53 (br.,
3H, CH2), 1.28 (d, 3JHH = 6.4 Hz, 12H, Me), 1.10 (br., 7H, CH2); 13C NMR (C6D6):  = 258.6
(Ccarbene), 60.0, 49.8 (2  br., 2  CH), 34.9 (br., CH2), 27.0 (Me), 24.4 (br., CH2).
1aSe: THF (5 mL) was cooled to 20 C and added to a mixture of 1bH[PF6] (93 mg, 0.20
mmol), sodium bis(trimethylsilyl)amide (37 mg, 0.20 mmol) and grey selenium powder (16
mg, 0.20 mmol). The mixture was stirred at ambient temperature for 2 h. Volatile components
were removed under vacuum. Pentane (10 mL) was added to the residue, followed by water (5
drops). The mixture was stirred for 10 min. Insoluble material was removed by filtration
through a Celite pad and washed with pentane (3 × 5 mL). The filtrate and extracts were
combined and volatile components removed under vacuum. The crude product was obtained
as a dark yellow oil, which was subjected to purification by column chromatography (silica
gel, pentane/ethyl acetate 9:1). The yellow oil was dissolved in a mixture of diethyl ether (20
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24
mL) and acetonitrile (20 drops). Slow evaporation of the diethyl ether afforded the product as
yellow crystals, which were dried under vacuum after removal of the mother liquor via
cannula. Yield 51 mg (64%). 1H NMR (CDCl3):  = 4.31 (quint, 3JHH = 8.6 Hz, 4H, CH), 1.91
(m, 16H, CH2), 1.75, 1.53 ppm (2 m, 2 × 8H, CH2); 13C NMR (CDCl3):  = 201.9 (CSe), 63.8
(CH), 29.9, 24.3 ppm (2 × CH2); 77Se NMR (CDCl3):  = 546 ppm; HRMS/ESI(+): m/z =
419.19248 [M + Na]+, 419.19414 calcd for [C21H36N2NaSe]+; elemental analysis calcd (%)
for C21H36N2Se (395.48): C 63.78, H 9.18, N 7.08; found: C 63.64, H 9.18, N 7.08.
1bSe: Grey selenium powder (79 mg, 1.00 mmol) was added to a solution of 1b (373 mg,
1.00 mmol) in hexane (20 mL). The mixture was stirred for 1 h. Trace amounts of insoluble
material were removed by filtration through a glass filter. The filtrate was reduced to dryness
under vacuum, which afforded the product as a yellow crystalline solid. Yield 379 mg (84%).
1H NMR (CDCl3):  = 4.06 (quint, 3JHH = 8.3 Hz, 4H, CH), 2.0  1.0 ppm (m, 40H, CH2); 13C
NMR (CDCl3):  = 203.0 (CSe), 64.0 (CH), 32.3, 26.9, 26.0 ppm (3 × CH2); 77Se NMR
(CDCl3):  = 539 ppm; HRMS/ESI(+): m/z = 967.46409 [2 M + Cu]+, 967.46354 calcd for
[C50H88N4CuSe2]+; elemental analysis calcd (%) for C25H44N2Se (451.59): C 66.49, H 9.82, N
6.20; found: C 67.70, H 9.72, N 6.15.
1cSe: A solution of sodium bis(trimethylsilyl)amide (50 mg, 0.27 mmol) in THF (1 mL) was
added dropwise to a stirred suspension grey selenium powder (24 mg, 0.30 mmol) and
1cH[PF6] (150 mg, 0.26 mmol) in THF (15 mL) cooled to 80 C. The cooling bath was
removed after 10 min. Stirring was continued for 1.5 h. Volatile components were removed
under vacuum. Hexane (20 mL) was added to the residue. Small amounts of insoluble
material were removed by filtration through a Celite pad. Volatile components were removed
from the filtrate under vacuum. The crude product was obtained as a yellow oil which showed
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25
no tendency to crystallise. Attempts to obtain an analytically pure sample by column
chromatography failed. Yield 83 mg (63%). 1H NMR (CDCl3):  = 3.85, (m, 4H, CH), 1.8 
1.1 ppm (m, 48H, CH2); 13C NMR (CDCl3):  = 198.2 (CSe), 65.0 (CH), 34.2, 28.2, 26.7,
25.0 (4 × CH2); 77Se NMR (CDCl3):  = 550 ppm; HRMS/ESI(+): m/z = 1079.45851 [2 M +
Cu]+, 1079.58874 calcd for [C58H104N4CuSe2]+.
2Se: The synthesis was performed in strict analogy to that described for 1cSe using 2H[PF6]
(100 mg, 0.23 mmol), grey selenium powder (20 mg, 0.25 mmol) and sodium
bis(trimethylsilyl)amide (44 mg, 0.24 mmol). The product was obtained as a red oil. Yield 56
mg (68%). 1H NMR (CDCl3):  = 4.34 (sept, 3JHH = 6.8 Hz, 2H, CHMe2), 3.93 (m, 2H,
NCH), 1.92 – 1.58 (m, 14H, CH2), 1.37 (d, 3JHH = 6.8 Hz, 12H, Me), 1.28 – 1.05 (m, 6H,
CH2); 13C NMR (CDCl3):  = 161.7 (CSe), 63.0, 53.3 (2  CH), 31.8, 26.6, 25.8, 21.4. 77Se
NMR (CDCl3):  = 550 ppm; HRMS/ESI(+): m/z = 395.19367 [M + Na]+, 395.19414 cald for
[C19H36N2NaSe]+.
3a: THF (20 mL) was cooled to 20 C and added to a mixture of 1aH[PF6] (2.31 g, 4.99
mmol) and sodium bis(trimethylsilyl)amide (920 mg, 5.02 mmol). The mixture was stirred for
10 min. The inert gas atmosphere was replaced by carbon monoxide. Stirring was continued
at ambient temperature for 2 h. Volatile components were removed under vacuum. The
residue was subjected to purification by column chromatography (silica gel, hexane/ethyl
acetate 1:9, which afforded the product as a yellow oil, which crystallised over the course of
several days. Crystals suitable for a single-crystal X-ray diffraction study were obtained by
sublimation (80 C, 10 mbar). Yield 1.22 g (71%). 1H NMR (CDCl3):  = 3.71 (s, 1H,
2
CHCO), 3.29 (quint, 3JHH = 7.8 Hz, 1H, C(O)NCH), 3.04 (br., 2H, CHNCHCH2), 1.9  1.0
ppm (m, 32H, CH2); 13C NMR (CDCl3):  = 168.8 (CO), 73.6 (Cquat), 71.5 (C(O)NCH), 60.8,
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56.1, 52.7 (3 × CH), 34.4, 31.7, 30.7, 30.1 (4 × CH2), 29.9 (br., CH2), 28.9, 24.9, 24.3 (3 ×
CH2), 24.0 (br., CH2), 23.3, 23.3 (2 × CH2), 22.7 ppm (br., CH2); HRMS/ESI(+): m/z =
1
367.30452 [M + Na]+, 367.27253 calcd for [C22H36N2NaO]+; IR (ATR): CO = 1722 cm ;
elemental analysis calcd (%) for C22H36N2O (344.53): C 76.69, H 10.53, N 8.13; found: C
76.13, H 10.47, N 7.85.
3b: 1b (373 mg, 1.00 mmol) was dissolved in hexane (20 mL). The inert gas atmosphere was
replaced by carbon monoxide and the solution stirred at ambient temperature for 2 h. Volatile
components were removed under vacuum, leaving the crude product as a reddish brown semi-
solid. Yield 365 mg (91%). 1H NMR (CDCl3):  = 3.77 (s, 1H, CHCO), 2.97 (quint, 3JHH
=
7.6 Hz, 1H, C(O)NCH), 2.55 (quint, 3JHH = 7.8 Hz, 2H, CHNCHCH2), 2.0  0.9 (m, 40H,
CH2); 13C NMR (CDCl3):  = 169.8 (CO), 74.0 (Cquat), 66.1, 52.1, 37.2 (3 × CH), 33.2 (br.,
CH2), 33.0, 32.5, 31.8, 31.2, 27.0 (5 × CH2), 26.5 (br., CH2), 25.9, 25.2, 24.1, 23.5 (4 × CH2);
1
IR (ATR): CO = 1720 cm . The product was converted to its hydrochloride, which was
easier to purify and analyse.
3bHCl: The crude product (300 mg, 0.75 mmol) obtained from the reaction of 1b with carbon
monoxide was dissolved in diethyl ether (5 mL). A solution of HCl in diethyl ether (2.0 M, 0.4
mL, 0.80 mmol) was added dropwise with stirring. The colourless precipitate was isolated by
filtration, washed with diethyl ether (2 × 1 mL) and dried under vacuum. Yield 306 mg
(93%). 1H NMR (CDCl3):  = 10.71 (br. s, 1H, NH+), 3.84 (br., 2H, CH), 3.64, 3.29 (2 m, ×
1H, NCH), 2.7  1.0 (m, 40H, CH2); 13C NMR (CDCl3):  = 160.1 (CO), 70.7, 64.9 (2 × CH),
64.1 (Cquat), 63.7, 56.5 (2 × CH), 37.4, 32.5, 31.3, 31.1, 28.3, 26.0, 25.5, 25.0, 24.7, 24.3,
23.1, 23.0 (12 × CH2); HRMS/ESI(+): m/z = 401.35144 [M  Cl]+, 401.35319 calcd for
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10.1002/chem.201805307
Chemistry - A European Journal
27
[C26H45N2O]+; elemental analysis calcd (%) for C26H45N2ClO (437.10): C 71.44, H 10.38, N
6.41; found: C 71.47, H 10.42, N 6.41.
3c: The synthesis was carried out in analogy to that described for 2a, using 1cH[PF6] (2.86 g,
4.99 mmol) and sodium bis(trimethylsilyl)amide (920 mg, 5.02 mmol). The product was
obtained as a beige oil, which slowly crystallised upon storage at 40 C. Yield 1.48 g (65%).
1H NMR (CDCl3):  = 3.89 (m, 1H, CH), 3.71 (s, 1H, CHCO), 3.24, 3.16 (2 × br. m, 2 × 1H,
CH), 2.7  1.1 (m, 48H, CH2); 13C NMR (CDCl3):  = 169.1 (CO), 77.0 (Cquat), 69.4, 55.4,
39.2 (3 × CH), 34.8, 34.2, 33.8, 31.7, 31.4, 31.5, 27.8, 27.7, 25.2, 24.9, 24.0, 23.8 (12 × CH2);
HRMS/ESI(+): m/z = 457.41002 [M + H]+, 457.41579 calcd for [C30H53N2O]+; IR (ATR): CO
1
= 1715 cm .
MIC tests: Compounds were tested against Escherichia coli DSM 30083, Acinetobacter
baumannii DSM 30007, Pseudomonas aeruginosa DSM 50071, Bacillus subtilis DSM 402,
Staphylococcus aureus DSM 20231, and Staphylococcus aureus ATCC 43300 (MRSA) in a
microtiter plate assay according to CLSI guidelines, as described in ref.[50] E. coli, A.
baumannii, S. aureus, and B. subtilis were grown in Mueller Hinton broth, P. aeruginosa in
cation-adjusted Mueller Hinton II. Compounds were dissolved in DMSO 1.25, 2.5, 5, or 10
mg/mL stock solution. Serial dilution in culture media were prepared with the Tecan Freedom
Evo 75 liquid handling workstation (Tecan, Männedorf, Switzerland). Dilutions, starting from
a 10 mg/mL stock solution, typically covered a range from 512 to 0.5 µg/mL. Compound
dilutions were inoculated with 5105 bacteria/mL from late exponential cultures grown in the
same media. Assay volumes were 200 µL per well. Cells were incubated for 16  18 h at 37
°C. The lowest compound concentration inhibiting visible bacterial growth was recorded as
MIC.
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10.1002/chem.201805307
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X-ray crystallography: For each data collection a single crystal was mounted on a micro-
mount and all geometric and intensity data were taken from this sample. Data collections were
carried out using MoKα radiation (λ = 0.71073 Å ) either on a Stoe IPDS2 diffractometer
equipped with a 2-circle goniometer and an area detector or on a Stoe StadiVari
diffractometer equipped with a 4-circle goniometer and a DECTRIS Pilatus 200K detector. 1b
and 1aSe were measured on a Stoe StadiVari Diffractometer using CuKα radiation (λ =
1.54186 Å ). The data sets were corrected for absorption (by integration), Lorentz and
polarisation effects. The structures were solved by direct methods (SIR 2008)[51] and refined
using alternating cycles of least-squares refinements against F2 (SHELXL2014/7).[52] H atoms
were included to the models in calculated positions with the 1.2 fold isotropic displacement
parameter of their bonding partner. Experimental details for each diffraction experiment are
given in Table S1 in the Supporting Information. CCDC 1874081  1874090 contain the
supplementary crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
Acknowledgements
The authors are grateful to the Deutsche Forschungsgemeinschaft for generous financial
support of this work (SI 429/19-1 and 429/19-2). Dr. Tim Schulz is thanked for providing a
sample of AHCl suitable for single-crystal X-ray diffraction.
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10.1002/chem.201805307
Chemistry - A European Journal
29
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