Rotation‐Inversion Isomerization of Tertiary Carbamates: Potential Energy Surface Analysis of Multi‐Paths Isomerization Using Boltzmann Statistics

Abstract

Potential energy surface (PES) analyses at the SMD[MP2/6–311++G(d,p)] level and higher‐level energies up to MP4(fc,SDTQ) are reported for the fluorinated tertiary carbamate N‐ethyl‐N‐(2,2,2‐trifluoroethyl) methyl carbamate (VII) and its parent system N,N‐dimethyl methyl carbamate (VI). Emphasis is placed on the analysis of the rotational barrier about the CN carbamate bond and its interplay with the hybridization of the N‐lone pair (NLP). All rotational transition state (TS) structures were found by computation of 1D relaxed rotational profiles but only 2D PES scans revealed the rotation‐inversion paths in a compelling fashion. We found four unique chiral minima of VII, one pair each of E‐ and Z‐rotamers, and we determined the eight unique rotational TS structures associated with every possible E/Z‐isomerization path. It is a significant finding that all TS structures feature N‐pyramidalization whereas the minima essentially contain sp2‐hybridized nitrogen. We will show that the TS stabilities are affected by the synergetic interplay between NLP/CO2 repulsion minimization, NLP→σ*(CO) negative hyperconjugation, and two modes of intramolecular through‐space electrostatic stabilization. We demonstrate how Boltzmann statistics must be applied to determine the predicted experimental rotational barrier based on the energetics of all eight rotamerization pathways. The computed barrier for VII is in complete agreement with the experimentally measured barrier of the very similar fluorinated carbamate N‐Boc‐N‐(2,2,2‐trifluoroethyl)‐4‐aminobutan‐1‐ol II. NMR properties of VII were calculated with a variety of density functional/basis set combinations and Boltzmann averaging over the E‐ and Z‐rotamers at our best theoretical level results in good agreement with experimental chemical shifts δ(13C) and J(13C,19F) coupling constants of II (within 6 %).

VT‐NMR Analysis of Rotation‐Inversion of N‐(4‐hydroxybutyl)‐N‐(2,2,2‐trifluoroethyl) tert‐butyl Carbamate: Utilizing the −CH2CF3 Appendage as a Reporter on E/Z‐Isomerization

“…The populations were determined to be p ( E − 1 )≈45 % and p ( Z − 1 )≈55 %. The rotamer populations p ( E − 4 )=44 % and p ( Z − 4 )=56 % were determined [12] using the energies of the E / Z ‐minima of 4 computed at the MP4/6‐311++G(d,p)//MP2/6‐311++G(d,p) level, and their good agreement with the measured populations of 1 justifies the selection of 4 as a suitable model system.…”

“…In Scheme 3 are shown two sets of E / Z ‐rotamers of 1 in analogy to the results of the structural study of 4 . Model system 4 features the same carbamate and fluorine functionality as 1 and two sets of E / Z rotamers were found by optimization of structures of 4 at the MP2/6‐311++G(d,p) level [12] . The minima of each rotamer ensemble are defined by the orientation of the carbamate ( E or Z ) and by the orientation of the N ‐alkyl substituents.…”

“…While developing a synthetic route for generating N ‐trifluoroethyl functionalized lysine and analogs, we observed two 13 C NMR quartet signals corresponding to a single CF 3 carbon for tert ‐butyloxycarbonyl (BOC) protected intermediates including N ‐(4‐hydroxybutyl)‐ N ‐(2,2,2‐trifluoroethyl) tert ‐butyl carbamate 1 , N ‐Boc‐ N ‐(2,2,2‐trifluoroethyl)‐4‐bromobutan‐1‐amine 2 , N ϵ ‐Boc‐ N ϵ ‐(2,2,2‐trifluoroethyl)‐ L ‐lysinate 3 (Scheme 1). [11] Analysis of the potential energy surface (PES) of the model system N ‐ethyl‐ N ‐(2,2,2‐trifluoroethyl) methyl carbamate 4 showed a large barrier to rotation‐inversion about the CN bond [12] . The presence of two E / Z ‐ensembles and of eight unique pathways connecting the minima created a complicated multi‐paths scenario and the application of proper Boltzmann statistics was required to model the experimentally measured rotational barrier.…”

Unnatural Lysines with Reduced Sidechain N‐Basicity: Synthesis of N‐trifluoroethyl Substituted Lysine and Homologs

“…In intermediates 3 – 6 , the 13 C NMR is of great interest due to the presence of two sets of −CF 3 quartets in the 13 C NMR spectrum. This was caused by the presence of two ensembles of non‐equilibrating rotational isomers caused by the boc carbamate protecting group [35] . The −CF 3 group in these compounds acts as a probe to observe the two rotamer ensembles, and the apparent signal strength of the −CF 3 signal is severely diminished since it is split into both a quartet by the 19 F nuclei and into two distinct rotamer populations.…”

Nuclear Magnetic Resonance Study of CO2 Capture by Fluoroalkylamines: Ammonium Ion pKa Depression via Fluorine Modification and Thermochemistry of Carbamylation

“…Note that the chemical shifts of the dε 2 and dα 3 signals are higher than for the ε 2 and α 3 signals, and this difference is due to conjugation. The nitrogen atom in the carbamate engages in negative hyperconjugation 32 and leads to a reduction of the N electron density, which propagates to the adjacent methylene groups.…”