In the present work, a molecular electron density theory (MEDT) study is carried out to shed light on the regio- and stereochemistry in two Diels–Alder (DA) reactions explored experimentally by Lemos ...and coworkers. These reactions involve the aza-Diels–Alder (ADA) reaction of an azoalkene
AA
with both furan
FU
and dihydrofuran
DHFU
in the presence of dichloromethane at room temperature. The regiochemistry of the obtained cycloadducts is completely opposite in the considered ADA reactions. The results of the local reactivity indices analysis based on the Parr functions confirmed the regiochemistry experimentally observed. Exploration of potential energy surfaces (PESs) indicated that the formation of
endo
adducts,
P-1n
and
P
DH
-2n
, are more favorable than
exo
ones. It was found that the electrostatic as well as the stabilizing π···π stacking interactions between two interacting fragments in the transition states associated with the
endo
attack can be considered as the origin of the
endo
stereochemistry predominance.
The domino process between DAA 2 and ANI 3 is initialized with a polar zw-type 32CA reaction in an entirely regioselective manner affording CA1n over the course of a non-concerted two-stage one-step ...molecular mechanism. CA1n is subsequently converted to PYZ 4 over the course of a stepwise 1,3-H shift reaction assisted by OAc− while the energetically very unfavorable N2 extrusion reaction affording CP 5 never find any chance to take place.
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•The domino reaction between DAA 2 and ANI 3 was theoretically studied.•This domino reaction is initialized with an entirely regioselective 32CA reaction.•While two subsequent 1,3-H shift and N2 extrusion reactions can potentially be involved, the former is entirely preferred.•The experimentally observed regioselectivity can be rationalized using Parr functions analysis.•ELF analysis allows us to establish the molecular mechanism involved in the initializing32CA reaction.
The domino process between a CF2H-containing diazoalkane, DAA 2, and an electron-deficient alkene, ANI 3, in the presence of chloroform was theoretically studied at the DFT-MPWB1 K/6-311G(d,p) computational level. The initializing step in this domino process is associated with the C1 nucleophilic attack of DAA 2 at the C4 carbon atom of ANI 3 over the course of a polar zw-type 32CA reaction in an entirely C1-C4 regioselective manner to furnish corresponding 1-pyrazoline derivative CA1n. While a stepwise 1,3-H shift reaction assisted by an acetate anion and/or a thermal N2 extrusion reaction can subsequently convert CA1n into corresponding 2- pyrazoline PYZ 4 or cyclopropane CP 5 derivatives, respectively, exploration of the relative Gibbs free energy profile evidently demonstrates that experimentally isolated PYZ 4 is the only reachable product of the studied domino reaction. Analysis of the calculated nucleophilic and electrophilic Parr functions at the reactive sites of DAA 2 and ANI 3, respectively, rationalizes the C1-C4 regioselectivity observed experimentally. An electron localization function (ELF) topological analysis of some selected points along the most favorable reactive channel involved in the initializing 32CA reaction allows establishing a non-concerted two-stage one-step molecular mechanism for the 32CA reaction of DAA 2 toward ANI 3.
The complete regioselective 32CA reaction of benzonitrile oxide toward phenyl SF5-acetylene in the presence of THF takes place via a non-concerted two-stage one-step molecular mechanism.
•A 32CA ...reaction in which SF5 group plays a key role was theoretically studied.•The studied 32CA reaction takes place via a complete regioselective pathway.•Total regioselectivity is controlled by steric effects rather than electronic ones.•An ELF analysis supports a non-concerted two-stage one-step molecular mechanism.
A theoretical study was performed on the 3+2 cycloaddition (32CA) reaction of benzonitrile oxide, BNO 4, toward phenyl SF5-acetylene, PAC 5, in the presence of tetrahydrofuran (THF) at the DFT-B3LYP/6-31G* level. Calculated relative Gibbs free energies indicate that the studied 32CA reaction takes place via a complete C1C4 regioselective channel passing through TS1 affording the unique formal 3+2 cycloadduct CA1 observed experimentally. While based on the calculated Parr functions on the interacting sites of reagents this cycloaddition should proceed via energetically unfavorable C1C5 channel passing through TS2, a natural steric analysis evidently showed that destabilizing repulsion effects, rather than the electronic ones, are responsible for the complete C1C4 regioselective fashion provided by the considered 32CA reaction. An ELF topological analysis of the bonding changes along this 32CA reaction supports a non-concerted two-stage one-step molecular mechanism in which the formation of second O3C5 single bond takes place when the formation of first C1C4 one is almost complete.
A theoretical study at the MPWB1K/6-31G(d) level was performed on the 3 + 2 cycloaddition (32CA) reaction of a stabilized N -lithiated azomethine ylide ( AZY 1 ) toward a π-deficient methyl acrylate ...( MA 11 ) in tetrahydrofuran (THF) to elucidate the regio- and stereoselectivity as well as the mechanistic aspects involved in this reaction. The energetics results, in excellent agreement with the experimental findings, indicate that between the two competitive C3–C4 and C3–C5 regioisomeric channels, the former is both kinetically and thermodynamically preferred over the latter, in which the electrophilic attack of the C4 carbon atom of MA 11 on the C3 carbon atom of AZY 1 through an endo approach mode passes the endo transition state TS1n , whose Gibbs free energy is 9.8 kcal mol −1 higher than those of the separate reagents. The analysis of the intrinsic reaction coordinate (IRC) curves of TS1n in the gas phase and in THF demonstrates that unlike the gas phase, the noticeable charge separation caused by the electron density delocalization from the carbonyl oxygen atom of the MA 11 moiety toward the Li cation of the AZY 1 moiety is sufficiently stabilized by the solvent polarity, leading to the formation of the zwitterionic intermediate IN1n according to a stepwise mechanism. Upon the formation of IN1n , during which the first C3–C4 single bond forms, the attractive electrostatic force between the oppositely charged C1 (+0.08e) and C5 (−0.51e) carbon atoms promotes the ring closure step via TS11n with a non-appreciable barrier of 1.3 kcal mol −1 , leading to the formation of a second C1–C5 single bond at the corresponding lithiated cycloadduct. The calculated electrophilic and nucleophilic Parr functions at the reactive sites of the reagents together with the presence of large steric hindrances along the unfavourable C3–C5 regioisomeric channel enables us to explain the C3–C4 regiospecificity observed experimentally. In addition, the origin of the endo-stereospecificity experimentally displayed by the 32CA reaction under consideration can be nicely portrayed using non-covalent interactions (NCIs) analysis at the exo TS1x and endo TS1n transition states involved in the preferred C3–C4 regioisomeric channel.
A Molecular Electron Density Theory (MEDT) study was performed on the nucleophilic amination of pyridine and benzene to elucidate the observed regioselectivity in the Chichibabin reaction. For this ...purpose, three possible reaction paths were considered between NaNH2 and the 2-, 3- and 4-positions of pyridine. The reaction of NaNH2 and benzene was also investigated. The results indicated that in each reaction, the first step involves the nucleophilic attack of the NH2‾ ion toward the aromatic system to produce an anionic intermediate. The second step, proceeds via hydride elimination of the anionic intermediate to produce the corresponding aromatic amine. This step is more favourable both kinetically and thermodynamically for the reaction at the 2-position of pyridine relative to the 4-position. In contrast to the Parr functions analysis which indicates that the 4-position is activated more electrophilically in pyridine, the PES analysis reveals that the 2-position attack with the NH2‾ ion is more favourable both thermodynamically and kinetically. The results for the reaction of sodium amide and benzene indicated that this reaction is not feasible due to the high activation barriers. In consistent with the experimental results, the ELF analysis indicated that in the first step of the reaction between pyridine and sodium amide, the formation of the C2–N bond takes place via a pseudoradical coupling between the C2 carbon atom of pyridine and the N atom of NaNH2. These variations occur in the second-half of the first step of the reaction. NCI analysis on the reaction revealed that the more attractive forces between the fragments, make the transition states for the 2-position attack more stable relative to the others. Thus, the NCI analysis can satisfactorily describe the observed regioselectivity in the Chichibabin reaction.
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•PES analysis confirms the observed regioselectivity in the Chichibabin reaction.•The 2-position attack is more favourable both kinetically and thermodynamically.•Due to the activation barriers, the reaction of benzene with NaNH2 is impossible.•The C2–N bond is formed via the coupling of the pseudoradical centers.•The NCI analysis describes satisfactorily the observed regioselectivity.
This study corresponds to a molecular electron density theory (MEDT) investigation to shed light on the energetics, selectivities, and molecular mechanistic aspects of an experimental domino ...reaction. Theoretical evidences at the M06–2X/6-31G(d) level indicates that this domino reaction includes three different successive steps and is initialized by a stepwise HCl elimination from precursor chlorohydrazone NPCH to yield nitrile imine NI-2. A subsequent stepwise and highly regioselective 3 + 2 cycloaddition (32CA) reaction of NI-2 toward tetramethylguanidine TMG-3 affords corresponding formal 3 + 2 cycloadduct CA-1 as the sole product. Finally, a stepwise HNMe2 elimination experienced by CA-1 leads to amino triazole ATA as an aromatic five-membered target product. Computed rate constants reveal that the HCl elimination step should be considered as the bottleneck of this domino reaction. However, a topological analysis of electron localization function (ELF) of NI-2 demonstrates a zwitterionic type (zw-type) 32 C A reaction is expected between NI-2 and TMG-3. This 32CA reaction also displays an almost noticeable polar character arising from moderate electrophilicity and strong nucleophilicity of NI-2 and TMG-3, respectively. The regioselectivity of 32CA reaction can be explained via analysis of Parr functions values calculated at the reactive sites of reagents. The molecular mechanism of the 32CA reaction was explored through portraying bond forming/breaking patterns involved in this polar, stepwise, and zw-type reaction by means of the ELF analysis. Indeed, formation of both C–N single bonds along the first and second steps takes place through coupling of the corresponding pseudoradical centers.
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•A comprehensive analysis was carried out on the kinetics and thermodynasmics.•ELF analysis showed a zwitterionic type 32 C A reaction between NI-2 and TMG-3.•The cycloaddition step showed high polarity in MeCN as a high polar solvent.•Both single bonds are formed via coupling of the pseudoradical centers.•The results are in good agreement with the experimental outcomes.
A theoretical study at the MPWB1K/6-311G(d) level was performed on the 3 + 2 cycloaddition (32CA) reaction of (
Z
)-2,2,2-trifluoro-
N
-methylethan-1-imine oxide (nitrone
10
) toward propane-2-thione ...(thioketone
11
) as a reduced computational model considered for experimentally studied 32CA reaction between (
Z
)-2,2,2-trifluoro-
N
-phenylethan-1-imine oxide (nitrone
6a
) and 2,4-dimethylpentane-3-thione (thioketone
8f
). Exploration of relative Gibbs free energy profile in the presence of THF obviously showed that among two feasible
meta
and
ortho
regioisomeric channels, the former is completely preferred over the latter both kinetically, ΔΔ
G
activation
= 11.1 kcal mol
−1
, and thermodynamically, ΔΔ
G
reaction
= −16.1 kcal mol
−1
. The energetic results of the modelled reaction, in complete agreement with the experimentally studied reaction, emphasize that the
meta
cycloadduct is the unique observable formal 3 + 2 yield. The moderate global nucleophilicity and electrophilicity characters found in nitrone
10
and thioketone
11
, respectively, are responsible for a very low polar character of the studied 32CA reaction. The complete regioselectivity in the modelled 32CA reaction can be explained using calculated electrophilic and nucleophilic Parr functions at the interacting sites of reagents. The ELF topological patterns indicate that in the 32CA reaction between nitrone
10
and thioketone
11
while the formation of a C-S single bond at one terminal takes place exactly according to the recently proposed Domingo's model, formation of an O-C single bond at the other terminal is a direct consequence of donation of some electron density of oxygen lone pairs of nitrone
10
to the carbon atom of thioketone
11
.
Regiospecific 32CA reaction of nitrone
10
toward thioketone
11
takes place
via
a non-concerted one-step mechanism confirmed by ELF analysis.
The domino process between a CF2H-containing diazoalkane, DAA 2, and an electron-deficient alkene, ANI 3, in the presence of chloroform was theoretically studied at the DFT-MPWB1 K/6-311G(d,p) ...computational level. The initializing step in this domino process is associated with the C1 nucleophilic attack of DAA 2 at the C4 carbon atom of ANI 3 over the course of a polar zw-type 32CA reaction in an entirely C1-C4 regioselective manner to furnish corresponding 1-pyrazoline derivative CA1n. While a stepwise 1,3-H shift reaction assisted by an acetate anion and/or a thermal N2 extrusion reaction can subsequently convert CA1n into corresponding 2- pyrazoline PYZ 4 or cyclopropane CP 5 derivatives, respectively, exploration of the relative Gibbs free energy profile evidently demonstrates that experimentally isolated PYZ 4 is the only reachable product of the studied domino reaction. Analysis of the calculated nucleophilic and electrophilic Parr functions at the reactive sites of DAA 2 and ANI 3, respectively, rationalizes the C1-C4 regioselectivity observed experimentally. An electron localization function (ELF) topological analysis of some selected points along the most favorable reactive channel involved in the initializing 32CA reaction allows establishing a non-concerted two-stage one-step molecular mechanism for the 32CA reaction of DAA 2 toward ANI 3.
