J Mol Model (2015) 21:131 DOI 10.1007/s00894-015-2680-7
ORIGINAL PAPER
The reactivity of phenancyl bromide under β-cyclodextrin as supramolecular catalyst: a computational survey Yali Wan 1 & Xueye Wang 1 & Na Liu 1
Received: 7 January 2015 / Accepted: 13 April 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Phenacyl bromide as one starting material in multicomponent reactions (MCRs) with β-cyclodextrin (β-CD) as catalyst can get an excellent yield in short reaction times. The interaction of β-CD with phenacyl bromide plays an important role in this process. This paper studies the complex of β-CD with phenacyl bromide using density functional theory (DFT) method. Energy is investigated to find out the lowest energy of two possible complexation models. Hydrogen bonds are researched on the basis of natural bonding orbital (NBO) analysis. The relative position between phenacyl bromide and β-CD is confirmed by 1H nuclear magnetic resonance (1HNMR). The results of frontier molecular orbitals and charge distribution reveal that β-CD catalyst improves the reactivity and electrophilicity of phenacyl bromide, meanwhile, the carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD as catalyst. The reactivity of phenancyl bromide under β-CD as supramolecular catalysis is improved. Keywords β-Cyclodextrin (β-CD) . Density functional theory (DFT) . Inclusion complex . Phenacyl bromide . Supramolecular catalyst
Introduction Cyclodextrins (CDs) are a class of macrocyclic oligosaccharides connected together by α-1.4 glycosidic bonds [1]. α-, * Xueye Wang [email protected] 1
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, Hunan 411105, People’s Republic of China
β-, and γ-CD, consisting of six, seven, and eight glucose units (Fig. 1), respectively, are most commonly used [2]. They have molecular-compatible cavities in which internal is hydrophobic and external is hydrophilic [3, 4]. The wider upper rim of cavity is surrounded by the secondary hydroxyl groups, while the narrower opening lines with the primary hydroxyl groups [3]. They can provide additional hydrogen bonds for the binding of guests [5]. Owing to their particular structures, they have the ability to form host−guest complexes with a wide range of guests [4]. Thus, CDs have been extensively employed in diverse fields ranging from pharmaceutical, agriculture to recognition [6–8]. In the past, CDs as catalyst have been widely used in organic synthesis [9–11] by the way of host−guest complexes to improve selectivities and high yields. Interest in the catalyst of CD is increasing for its excellent property. Currently, many reviews about CD catalyst have been published [12–14]. However, the research about CD catalyst mostly concentrated on the method of experiment. Phenacyl bromide is the organic compound which is a powerful lachrymator as well as useful precursor to other organic compounds. Thus, it is widely used as one starting material in multicomponent reactions (MCRs) to form a product [5, 15–19]. Some works have reported the synthesis of pyrroles [5, 19] and quinoxalines [16–18] using phenacyl bromide as a reactant, and a convenient method for the synthesis in the presence of β-CD has been developed [5, 16]. Therefore, it can be believed that cyclodextrin by supramolecular interaction effects activation of phenacyl bromides through formation of host-guest complex during the course of reaction and thus facilitates the reaction (Fig. 2). The pyrrole has the potential to be a conducting material [20] and quinoxaline is a core constituent of many pharmaceuticals as well as agrochemicals [21]. Therefore, the physicochemical properties of phenacyl bromide in the presence and absence of β-CD are worth investigating.
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axis from 5 Å to −5 Å with a stepwise 1 Å and revolves from 0 to 360° around the Z-axis at 30° intervals. Computational method
Fig. 1 The structure of cyclodextrin
In this work, the computational method is used to describe the phenacyl bromide in the presence and absence of β-CD. Attention is more focused on the interaction of β-CD and phenacyl bromide using density functional theory (DFT) method. The orientation and position of the guest in the host cavity are investigated. To know more details, the natural bonding orbital (NBO), nuclear magnetic resonance (NMR) spectra, frontier molecular orbitals, Mulliken charge, and NPA charge are discussed.
All the calculations are performed using the Gaussian03 software package [22]. The method of DFT B3LYP [23] is employed. The isolated β-CD and guest are optimized using 6-31G(d,p) basis set firstly in gas phase, then the solvent effect of water (ε=78.390) is considered using the polarizable continuum model (PCM) [24]. The inclusion complexes of each step are optimized by PM3 without any restriction. The precise optimization of inclusion complex is calculated at the B3LYP/6-31G(d,p) level in gas phase which is based on the result of the preliminary PM3 calculation and then in water. In addition, the same level is employed to obtain NBO, NMR, frontier molecular orbital, Mulliken charge, and NPA charge. The NMR is investigated with gauge-including atomic orbital (GIAO) method [25] and the tetra methyl silane (TMS) as internal reference for 13C and 1H [26].
Results and discussion Energy analysis
Computational section Computational model The initial geometry of β-CD is constructed in Chem3D Ultra (Version8.0) according to the crystal structure, and the structure of phenacyl bromide is built using Gauss view. The hostguest complexes of β-CD and phenacyl bromide are constructed by manually, in Gauss view, making the phenacyl bromide into β-CD cavity through two possible ways (Fig. 3). The glycosidic oxygen atoms of β-CD are placed on XY plane and their center is defined the same as the coordinate system, meanwhile, the center of the guest is placed on Z-axis [3]. The relative position between host and guest is measured by the distance between the centers of phenacyl bromide and β-CD. The guest molecule passes through the host cavity along the Z-
The energy of the preliminary optimization is calculated at PM3 level to find the minimum. The relationship between the energy of the inclusion complex and position for two possible complexation models are shown in Fig. 4. Multiple local minima can be found for the entire process of inclusion in model a and model b. Only the global minimum of the two models are compared to a minimum. It is easy to find that the global minimum in model a is more negative than in model b. Thus, this inclusion complex is further refined and it is named complex a (CA). Generally, the synthesis is performed with β-CD as catalyst in water. Therefore, the single point energy of CA is further investigated in water. The single point energy of CA in gas phase and in water is −18,986,022.6 kJ mol−1 and −18,986, 306.3 kJ mol−1, respectively. The single point energies of CA in water are more negative than in gas phase, which indicates O
Fig. 2 Formation of an inclusion complex between phenacyl bromide and β-CD
Br
O
β -cyclodextrin
Br
β -cyclodextrin-phenacyl bromide complex
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X
Fig. 3 The two possible complexation models of phenacyl bromide into β-CD
O
model a Br
Z
Y X
O
Br
Z
model b
Y
that the complex formation of phenacyl bromide with β-CD in water is energetically favored.
NMR study To confirm the binding of phenacyl bromide into the β-CD cavity, the significant changes in the chemical shift are calculated. The isotropic chemical shift (δ) and chemical shift displacement (Δδ) are calculated according to: δ ¼ σΤΜS −σ Table 1
H1 H2 H3 H4 H5 H6 Fig. 4 Graphic diagram of the energy for the inclusion complex of phenacyl bromide into β-CD at different positions
ð1Þ
HNMR chemical shift (ppm) of β-CD in free and CA
1
δfreecal
δCAcal
Δ δcal
δfreeexp
δCAexp
Δ δexp
5.083 3.365 3.915 3.590 3.873 3.719
5.095 3.355 3.775 3.575 3.515 3.665
0.012 −0.010 −0.140 −0.015 −0.358 −0.054
– – 3.871 – 3.732 3.765
– – 3.830 – 3.677 3.759
– – −0.041 – −0.055 −0.006
Expermental data from ref [16]
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Table 2 Bond lengths(Å), angles(°), and stabilization energy E(2) (kcal mol−1) of hydrogen bonds in CA
From β-CD to guest
From guest to β-CD
a
Hydrogen bond
RY…H
θ
E(2)
C159-H163⋅⋅⋅O92 C156-H160⋅⋅⋅O122 C149-H151⋅⋅⋅O126 O105-H134⋅⋅⋅O154
2.33 2.69 2.94 1.97
157.78 150.75 163.49 164.42
2.28 087a 0.34 10.04a
C20-H67⋅⋅⋅O154
2.36
139.68
2.28a
Free HOMO
Free LUMO
Cross hydrogen bond with two coordination
Δδ ¼ δcomplex −δ f ree
ð2Þ
where σ is isotropic shielding value. The spectra data are shown in Table 1. The H3 and H5 protons located inside the cavity have obvious upfield shift, whereas only little changes in the chemical shifts of H2 and H4 protons located outside the cavity of β-CD are observed. This observation indicates that the internal H3 and H5 protons are more sensitive to the complexation effect than the other protons located outside. A relatively high association between phenacyl bromide and internal protons of β-CD which is in agreement with experimental result [16].
Hydrogen bond interactions To know more details about the supramolecular interaction of host-guest complex, the hydrogen bond is investigated by the natural bond orbital (NBO) analysis [27]. The results are summarized in Table 2. The second-order Møller-Plesset perturbation stabilization energy E(2), which is in relation to the donor-acceptor delocalization [28], is performed to measure the strength of hydrogen bonds.
CA HOMO
CA LUMO
Fig. 6 HOMO and LUMO orbitals of free phenacyl bromide and CA
The total of E(2) indicates the hydrogen bonds strength between β-CD and phenacyl bromide. The value of E(2) in CA reveals that more hydrogen bonds form from β-CD to phenacyl bromide, but these lone pairs are mainly delocalized to the anti-bonds of β-CD. This phenomenon is decided by the oxygen atom (O154) of carbonyl group delocalized to O105-H134 which results strong stabilization energy. Additionally, the calculated data indicate that there are three classical hydrogen bonds and two weak hydrogen bonds in CA (Fig. 5). Thus, it can imply that the hydrogen bonds play a significant role in CA, and the hydrogen bond between oxygen atom (O154) and O105H134 makes a great contribution to driving the phenacyl bromide molecule into the cavity of β-CD and activating phenacyl bromide. Thereby, the role of β-CD in synthesis is to activate phenacyl bromide and promote the reaction through H-bonding interactions.
Frontier molecular orbital The frontier molecular orbital which can reflect the electronic structures is investigated. Highest occupied molecular orbital (HOMO) and lowest virtual molecular orbital (LUMO) of CA are shown in Fig. 6. It should be noted that the HOMO is Table 3 complex
Free guest CA Fig. 5 Hydrogen bonds formed in CA
HOMO-LUMO energy (eV) for free guest and guest in IP (eV)
EA (eV)
ELUMO-EHOMO (eV)
ω (eV)
7.2110 6.7756
1.7959 2.5579
5.4151 4.2177
3.7453 5.1636
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Mulliken charge and NPA charge analysis for isolated phenacyl bromide and phenacyl bromide in CA at B3LYP/6-31G(d,p) level
Atom
Mulliken charge
NPA charge
Isolated phenacyl bromide
Phenacyl bromide in CA
Isolated phenacyl bromide
Phenacyl bromide in CA
Total charges of carbon atoms in phenyl group
−0.415
−0.495
−1.233
−1.253
Total charges of hydrogen atoms in phenyl group Charge of carbon atom in carbonyl group Charge of oxygen atom in carbonyl group Charge of carbon atom close to carbonyl group Total charges of hydrogen atoms close to carbonyl group Charge of bromine atom Total charges
0.509 0.402 −0.432 −0.301 0.340 −0.103 0
0.612 0.413 −0.470 −0.320 0.386 −0.084 0.042
1.241 0.554 −0.521 −0.613 0.550 0.022 0
1.284 0.583 −0.586 −0.606 0.574 0.024 0.020
mainly spread around β-CD, the LUMO almost focuses on phenacyl bromide. The HOMO represents the ability to donate electron while the LUMO as an electron acceptor represents the ability to obtain an electron [29]. Thus, the phenacyl bromide in CA is more likely to accept electrons than isolated phenacyl bromide. The HOMO energy can be used to measure the ionization potential (IP≈−EHOMO) [30, 31] and the LUMO energy has association with the electron affinity (EA ≈ −ELUMO) [31], in addition, the energy gap between HOMO and LUMO is a significant sign for chemical activity and larger value of energy gap means more stability [32]. In this case, these data are investigated to know more details about β-CD in catalyzing phenacyl bromide. The parameters are recorded in Table 3. The
electrophilicity (ω) [33] of free phenacyl bromide and CA are calculated according to: . ω ¼ μ2 2η ð3Þ μ¼
1 ðEHOMO þ E LUMO Þ 2
ð4Þ
η¼
1 ðE LUMO −EHOMO Þ 2
ð5Þ
The energy of IP is smaller in complex than in free, while the EA is larger. The energy gap becomes lower and the electrophilicity of phenacyl bromide is greater after formation of inclusion complex. This suggests that ionization potential of phenacyl bromide is decreased and electron affinity is
Fig. 7 The molecular electrostatic potential of free phenacyl bromide and CA a side view b top view
-5.00e-2
5.00e-2
a
b
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Fig. 8 Proposed mechanism for phenacyl bromide catalyzed by βCD
H O
O
enhanced upon complexation. The phenacyl bromide in the cavity of β-CD is more active and electrophilic than free. Charge distribution In order to confirm the results about electronic distribution, the electrostatic potential (ESP) and charge analyses for isolated guest and CA are researched, and recorded in Fig. 7 and Table 4, respectively. The ESP is related to the electronic density which provides a visual method to understand the sites for electrophilic and nucleophilic of a compound. Red and blue colors in the ESP map represent the regions of negative and positive potentials, respectively, and the green area signifies the neutral electrostatic potential. As shown in Fig. 7, three colors can be found in free phenacyl bromide, whereas only blue and green colors can be seen in phenacyl bromide of CA. The blue refers to the positive region and corresponds to the electron-poor. This result indicates that the phenacyl bromide in CA is electron-poor with electrophilic. The total Mulliken charges of phenacyl bromide change from 0 to 0.042 upon complexation, and the total NPA charges of phenacyl bromide change from 0 to 0.020 upon complexation. The same trend indicates the phenacyl bromide with positive charges in the complex. In other words, the phenacyl bromide donates electron upon complexation and the total charges of all atoms are certainly zero, so β-CD in CA must accept electron and vice versa. Therefore, phenacyl bromide is electron-deficient with electrophilicity in complex, which is in good agreement with the conclusion from frontier molecular orbitals analysis. While, the obvious negative change concentrates on oxygen atom in carbonyl group. Thus, the carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD.
Br
O
H O
Br
mechanism of β-CD as catalyst with phenacyl bromide is discussed. In the presence of β-CD, the phenacyl bromide enters into the cavity of β-CD forming hydrogen bonds between oxygen atom (O154) and secondary hydroxyl, then the electron density redistributes between β-CD and acetophenone. The electrophilic region is prevailing on the phenacyl bromide molecule and the carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD as shown in Fig. 8. Therefore, β-CD plays a significant role by forming an inclusion complex with phenacyl bromide from the secondary side and activating the molecule.
Conclusions The energy results show that the phenacyl bromide can bind with β-CD efficiently in water. The NBO analysis suggests that the hydrogen bonds between oxygen atom (O154) and secondary hydroxyl make a great contribution to driving the guest into the cavity of β-CD and keeping stability of complex. The proposed orientation of phenacyl bromide in the complex is affirmed by 1 HNMR of β-CD. The phenacyl bromide in the cavity of β-CD is more active and electrophilic than free. The carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD. Therefore, β-CD plays a significant role by forming an inclusion complex with phenacyl bromide from the secondary side and activating the molecule. Acknowledgments The authors wish to acknowledge the financial support from the Scientific Research Fund of Hunan Provincial Education Department (No. 12A132) for the research work.
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ORIGINAL PAPER
The reactivity of phenancyl bromide under β-cyclodextrin as supramolecular catalyst: a computational survey Yali Wan 1 & Xueye Wang 1 & Na Liu 1
Received: 7 January 2015 / Accepted: 13 April 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Phenacyl bromide as one starting material in multicomponent reactions (MCRs) with β-cyclodextrin (β-CD) as catalyst can get an excellent yield in short reaction times. The interaction of β-CD with phenacyl bromide plays an important role in this process. This paper studies the complex of β-CD with phenacyl bromide using density functional theory (DFT) method. Energy is investigated to find out the lowest energy of two possible complexation models. Hydrogen bonds are researched on the basis of natural bonding orbital (NBO) analysis. The relative position between phenacyl bromide and β-CD is confirmed by 1H nuclear magnetic resonance (1HNMR). The results of frontier molecular orbitals and charge distribution reveal that β-CD catalyst improves the reactivity and electrophilicity of phenacyl bromide, meanwhile, the carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD as catalyst. The reactivity of phenancyl bromide under β-CD as supramolecular catalysis is improved. Keywords β-Cyclodextrin (β-CD) . Density functional theory (DFT) . Inclusion complex . Phenacyl bromide . Supramolecular catalyst
Introduction Cyclodextrins (CDs) are a class of macrocyclic oligosaccharides connected together by α-1.4 glycosidic bonds [1]. α-, * Xueye Wang [email protected] 1
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, Hunan 411105, People’s Republic of China
β-, and γ-CD, consisting of six, seven, and eight glucose units (Fig. 1), respectively, are most commonly used [2]. They have molecular-compatible cavities in which internal is hydrophobic and external is hydrophilic [3, 4]. The wider upper rim of cavity is surrounded by the secondary hydroxyl groups, while the narrower opening lines with the primary hydroxyl groups [3]. They can provide additional hydrogen bonds for the binding of guests [5]. Owing to their particular structures, they have the ability to form host−guest complexes with a wide range of guests [4]. Thus, CDs have been extensively employed in diverse fields ranging from pharmaceutical, agriculture to recognition [6–8]. In the past, CDs as catalyst have been widely used in organic synthesis [9–11] by the way of host−guest complexes to improve selectivities and high yields. Interest in the catalyst of CD is increasing for its excellent property. Currently, many reviews about CD catalyst have been published [12–14]. However, the research about CD catalyst mostly concentrated on the method of experiment. Phenacyl bromide is the organic compound which is a powerful lachrymator as well as useful precursor to other organic compounds. Thus, it is widely used as one starting material in multicomponent reactions (MCRs) to form a product [5, 15–19]. Some works have reported the synthesis of pyrroles [5, 19] and quinoxalines [16–18] using phenacyl bromide as a reactant, and a convenient method for the synthesis in the presence of β-CD has been developed [5, 16]. Therefore, it can be believed that cyclodextrin by supramolecular interaction effects activation of phenacyl bromides through formation of host-guest complex during the course of reaction and thus facilitates the reaction (Fig. 2). The pyrrole has the potential to be a conducting material [20] and quinoxaline is a core constituent of many pharmaceuticals as well as agrochemicals [21]. Therefore, the physicochemical properties of phenacyl bromide in the presence and absence of β-CD are worth investigating.
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axis from 5 Å to −5 Å with a stepwise 1 Å and revolves from 0 to 360° around the Z-axis at 30° intervals. Computational method
Fig. 1 The structure of cyclodextrin
In this work, the computational method is used to describe the phenacyl bromide in the presence and absence of β-CD. Attention is more focused on the interaction of β-CD and phenacyl bromide using density functional theory (DFT) method. The orientation and position of the guest in the host cavity are investigated. To know more details, the natural bonding orbital (NBO), nuclear magnetic resonance (NMR) spectra, frontier molecular orbitals, Mulliken charge, and NPA charge are discussed.
All the calculations are performed using the Gaussian03 software package [22]. The method of DFT B3LYP [23] is employed. The isolated β-CD and guest are optimized using 6-31G(d,p) basis set firstly in gas phase, then the solvent effect of water (ε=78.390) is considered using the polarizable continuum model (PCM) [24]. The inclusion complexes of each step are optimized by PM3 without any restriction. The precise optimization of inclusion complex is calculated at the B3LYP/6-31G(d,p) level in gas phase which is based on the result of the preliminary PM3 calculation and then in water. In addition, the same level is employed to obtain NBO, NMR, frontier molecular orbital, Mulliken charge, and NPA charge. The NMR is investigated with gauge-including atomic orbital (GIAO) method [25] and the tetra methyl silane (TMS) as internal reference for 13C and 1H [26].
Results and discussion Energy analysis
Computational section Computational model The initial geometry of β-CD is constructed in Chem3D Ultra (Version8.0) according to the crystal structure, and the structure of phenacyl bromide is built using Gauss view. The hostguest complexes of β-CD and phenacyl bromide are constructed by manually, in Gauss view, making the phenacyl bromide into β-CD cavity through two possible ways (Fig. 3). The glycosidic oxygen atoms of β-CD are placed on XY plane and their center is defined the same as the coordinate system, meanwhile, the center of the guest is placed on Z-axis [3]. The relative position between host and guest is measured by the distance between the centers of phenacyl bromide and β-CD. The guest molecule passes through the host cavity along the Z-
The energy of the preliminary optimization is calculated at PM3 level to find the minimum. The relationship between the energy of the inclusion complex and position for two possible complexation models are shown in Fig. 4. Multiple local minima can be found for the entire process of inclusion in model a and model b. Only the global minimum of the two models are compared to a minimum. It is easy to find that the global minimum in model a is more negative than in model b. Thus, this inclusion complex is further refined and it is named complex a (CA). Generally, the synthesis is performed with β-CD as catalyst in water. Therefore, the single point energy of CA is further investigated in water. The single point energy of CA in gas phase and in water is −18,986,022.6 kJ mol−1 and −18,986, 306.3 kJ mol−1, respectively. The single point energies of CA in water are more negative than in gas phase, which indicates O
Fig. 2 Formation of an inclusion complex between phenacyl bromide and β-CD
Br
O
β -cyclodextrin
Br
β -cyclodextrin-phenacyl bromide complex
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X
Fig. 3 The two possible complexation models of phenacyl bromide into β-CD
O
model a Br
Z
Y X
O
Br
Z
model b
Y
that the complex formation of phenacyl bromide with β-CD in water is energetically favored.
NMR study To confirm the binding of phenacyl bromide into the β-CD cavity, the significant changes in the chemical shift are calculated. The isotropic chemical shift (δ) and chemical shift displacement (Δδ) are calculated according to: δ ¼ σΤΜS −σ Table 1
H1 H2 H3 H4 H5 H6 Fig. 4 Graphic diagram of the energy for the inclusion complex of phenacyl bromide into β-CD at different positions
ð1Þ
HNMR chemical shift (ppm) of β-CD in free and CA
1
δfreecal
δCAcal
Δ δcal
δfreeexp
δCAexp
Δ δexp
5.083 3.365 3.915 3.590 3.873 3.719
5.095 3.355 3.775 3.575 3.515 3.665
0.012 −0.010 −0.140 −0.015 −0.358 −0.054
– – 3.871 – 3.732 3.765
– – 3.830 – 3.677 3.759
– – −0.041 – −0.055 −0.006
Expermental data from ref [16]
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Table 2 Bond lengths(Å), angles(°), and stabilization energy E(2) (kcal mol−1) of hydrogen bonds in CA
From β-CD to guest
From guest to β-CD
a
Hydrogen bond
RY…H
θ
E(2)
C159-H163⋅⋅⋅O92 C156-H160⋅⋅⋅O122 C149-H151⋅⋅⋅O126 O105-H134⋅⋅⋅O154
2.33 2.69 2.94 1.97
157.78 150.75 163.49 164.42
2.28 087a 0.34 10.04a
C20-H67⋅⋅⋅O154
2.36
139.68
2.28a
Free HOMO
Free LUMO
Cross hydrogen bond with two coordination
Δδ ¼ δcomplex −δ f ree
ð2Þ
where σ is isotropic shielding value. The spectra data are shown in Table 1. The H3 and H5 protons located inside the cavity have obvious upfield shift, whereas only little changes in the chemical shifts of H2 and H4 protons located outside the cavity of β-CD are observed. This observation indicates that the internal H3 and H5 protons are more sensitive to the complexation effect than the other protons located outside. A relatively high association between phenacyl bromide and internal protons of β-CD which is in agreement with experimental result [16].
Hydrogen bond interactions To know more details about the supramolecular interaction of host-guest complex, the hydrogen bond is investigated by the natural bond orbital (NBO) analysis [27]. The results are summarized in Table 2. The second-order Møller-Plesset perturbation stabilization energy E(2), which is in relation to the donor-acceptor delocalization [28], is performed to measure the strength of hydrogen bonds.
CA HOMO
CA LUMO
Fig. 6 HOMO and LUMO orbitals of free phenacyl bromide and CA
The total of E(2) indicates the hydrogen bonds strength between β-CD and phenacyl bromide. The value of E(2) in CA reveals that more hydrogen bonds form from β-CD to phenacyl bromide, but these lone pairs are mainly delocalized to the anti-bonds of β-CD. This phenomenon is decided by the oxygen atom (O154) of carbonyl group delocalized to O105-H134 which results strong stabilization energy. Additionally, the calculated data indicate that there are three classical hydrogen bonds and two weak hydrogen bonds in CA (Fig. 5). Thus, it can imply that the hydrogen bonds play a significant role in CA, and the hydrogen bond between oxygen atom (O154) and O105H134 makes a great contribution to driving the phenacyl bromide molecule into the cavity of β-CD and activating phenacyl bromide. Thereby, the role of β-CD in synthesis is to activate phenacyl bromide and promote the reaction through H-bonding interactions.
Frontier molecular orbital The frontier molecular orbital which can reflect the electronic structures is investigated. Highest occupied molecular orbital (HOMO) and lowest virtual molecular orbital (LUMO) of CA are shown in Fig. 6. It should be noted that the HOMO is Table 3 complex
Free guest CA Fig. 5 Hydrogen bonds formed in CA
HOMO-LUMO energy (eV) for free guest and guest in IP (eV)
EA (eV)
ELUMO-EHOMO (eV)
ω (eV)
7.2110 6.7756
1.7959 2.5579
5.4151 4.2177
3.7453 5.1636
J Mol Model (2015) 21:131 Table 4
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Mulliken charge and NPA charge analysis for isolated phenacyl bromide and phenacyl bromide in CA at B3LYP/6-31G(d,p) level
Atom
Mulliken charge
NPA charge
Isolated phenacyl bromide
Phenacyl bromide in CA
Isolated phenacyl bromide
Phenacyl bromide in CA
Total charges of carbon atoms in phenyl group
−0.415
−0.495
−1.233
−1.253
Total charges of hydrogen atoms in phenyl group Charge of carbon atom in carbonyl group Charge of oxygen atom in carbonyl group Charge of carbon atom close to carbonyl group Total charges of hydrogen atoms close to carbonyl group Charge of bromine atom Total charges
0.509 0.402 −0.432 −0.301 0.340 −0.103 0
0.612 0.413 −0.470 −0.320 0.386 −0.084 0.042
1.241 0.554 −0.521 −0.613 0.550 0.022 0
1.284 0.583 −0.586 −0.606 0.574 0.024 0.020
mainly spread around β-CD, the LUMO almost focuses on phenacyl bromide. The HOMO represents the ability to donate electron while the LUMO as an electron acceptor represents the ability to obtain an electron [29]. Thus, the phenacyl bromide in CA is more likely to accept electrons than isolated phenacyl bromide. The HOMO energy can be used to measure the ionization potential (IP≈−EHOMO) [30, 31] and the LUMO energy has association with the electron affinity (EA ≈ −ELUMO) [31], in addition, the energy gap between HOMO and LUMO is a significant sign for chemical activity and larger value of energy gap means more stability [32]. In this case, these data are investigated to know more details about β-CD in catalyzing phenacyl bromide. The parameters are recorded in Table 3. The
electrophilicity (ω) [33] of free phenacyl bromide and CA are calculated according to: . ω ¼ μ2 2η ð3Þ μ¼
1 ðEHOMO þ E LUMO Þ 2
ð4Þ
η¼
1 ðE LUMO −EHOMO Þ 2
ð5Þ
The energy of IP is smaller in complex than in free, while the EA is larger. The energy gap becomes lower and the electrophilicity of phenacyl bromide is greater after formation of inclusion complex. This suggests that ionization potential of phenacyl bromide is decreased and electron affinity is
Fig. 7 The molecular electrostatic potential of free phenacyl bromide and CA a side view b top view
-5.00e-2
5.00e-2
a
b
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Fig. 8 Proposed mechanism for phenacyl bromide catalyzed by βCD
H O
O
enhanced upon complexation. The phenacyl bromide in the cavity of β-CD is more active and electrophilic than free. Charge distribution In order to confirm the results about electronic distribution, the electrostatic potential (ESP) and charge analyses for isolated guest and CA are researched, and recorded in Fig. 7 and Table 4, respectively. The ESP is related to the electronic density which provides a visual method to understand the sites for electrophilic and nucleophilic of a compound. Red and blue colors in the ESP map represent the regions of negative and positive potentials, respectively, and the green area signifies the neutral electrostatic potential. As shown in Fig. 7, three colors can be found in free phenacyl bromide, whereas only blue and green colors can be seen in phenacyl bromide of CA. The blue refers to the positive region and corresponds to the electron-poor. This result indicates that the phenacyl bromide in CA is electron-poor with electrophilic. The total Mulliken charges of phenacyl bromide change from 0 to 0.042 upon complexation, and the total NPA charges of phenacyl bromide change from 0 to 0.020 upon complexation. The same trend indicates the phenacyl bromide with positive charges in the complex. In other words, the phenacyl bromide donates electron upon complexation and the total charges of all atoms are certainly zero, so β-CD in CA must accept electron and vice versa. Therefore, phenacyl bromide is electron-deficient with electrophilicity in complex, which is in good agreement with the conclusion from frontier molecular orbitals analysis. While, the obvious negative change concentrates on oxygen atom in carbonyl group. Thus, the carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD.
Br
O
H O
Br
mechanism of β-CD as catalyst with phenacyl bromide is discussed. In the presence of β-CD, the phenacyl bromide enters into the cavity of β-CD forming hydrogen bonds between oxygen atom (O154) and secondary hydroxyl, then the electron density redistributes between β-CD and acetophenone. The electrophilic region is prevailing on the phenacyl bromide molecule and the carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD as shown in Fig. 8. Therefore, β-CD plays a significant role by forming an inclusion complex with phenacyl bromide from the secondary side and activating the molecule.
Conclusions The energy results show that the phenacyl bromide can bind with β-CD efficiently in water. The NBO analysis suggests that the hydrogen bonds between oxygen atom (O154) and secondary hydroxyl make a great contribution to driving the guest into the cavity of β-CD and keeping stability of complex. The proposed orientation of phenacyl bromide in the complex is affirmed by 1 HNMR of β-CD. The phenacyl bromide in the cavity of β-CD is more active and electrophilic than free. The carbonyl group of phenacyl bromide more easily gives a carbocationic intermediate in the presence of β-CD. Therefore, β-CD plays a significant role by forming an inclusion complex with phenacyl bromide from the secondary side and activating the molecule. Acknowledgments The authors wish to acknowledge the financial support from the Scientific Research Fund of Hunan Provincial Education Department (No. 12A132) for the research work.
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