Diacylation of 4-Methylanisole: A Second Term Organic Project Using

Chapter 10

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Diacylation of 4-Methylanisole: A Second Term Organic Project Using HSQC and HMBC Vernon R. Miller* Department of Chemistry, Roanoke College, 221 College Lane, Salem, Virginia 24153, United States *E-mail: [email protected]

Structures of molecules are very important in organic chemistry, and NMR spectroscopy is very useful in experimentally determining structures of organic compounds. This chapter describes the use of two-dimensional HSQC and HMBC NMR experiments in determining the structures of unexpected reaction products in the final projects experiment in sophomore Organic Chemistry lab.

Introduction At Roanoke College, the last experiment of the second term of Organic Chemistry lab typically is a multi-week, projects lab with teams of 2-4 students doing different projects, and ending with oral presentations. The students are given a few details on the experiment, from which they are to develop a protocol and then execute the protocol and characterize the products. Typically there is a “twist” to the experiment in that they cannot predict the product(s) or the product(s) are not what would be expected. This chapter presents an experiment in which the students are instructed to use a Friedel-Crafts reaction to add two propionyl groups to 4-methylanisole. The interesting “twist” in this reaction is that, depending on the conditions, the OCH3 group of the 4-methylanisole can be converted to an OH group. The use of the proton and carbon NMR, along with HSQC and HMBC techniques, gives information which can be used to completely identify the reaction product. This chapter presents a research-type project that can be completed in two weeks. The product(s) of this project cannot be found on the internet and cannot be predicted from material normally covered in the first year of organic chemistry. © 2016 American Chemical Society

Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


This chapter does not present a thorough analysis of the products that might be formed in these reactions. Since the students are given minimal guidance, they come up with different reaction conditions and thus, different products. This chapter shows that through the use of 1H and 13C NMR spectra, including HSQC and HMBC techniques, the identities of the products can be determined, even in mixtures. The project presented in this chapter has been performed over three years by three teams for a total of ten students. With instructor guidance, all the teams eventually realized that much more was happening than diacylation, and they got some understanding of the identities of the products. The identities of these products depended on the reaction conditions.

Friedel-Crafts Acylation Reactions The Friedel-Crafts acylation reaction is a common experiment used in second term organic chemistry labs (1). The addition of an acyl group to an aromatic compound deactivates the compound toward electrophilic attack and makes it more difficult to add another acyl group. With appropriate conditions these reactions typically give a product that is predominantly one compound. This is one of the experiments all the students do before the projects lab. For the projects lab, one of four or five projects is given to each student team. One of the projects is an extension of the Friedel-Crafts reaction the students already have run in which they are instructed to try to add two acyl groups to the aromatic compound. One of the “twists” is that with excess aluminum chloride, the OCH3 group can be converted to an OH group. With heat and excess acyl chloride and aluminum chloride the diacylated phenol can also be obtained. While mixtures typically are obtained and not purified, the use of proton, carbon, HSQC, and HMBC NMR techniques can be used to identify the products and to assign specific proton and carbon NMR signals to specific atoms in the compounds. That the students can use their results from the Friedel-Crafts monoacylation reaction from earlier in the term can be quite helpful. Scheme 1 gives a summary of the reactions involved.

Scheme 1. Summary of reactions involved. Usually product mixtures are obtained. 138 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


NMR Background In recent years the use of more advanced NMR techniques, such as HSQC, HMBC, and COSY has been described in the literature (2–5). In HSQC the proton spectrum is shown on the X (or Y) axis and the carbon spectrum is shown on the Y (or X) axis. The HSQC signal is presented as concentric circles between the axes. The HSQC information is obtained by going straight up to the peak on the proton spectrum and going straight across to the peak on the carbon spectrum. This correlation indicates that the hydrogen associated with that peak in the proton spectrum is directly attached to the carbon associated with that peak in the carbon spectrum. Thus, HSQC analysis provides information on which hydrogen(s) are directly connected to which carbon. In addition the color of the HSQC peak can indicate whether the carbon has an even number of hydrogen atoms attached (CH2, usually blue) or an odd number of hydrogens attached (CH or CH3, usually red). Figure 1 shows the HSQC spectrum of ethanol, with lines drawn showing how to obtain the HSQC information. The concentric circles in the upper right hand corner of the spectrum is one of the HSQC peaks, while the lines straight up and straight across show that the atoms of these signals on the proton and carbon spectra are directly attached to each other. Similarly, the concentric circles near the lower left shows that the hydrogen responsible for the hydrogen quartet at 3.6 ppm is directly attached to the carbon responsible to the carbon signal at 59 ppm. The color information (not shown) indicates that the lower left HSQC signal is associated with a CH2 group and that the upper right HQSC signal is associated with a CH3 or a CH. (Other information must be used to choose between the CH3 and CH possibilities.) Note that the signal at 2.4 ppm for the hydrogen on the oxygen does not show an HSQC signal.

Figure 1. HSQC NMR spectrum of ethanol.

An HMBC spectrum is quite similar to an HSQC spectrum, except there can be multiple signals for each carbon and hydrogen, and that each signal shows two or three bond coupling. Another difference is that not all the possible signals appear. The lack of a signal is not reliable evidence.

139 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

HSQC and HMBC analysiss relies on coupling constants between the two atoms. For HSQC analysis the default coupling constant in the NMR program parameters works well. For HMBC analysis there is more variation in coupling constants. The coupling constant can be changed in the NMR program parameters, but for the data presented here, that was not necessary.


Nomenclature This chapter discusses compounds formed from 4-methylanisole starting material. In some of the derivative products, the methoxy group of the anisole is converted to a hydroxy group. In the standard system of nomenclature this changes the base name of the compound and the numbering system. To make it easier to follow the changes and not have the numbering of the positions change, the compounds will be named as derivatives of toluene. Thus, 4-methylanisole will be named 4-methoxytoluene, 4-methyl-2-propionylanisole will be named 4-methoxy-3-propionyltoluene, and the name of the compound formed when the methoxy group of 4-methyl-2-propionylanisole is converted to a hydroxy group will be named 4-hydroxy-3-propionyltoluene.

Experimental Section NMR spectra were recorded with a Varian 400MR on 20-40 mg of sample in CDCl3. The total time per sample for 1H, 13C, HSQC, HMBC, and COSY experiments was about an hour. Default parameters with the VnmrJ software, VERSION 3.2, REVISION A were used. The only attempts to modify these parameters were to increase the number of acquisitions to increase the signal to noise ratio, which occasionally was useful, and to increase the resolution in HSQC and HMBC by increasing the number of carbon increments. This latter did not seem to be useful. While the spectra are referred to as HSQC, HMBC, and COSY, the spectra that actually were recorded were HSQCAD, gHMBCAD, and gCOSY, respectively, where the g stands for gradient and the AD stands for adiabatic. 1H spectra were recorded with an acquisition time of 2.6 sec, a relaxation delay of 1.0 sec, a 45 degree observe pulse, and 8 scans, for a total acquisition time of 29 sec. While these settings might not have allowed for complete relaxation, the relative integral values were close enough. 13C spectra were recorded with an acquisition time of 1.3 sec, a relaxation delay of 1.0 sec, a 45 degree observe pulse, and 256 scans, for a total acquisition time of 9 minutes, 52 sec. For HSQC spectra, the acquisition in F2 (hydrogen) had an acquisition time of 0.15 sec and a relaxation delay of 1.0 sec at a 45 degree pulse. F1 (carbon) acquisition had 96 t1 increments with two scans per t1 increment, for a total acquisition time of 10 minutes, 37 sec. 1H-13C multiplicity was enabled. The parameters were for one-bond J1xh of 146 Hz. For HMBC spectra the acquisition in F2 (hydrogen) had an acquisition time of 0.15 sec and a relaxation delay of 1.0 sec at a 45 degree pulse. F1 (carbon) acquisition had 200 t1 increments with four scans per t1 increment, for a total acquisition time of 33 minutes, 31 sec. The parameters were for multiple 140



bond Jnxh of 8 Hz. A 2-step J1xh filter was applied. For COSY spectra the acquisition in F2 had an acquisition time of 0.15 sec and a relaxation delay of 1.0 sec at a 45 degree pulse. F1 acquisition had 128 t1 increments with one scan per t1 increment, for a total acquisition time of 3 minutes, 10 sec. The experimental procedure was adapted from the Friedel-Crafts experiment in Pavia et al. (1). The glassware was dried at 100-120°C overnight. During the reaction, the system was protected from moisture by two drying tubes of anhydrous calcium chloride. The anhydrous aluminum chloride was from stock and might have picked up some water. In one student protocol, 18 mmol of propionyl chloride in 5 mL of CH2Cl2 was added over 10 minutes to 18 mmol of anhydrous aluminum chloride in 5 mL of CH2Cl2 cooled in ice. Then 4.3 mmol of 4-methoxytoluene 1 (4-methylanisole) in 5 mL of CH2Cl2 was added over 10 min. The reaction mixture was removed from the ice water bath and allowed to come to room temperature over 30 min. This mixture was added to 5 mL of conc. HCl and 10 g of ice and then mixed for 10 min. The mixture was partitioned in a separatory funnel and the aqueous layer extracted with 5 mL of CH2Cl2. The organic layer was washed with 2-5 mL portions of saturated aqueous sodium bicarbonate, dried with anhydrous sodium sulfate, and the solvent removed under vacuum to give 0.30 g of an oil. This sample was used without further purification. 1H NMR analysis showed this sample to be a 1:2 mixture of 4-hydroxy-3-propionyltoluene 3:4-methoxy-3-propionyltoluene 2, a 40% conversion of the starting 4-methoxytoluene to products. In a similar reaction run in a previous year, 1,2-dichloroethane was used instead of dichloromethane and after warming to room temperature the mixture was gently refluxed for 60 min, 33 mmol of 4-methoxytoluene, 83 mmol of aluminum chloride, and 85 mmol of propionyl chloride gave 3.41 g of an oil. 1H NMR analysis showed this sample to be a 1:3 mixture of 4-hydroxy-3,5-dipropionyltoluene 4: 4-hydroxy-3-propionyltoluene 3, a 57% conversion of the starting 4-methoxytoluene to products.

Identification of the Product of the Standard Acylation Reaction Previously in the term, students had prepared and characterized the 4-methoxy-3-propionyltoluene product from the Friedel-Crafts reaction. For this product, 1D NMR alone cannot be used to completely identify the product. 1H NMR analysis (Figure 2) shows that a propionyl group was added to the ring, but it does not show whether it added ortho or meta to the methoxy group. Students used HSQC and HMBC analysis to identify where the propionyl group added to the ring. They were expected to use the information gained from this earlier assignment to the products in the project lab.



Figure 2. 1H NMR spectrum of the 4-methoxy-3-propionyltoluene. The small peak at 7.24 ppm is CDCl3.

Table I gives the NMR assignments for the 4-methoxy-3-propionyltoluene product. The instructions to the students for completing this table were: 1. 2.

3. 4. 5.

6.

Use the carbon spectrum and enter the carbon chemical shifts, to 0.1 ppm, in numerical order, starting with the largest chemical shift. Use the HSQC spectrum and enter the approximate hydrogen chemical shifts of the hydrogens attached to each carbon, and to enter the color of the HSQC peak. Use the integrated hydrogen spectrum and enter the exact chemical shifts (to 0.001 ppm), their appearances, and their integrated areas. Use the intregral areas to determine the number of hydrogen atoms in each signal. Use all the information in the table and correlate as many hydrogen and carbon NMR signals to specific atoms in the product as possible, realizing that not all the correlations can be made. Use HMBC to make the rest of the correlations. If there were still ambiguities, they were to state this specifically.

While using proton, carbon, and HSQC, all of the signals need to be considered and some, such as residual NMR solvent signals, need to be dismissed. It also is true that for a rigorous determination of the structure, all of the HMBC signals need to be considered. However, many times only one signal will reveal the identity of the product. It is helpful if the students are given guidance with using HMBC. Such guidance could be to first have them examine the structure of the possible products and decide which HMBC signals would be useful. Then have them zoom in on the region.


Table I. NMR Data for 4-Methoxy-3-propionyltoluene 1H


shift, ppm

HSQC Color

H Atom

Appearance#

7.211

red

6

doublet with fine structure, (doublet of doublets, J=8.4, 2.4 Hz)

7.450

red

2

Singlet with fine structure (doublet, J=2.4 Hz)

Number of H

13C

shift, ppm

C Atom

*

203.7

8

156.5

4

*

1

133.5

6

*

1

130.4

2

*

129.8

1

*

128.2

3

* *

6.830

red

5

doublet (J=8.4 Hz)

1

111.5

5

3.839

red

11

Singlet

3

55.5

11

2.956

blue

9

Quartet

2

36.9

9

2.274

red

7

Singlet

3

20.2

7

1.134

red

10

Triplet

3

8.4

10

*

An asterisk in this column indicates that HMBC was necessary to assign this signal to specific atoms. # Typically the appearance relates to three bond coupling. With good resolution longer range coupling can be seen. The first description relates to three bond coupling, while the second description is what is can be seen with good resolution.

Another approach would be to have them zoom in on a specified region of the HMBC spectrum. The specifications could be hydrogen and carbon chemical shift values. The specifications could also be something like “the region in the HMBC spectrum that would show two and three bond correlations between the carbon atom of the methyl group that is directly attached to the aromatic ring and the hydrogen atoms on the aromatic ring”. Then ask the students what information can be drawn from these HMBC signals and what does it say about the identity of the product? For the monoacylation product of 4-methoxytoluene the easiest way to determine if the propionyl group adds ortho or meta to the aromatic methyl group is to look at the HMBC region covering 2.274 ppm in the hydrogen region and 6.8-7.5 ppm in the carbon region (the region covering the signals for C7 and the aromatic ring hydrogens). If C7 shows only one cross signal with an aromatic hydrogen, then the propionyl group added ortho to the aromatic methyl group. If C7 shows two cross signals with aromatic hydrogens, then the propionyl group added meta to the aromatic hydrogen. Figure 3 shows the expanded HMBC of this region, showing that the product is 4-methoxy-3-propionyltoluene.



Figure 3. Expanded HMBC Spectrum of 4-methoxy-3-propionyltoluene. The hydrogen signal at 7.24 ppm is CDCl3.

Identification of the Products of the Diacylation Attempt at Room Temperature Figure 4 gives the 1H NMR spectrum of the product of the reaction of 4methoxytoluene with excess aluminum chloride and propionyl chloride that gives the 1:2 mixture of 4-hydroxy-3-propionyltoluene:4-methoxy-3-propionyltoluene as described in the experimental section.

Figure 4. 1H NMR of the 1:2 mixture of 4-hydroxy-3-propionyltoluene:4methoxy-3-propionyltoluene. The small peak at 7.24 ppm is CDCl3. The shaded areas are of the methoxy compound. 144 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Table II gives the NMR assignments for the 4-hydroxy-3-propionyltoluene as obtained from Figure 4. A first glance at the hydrogen spectrum shows an interesting signal near 12 ppm. While this is in the range for a carboxylic acid, such acid signals are usually very broad. A more careful examination of the spectrum suggests that there are two compounds present, in a 1:2 ratio. Area measurements confirm the 1:2 ratio, and the striking similarities of the two sets of signals suggest that they might be isomers with different substitution positions on the aromatic ring. However, an even more careful examination reveals that there is only one methoxy signal, near 4 ppm. Comparison of the NMR spectrum of this mixture with the spectrum of the pure compound obtained and characterized earlier in the term shows which peaks belong to the new compound.

Table II. NMR Data for 4-Hydroxy-3-propionyltoluene. Data taken from a 1:2 mixture of 4-hydroxy-3-propionyltoluene:4-methoxy-3-propionyltoluene. 1H

shift, ppm

HSQC Color

H Atom

Appearance

7.247

red

6

Doublet with fine structure (Doublet of doublets, J=8.8, 2.2 Hz)

7.517

red

2

Singlet with fine structure (Doublet, J=2.0 Hz)

Number of H

13C

shift, ppm

C Atom

207.0

8

160.2

4

*

1

137.2

6

*

1

129.5

2

*

127.9

1

*

118.8

3

* *

6.858

red

5

Doublet, J=8.4

1

118.2

5

3.002

blue

9

Quartet

2

31.5

9

2.284

red

7

Singlet

3

20.5

7

1.208

red

10

Triplet

3

8.2

10

11

Singlet

1

12.168

*

*

An asterisk in this column indicates that HMBC was necessary to assign this signal to specific atoms.

The only hydrogen signal unaccounted for is the interesting one at about 12 ppm that has an area of one. The absence of an area three methoxy signal and the presence of a new, area one signal can be interpreted as showing that somehow, the methoxy group has been converted to a hydroxy group. The large downfield shift can be explained by hydrogen bonding with the oxygen of the carbonyl. 145 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The HMBC signals of this hydrogen at about 12 ppm with the carbon attached to the oxygen on the ring at 160.2 ppm support the conversion of the methyl of the methoxy to a hydrogen. While there is an HMBC signal that can be correlated to the 11.168 ppm signal on the hydrogen axis, there are two peaks (118.2 and 118.8 ppm) on the carbon axis to which it can be correlated. The normal resolution of HMBC spectra does not allow correlating this signal with the carbon signal at 118.2 ppm (C5) and/or the carbon signal at 118.8 ppm (C3). This expanded part of the HMBC spectrum is shown in Figure 5.

Figure 5. The expanded part of the HMBC spectrum of 4-hydroxy-3propionyltoluene showing the signals of the hydrogen at about 12 ppm with the aromatic carbons.

Identification of the Products of the Diacylation Attempt at 80 °C Figure 6 gives the 1H NMR spectrum of the products of the reaction run at 80 °C with excess aluminum chloride and propionyl chloride that gives the 1:3 mixture of 4-hydroxy-3,5-dipropionyltoluene:4-hydroxy-3-propionyltoluene as described in the experimental section. Table III gives the NMR assignments for the 4-hydroxy-3,5dipropionyltoluene as obtained from Figure 6. The identification of the products of the reaction with excess aluminum chloride and propionyl chloride at 80 °C is more complicated because the information from the Friedel-Crafts reaction earlier in the term is not as useful. 146 Soulsby et al.; NMR Spectroscopy in the Undergraduate Curriculum: First Year and Organic Chemistry Courses Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 6. 1H NMR of the 1:3 mixture of 4-hydroxy-3,5-dipropionyltoluene:4hydroxy-3-propionytoluene. The large peak at 3.7 ppm is residual dichloroethane while the small peak at 7.24 ppm is CDCl3. Part B is the entire spectrum while part A shows the pertanent areas. The shaded areas in B are of the monohydroxy compound. There is substantial overlap of the triplets around 1.2 ppm.

Again, the most unusual signals in the hydrogen spectrum are the sharp singlets at 12-13 ppm. After realizing that the large singlet at 3.7 ppm is residual C2H4Cl2, the second most striking aspect of this spectrum is that there are no methyl groups attached to oxygen. Once the possibility of the methoxy groups being converted to hydroxy groups has been realized, the spectrum is much easier to interpret. There are too many aromatic peaks for a single compound, and there are two sets of methylene quartets. Therefore, this sample must be a mixture. One reasonable assumption is that only one propionyl group added, but to different positions on the ring. This can be mostly ruled out by the absence of enough aromatic hydrogen signals. Another assumption is that there is a compound with one propionyl group added and another compound with two propionyl groups added. After integrating the signals and drawing reasonable products from postulates made so far, there are various different ways to arrive at the conclusion of a 1:3 mixture of 4-hydroxy-3,5-dipropionyltoluene:4-hydroxy-3-propionytoluene. The HMBC spectrum shows cross peaks for the hydrogen signal at 2.276 ppm (H7) coupled to the carbon signal at 136.0 ppm (C2,6) and for the hydrogen signal at 7.712 ppm (H2) coupled to the carbon signal at 20.3 ppm (C7). This is confirmation that the propionyl groups added meta to the methyl group on the aromatic ring.


Table III. NMR Data for 4-Hydroxy-3,5-dipropionyltoluene. Data taken from a 1:3 mixture of 4-hydroxy-3,5-dipropionyltoluene:4-hydroxy-3propionyltoluene. 1H

shift, ppm

HSQC Color

H Atom

Appearance

Number of H

8,11


7.712

red

2,6

singlet

2

13C

shift, ppm

C Atom

204.7

8,11

160.1

4

136.0

2,6

127.6

1

123.7

3,5

* #

*

*

2.027

blue

9,12

quartet

4

34.5

9,12

2.276

red

7

singlet

3

20.3

7

#

1.163

red

10,13

triplet

6

8.1

10,13

#

13.156

14

1

*

An asterisk in this column indicates that the carbon assignment is tentative. # A number sign in this column indicates that relative intensities were used to differentiate the carbon in this compound from a carbon in the mono phenol.

Concluding Remarks This is one of the more challenging end-of-term projects, and students may need guidance with analyzing the data. One thing that students often need to be reminded, is that for a compound to be present, ALL the signals need to be present, or accounted for in some way. Another stumbling block is that students often forget to consider and eliminate non-sample signals, such as those signals from the NMR solvent, the reaction and recrystallization solvents, unreacted starting materials, etc. Sometimes students need to be reminded to consider all experimental data concurrently and not to completely analyze one spectrum before moving on to the next. The students might need to be told they are expected to use the experience and data from the standard Friedel-Crafts reaction they did earlier in the term. It is preferable to have 3-4 students carry out the reactions, under somewhat different conditions, so they can get different product ratios. A 1:1 product ratio is difficult to interpret because integral areas are not useful in deciding which signals belong to which compounds. A 1:2 or 1:3 product ratio is better. We also had students obtain COSY NMR spectra and GC-MS data, however, the COSY spectra were not useful. The GC data are useful in helping determine the number of compounds present. However, the relative areas of the GC peaks do not relate very well with the ratios of the compounds present. Students often forget that areas in GC are not nearly so useful as areas in NMR. The mass spectra are not useful in identifying the compounds by a library search because these compounds are not in the library database. The spectra do show molecular ions, but we haven’t discussed fragmentation enough to make the mass spectra more valuable for students. 148


Sometimes long range (four bond) coupling appears in aromatic regions of the NMR spectra and can be confusing to students. When it does show, it can be quite useful. However, concentration, shimming, and the presence of other compounds can cause such coupling to not show.

References


1.

2.

3. 4. 5.

Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Engel, R. G. Introduction to Organic Laboratory Techniques: A Small Scale Approach, 2nd ed.; Brooks/ Cole: Belmont, CA, 2005. Two-Dimensional Experiments with Vnmrj 2.2. http:// http://www.umich.edu/~chemnmr/docs/2D_experiments-v2.pdf (accessed November 29, 2015). Simpson, J. H. Organic Structure Determination Using 2-D NMR Spectroscopy: A Problem-Based Approach; Elsevier, Boston, MA, 2008. Richards, S. A.; Hollerton, J. C. Essential Practical NMR for Organic Chemistry; Wiley: West Sussex, U.K., 2011. Miller, V. R. Use of HSQC, HMBC, and COSY in Sophomore Organic Chemistry Lab. In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., Anna, L. A., Wallner, A. S., Eds.; ACS Symposium Series 1128; American Chemical Society: Washington, DC, 2013; pp 103−128.


Diacylation of 4-Methylanisole: A Second Term Organic Project Using

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