Application of 1H and 1D TOCSY NMR Spectroscopy to the Free

Chapter 6

Downloaded by UNIV OF FLORIDA on December 7, 2016 | http://pubs.acs.org Publication Date (Web): September 15, 2016 | doi: 10.1021/bk-2016-1221.ch006

Application of 1H and 1D TOCSY NMR Spectroscopy to the Free Radical Chlorination of Alkanes Experiment David Soulsby* Department of Chemistry, University of Redlands, Redlands, California 92374, United States *E-mail: [email protected]

The free radical halogenation of alkanes experiment is found in many organic chemistry laboratory curricula because it can be used to introduce many important concepts. We describe how 1H NMR spectroscopy can be used to quantitate the chlorinated products from a structurally diverse group of substrates. Through data sharing and the use of characteristic chemical shift data for each product, organic chemistry students can calculate relative reactivity values for an array of different types of hydrogen atoms. They then use their data to develop an understanding of the important role that substitution and functionality play in radical reactivity. Our advanced students are not provided with chemical shift data, and instead use a series of 1D 1H TOCSY NMR experiments to elucidate the structure of each product before determining relative reactivity values.

Introduction The free radical chlorination of alkanes experiment is found in many undergraduate organic chemistry laboratory sequences because it provides an opportunity to introduce numerous topics that are central to organic chemistry (1–5). These topics include the introduction of a powerful method for functionalizing alkanes, the use of advanced instrumentation to analyze product distributions, and the application of physical organic chemistry concepts such as bond dissociation energies, reaction coordinate-energy diagrams, Hammond’s © 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.


postulate, and reaction selectivity. The analysis of multiple substrates, and the sharing of data, means that students can determine trends and answer more complex chemistry questions than if only one substrate was analyzed. This can strengthen the construction of knowledge and reinforce the relationships between experimental and theoretical work (6–9). Since this experiment is highly amenable to adaptation in the undergraduate curriculum, a discussion of the experiment is provided prior to a discussion of the application of NMR spectroscopy. The synthesis of the monochlorinated alkanes begins with the generation of a chlorine radical typically using either thermal initiation or photochemical initiation methods, Figure 1.

Figure 1. Free radical chlorination of 1-chlorobutane using thermal and photochemical initiation approaches. With thermal initiation, 2,2′-azobisisobutyronitrile (AIBN) or a peroxide (typically benzoyl peroxide) is heated until homolytic cleavage occurs to give a stabilized radical. This radical then reacts with sulfuryl chloride that is present in solution to generate the chlorine radical. This process requires elevated temperatures, can take 20-30 minutes to ensure complete reaction, and generates toxic gases. Additionally, both of these initiators are toxic and the benzoyl peroxide is potentially explosive. Photochemical initiation provides a more viable alternative to the generation of chlorine radicals, with diatomic chlorine generated in situ via the reaction of hydrochloric acid and bleach. Chlorine is then transferred from the aqueous layer to the organic layer via shaking or magnetic stirring. There it is homolytically cleaved to the chlorine radical in the presence of a light source, usually an unfrosted light bulb. Reaction times using this method are typically only 5-10 minutes. Despite the generation of only small amounts of chlorine, its toxicity presents a serious hazard, meaning that the reaction scale should be small and it should be carried out in a fully functioning fume hood. The rate-determining step of the reaction occurs in the first propagation step and involves abstraction of a hydrogen atom from the alkane by the chlorine radical, Figure 2 (10). Bond forming and bond breaking (C-H and H-Cl bonds) for the primary and secondary radicals are reflected by the ΔH° values. Hammond’s postulate relates the location, energy and structure of a transition state to the energies and 82

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.


structure of the reactants and products. Since free radical chlorination reactions are moderately exothermic (though not as exothermic as fluorination reactions), they have moderately early transition states with energies and structures that reflect more contribution from the reactants than the products. The energies of activation for each pathway reflect this difference, resulting in a small but not insignificant difference in the relative rates of reaction for each pathway. When radical formation is endothermic, as in the free radical bromination of alkanes, increased selectivity is observed because the transition state is much later. The ΔΔH° value remains 13 kJ/mol, since it is reflective of the bond energies leading to the primary and secondary radicals, however the late transition state means that the difference between the activation energies is now 12 kJ/mol (instead of 2 kJ/mol with chlorination), and much more closely reflects the stabilities of the radical products. The significant rate differences for each pathway now lead to near exclusive formation of the most stable radical product for bromination.

Figure 2. Chlorine radical abstraction of a primary and secondary hydrogen atom from propane.

The second step of the chain reaction, occurs by reaction of the alkyl radical with chlorine to afford the alkyl halide product and to regenerate the chlorine radical, Figure 3.

Figure 3. Free radical reaction with chlorine to generate 1-chloro- and 2-chloropropane.

The highly exothermic nature of the second step for both chlorination and bromination mean that the transition states occur early, with negligble activation energies. Since the reaction is kinetically controlled, the amount of each product formed can be used as a measure of the energy differences of the different pathways that occur in the rate-determining step. These concepts are often integrated into a discussion prior to the experiment since they serve to reinforce material that has been taught in lecture. A guided-approach that uses free radical halogenation reactions in the context of Hammond’s postulate, reaction coordinate-energy diagrams, and reaction reactivity has been described (11). The factors that influence the reactivity of a hydrogen atom in the rate-determining step of the reaction have been studied, Table 1. 83 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 1. Factors That Affect the Reactivity of Free Radical Chlorination Reactions Factor

Role

Ref.

Substituents

Proximity to electron donating groups stabilize the transition state leading to increased reactivity. Proximity to electron withdrawing groups destabilize the transition state leading to decreased reactivity.

(12–14)

Aromatic, carbon disulfide, and chlorinated and brominated solvents form solvent-radical complexes that exhibit increased selectivity as compared to alkyl solvents and polar protic solvents.

(15, 16)


Solvent

Temperature Chlorinating Agent

Steric Hindrance

Increasing temperature decreases the selectivity. The use of sulfuryl chloride to generate chlorine radicals exhibits increased selectivity as compared to the use of NaOCl and HCl. Conformational effects in hindered systems decreases selectivity.

(17) (18, 19)

(12)

Unhindered and unfunctionalized alkanes exhibit the expected reactivity order of tertiary > secondary > primary hydrogen atoms because of increased stabilization of the transition state by electron donating alkyl substituents (12). Electron withdrawing substituents proximal to the developing electron deficient radical intermediate destabilize the transition states, resulting in decreased reactivity at that position. This is often exemplified by the free radical chlorination of 1-chlorobutane where the 2- and 1-positions exhibit increasingly diminished reactivity due to their proximity to the chlorine atom (13, 14). Solvents have also been shown to play an important role in the reaction (15, 16), with aromatic solvents and carbon disulfide increasing the selectivity of the reaction through a more stable chlorine radical complex that has a later transition state. However, the use of alkyl, alcohol, and chlorinated solvents have little to no effect on the selectivity of the reaction. An increase in temperature means that higher energy pathways are now more likely, resulting in a decrease in selectivity (17). The chlorinating reagent also plays a significant role, with sulfuryl chloride providing enhanced selectivity values over photochlorination possibly due to a similar complexation effect observed when aromatic compounds are used as solvents (18, 19). Finally, substrates such as 2,4-dimethylpentane and 2,2,4-trimethylpentane exist in conformations that hinder the approach of the chlorine radical to the tertiary hydrogen (14). This decreases the reactivity at the tertiary site relative to the secondary hydrogen atoms, resulting in a reversal of the expected reactivity order (secondary > tertiary). Understanding the role that each of these factors can play in the reaction ensures that students are not confused by the more subtle effects that they can encounter when studying particular substrates. Quantitation of the products resulting from the free radical chlorination of an alkane is typically carried out using gas chromatography (GC), though gas 84



chromatography-mass spectrometry has also been used (20). Retention times are often given to the students to aid in the identification of the products, though students may also be able to assign products based upon boiling point and elution order. Since the detector corresponds to how much of each product is present, the integration of each signal provides a ratio of the amount of each product. Relative reactivity values are then calculated by normalizing each area by the number of hydrogen atoms that can be removed to give each product. If more than one alkane is to be studied, then column selection and GC oven conditions may have to be changed to ensure baseline separation of all products. Finding appropriate conditions to afford complete separation of all products means that only one alkane is typically studied in a given laboratory period. Compounds can also have different responses to the GC detectors, so response factors must be calculated for each product and these must be factored into the analysis (21). Overall, these issues can minimize the ability of students to collect sufficient data for them to construct a more complete model that explains the role that substitution and functionality has on radical reactivity. Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful and flexible spectroscopic techniques available to students. 1D 1H NMR spectroscopy is a particularly versatile experiment because it observes a high-abundance nucleus, which often means short acquisition times. It also provides information about the chemical environment (chemical shift), the number and environment of neighboring hydrogen atoms (homonuclear coupling), and the number of hydrogen atoms contributing to that signal (integration). It has advantages over GC since it can observe multiple compounds simultaneously, and the response factor (or integration) is independent of the compound being studied as long as appropriate experimental conditions are used. The linear dependence on the number of hydrogen atoms that are contributing to a given signal are easily accounted for when the structure of the compound is known. These features mean that the 1D 1H NMR experiment can provide a tremendous amount of structural and quantitative information over other instrumental techniques. However, a major disadvantage with 1H NMR spectroscopy is a narrow spectral width of only 12 ppm, with shielded alkane protons generally occurring over an even narrower range of 1.5 ppm. This means that complex samples or mixtures often give spectra with regions of significant signal overlap, making structural determination and quantitation very challenging. Fortunately, the introduction of electronegative atoms deshield any adjacent protons, with these signals now residing in an area of the spectrum less prone to overlap. The selective or 1D 1H total correlation spectroscopy (TOCSY) NMR experiment is a powerful variant of the 1D 1H NMR experiment which allows for the deconvolution of complex spectra (22). In this experiment a well-resolved signal from the 1D 1H NMR experiment is selected and irradiated. This energy is then allowed to propagate through the spin system that belongs to the irradiated signal, with the resulting edited 1H NMR spectrum showing only those signals that belong to that spin system. While the TOCSY experiment is most commonly used as a 2D experiment, where all of the spin systems are examined in one experiment, the selective 1D experiment is often preferred because it can have shorter acquisition times and provides splitting patterns that can be examined to 85


give structural information. Applications of the 1D TOCSY experiment include examining the subunits of peptides (23) or in identifying single compounds within complex mixtures (24, 25).


Experimental Procedure To a 10 mL vial containing a stir bar is added the alkane (10 mmol) (chosen from pentane, hexane, 2-methylbutane, 2,3-dimethylbutane, 1-chlorobutane, and propylbenzene) and new concentrated Clorox® bleach (1.9 mL, 2 mmol, 8.25 % NaOCl that yields 7.85 % available chlorine). (Pentane and 2-methylbutane are quite volatile so it is often preferable to use double the indicated amounts of alkane and reagents to ensure that there is sufficient product at the end of the reaction.) The vial is transferred to a fully functioning fume hood and placed in a test-tube holder. With rapid stirring 3M HCl (1 mL, 3 mmol) is added dropwise. A vigorous reaction occurs after about half of the 3M HCl is added. A cap is then loosely placed on the vial and a 60 W unfrosted A15 light bulb is turned on and placed 5-10 cm in front of the vial. Stirring is continued for another 5-10 minutes or until the green color has faded. The organic top layer is then carefully removed using a pipet and transferred to a clean, dry vial. Though not always necessary, the organic layer can be dried with a small amount of anhydrous MgSO4 and filtered directly into an NMR tube. Finally, an appropriate amount of CDCl3 is added and the sample is submitted for NMR analysis. NMR spectra were recorded on a Varian 400MR spectrometer (1H frequency 399.765 MHz) equipped with a 5mm AutoX DB probe. Acquisition and processing of spectra were made using VnmrJ 4.2 (Agilent Technologies, Santa Clara). The spectrometer was locked on CDCl3 and all spectra were acquired at 28°C and referenced to TMS. 1H NMR spectra were recorded using the PROTON (s2pul) pulse sequence (VnmrJ 4.2, Agilent Technologies, Santa Clara) with a 90° pulse angle (10.8 µs), 8 scans, and a relaxation delay of 25 seconds (total experiment time = 3:30 minutes). Selective 1D 1H TOCSY spectra were taken using the 1D zTOCSY pulse sequence (VnmrJ 4.2, Agilent Technologies, Santa Clara) with a spin-lock mixing time of 150 ms and a relaxation delay of 1 s. Data were collected into 16k data points after 512 scans plus 8 dummy scans (total experiment time = 55 minutes). Signals chosen for irradiation were highlighted using the 1H NMR spectrum for that compound.

Results and Discussion Our implementation of the free radical chlorination of alkanes experiment focused on the use of pentane, hexane, 2-methylbutane, 2,3-dimethylbutane, propylbenzene, and 1-chlorobutane as model substrates. The data from the products can be used by students to better understand the importance of how substitution and functionality affects radical reactivity. Furthermore, since each substrate can only generate three or four monochlorinated products, analysis is simplified. Synthesis time is short, often less than 30 minutes per substrate, meaning that students can potentially examine multiple substrates in 86 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.


one laboratory period, if resources allow. Alternatively, students can work with just one substrate, sharing their data using previously described cloud-based approaches (26, 27). Figure 4 shows the 1H NMR spectrum of the product mixture resulting from the free radical chlorination of hexane.

Figure 4. 1H NMR spectrum showing the products arising from the free radical chlorination of hexane. Starred signals at 1.3 and 0.9 ppm are unreacted hexane. As expected, the alkane region (1.9-0.6 ppm) is very complex due to overlapping signals arising from the starting materials and products. However, the addition of the electronegative chlorine atom in the products leads to significant deshielding of the directly adjacent protons, resulting in well-separated signals between 4.1 and 3.4 ppm. The high sensitivity and large dynamic range of modern NMR spectrometers means that despite the presence of very large residual starting material signals, the product signals are easily observed. The three possible products, 2-chloro-, 3-chloro-, and 1-chlorohexane, give well-resolved deshielded signals at 4.01 (sextet), 3.83 (m), and 3.52 (t) ppm, respectively. Though the products are structurally straightforward, the complexity of the methine signal of 3-chlorohexane illustrates how the neighboring diastereotopic protons leads to second-order effects and more complex splitting patterns. The products arising from the free radical monochlorination of pentane afford a very similar 1H NMR spectrum with signals at 4.02 (m), 3.77 (m), and 3.52 (t) ppm for the 2-chloro-, 3-chloro-, and 1-chloropentane isomers, respectively. 2-Methylbutane provides an opportunity to study the reactivity of primary, secondary, and tertiary hydrogen atoms in one substrate, Figure 5. 87



Figure 5. 1H NMR spectrum showing the products arising from the free radical chlorination of 2-methylbutane. Starred signals indicate unreacted 2-methylbutane. Similarly to hexane and pentane, the products resulting from abstraction of primary and secondary hydrogen atoms give well-resolved characteristic deshielded signals at 3.96 (dq), 3.55 (t), and 3.45 (m) ppm for 2-chloro-3-methyl, 1-chloro-3-methyl-, and 1-chloro-2-methylbutane, respectively. 2-chloro-2methylbutane has no adjacent deshielded hydrogen atom, so no deshielded signal is observed. Fortunately, the singlet that arises from the equivalent methyl groups is well-resolved at 1.55 ppm. Unfortunately, this signal coincides with the residual water signal which means that if the organic layer is contaminated with any water over integration of this signal will result. Drying the organic layer with a small amount of magnesium sulfate prior to analysis eliminates this issue. Similarly, the monochlorination of 2,3-dimethylbutane, gives characteristic signals at 3.47 (m) and 1.55 (s) ppm which correspond to 1-chloro-, and 2-chloro-2,3-dimethylbutane, respectively. Again, drying of the crude reaction products is highly recommended. The use of propylbenzene provides an example of the effect that a benzene ring has on the reaction, Figure 6. Deshielding caused by the addition of the chlorine atom and proximity to the benzene ring results in a remarkable dispersion of signals that correspond to each of the products. The most deshielded non-aromatic product signal is at 4.68 (m) ppm and corresponds to the 1-chloro-1-phenylpropane product. The less deshielded products, 2-chloro- and 3-chloro-1-phenylpropane, give signals at 4.12 (sextet) and 3.39 (t) ppm, respectively. 88



Figure 6. 1H NMR spectrum showing the products arising from the free radical chlorination of propylbenzene. Starred signals indicate unreacted propylbenzene. Finally, the presence of an electron-withdrawing substituent can be investigated with 1-chlorobutane, Figure 7. As expected, the methine of the 1,1-dichlorobutane isomer is highly dehsielded, giving a triplet at 5.72 ppm. The 1,2- and 1,3-dichlorobutane isomers also show well-resolved signals at 3.96 (sextet) and 4.21 (m) ppm, respectively. Unfortunately, the deshielded methylene of the 1,4-dichlorobutane isomer overlaps with the starting material at about 3.52 ppm. Fortunately, the more shielded methylene group is well resolved at 1.94 ppm. Tables listing characteristic chemical shifts for each product and the number of hydrogen atoms to which each chemical shift corresponds are provided to the students. After processing their data using freely available software (28), students integrate each signal listed in the table, setting the integration to 1 for the most deshielded signal. They then add those values to the table and continue to calculate the reactivity value for each type of hydrogen atom. Table 2 provides a completed example of the table for hexane. With integration values added to column B, students then determine the integration per hydrogen atom for each product (D). They then divide by the number of hydrogen atoms that can generate that product to give relative reactivity values (F). Finally, these numbers are normalized to the least hindered methyl group (indicated by a star), allowing for substrate comparisons. Tables for the remaining substrates are then filled out by the students using either their own data or shared data. When this experiment is used with more advanced students in our 89



advanced organic chemistry class, no values are given for column A and column C. Table 3 provides a summary of all of the substrates used in this version of the experiment.

Figure 7. 1H NMR spectrum showing the products arising from the free radical chlorination of 1-chlorobutane. Starred signals indicate unreacted 1-chlorobutane.

Table 2. Student Calculation Table for Hexane

90 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 3. Products, Chemical Shift Data, Substitution of Hydrogen Atom, and Normalized Relative Reactivity Values for the Substrates Used in This Experiment


Entry

Isomer

Chemical Shift (ppm)

Substitution

Normalized Relative Reactivity

1

1-Chlorohexane*

3.52

1°

1.0

2

2-Chlorohexane

4.01

2°

2.5

3

3-Chlorohexane

3.84

2°

2.4

4

1-Chloropentane*

3.52

1°

1.0

5

2-Chloropentane

4.02

2°

2.5

6

3-Chloropentane

3.77

2°

2.7

7

1-Chloro-2-methylbutane

3.45

1°

0.9

8


1.56

3°

3.7

9


3.96

2°

2.8

10

1-Chloro-3-methylbutane*

3.55

1°

1.0

11

1-Chloro-2,3-dimethylbutane*

3.48

1°

1.0

12

2-Chloro-2,3-dimethylbutane

1.55

3°

4.0

13

1-Chloro-2,4,4-trimethylpentane‡

3.40

1°

0.8

14

1-Chloro-2,2,4-trimethylpentane‡*

3.36

1°

1.0

15


3.71

2°

2.6

16


nd

3°

nd

17

1-Chloro-1-phenylpropane

4.68

2°

12.5

18

2-Chloro-1-phenylpropane

4.12

2°

5.1

19

3-Chloro-1-phenylpropane*

3.39

1°

1.0

20

1,1-Dichlorobutane

5.72

2°

0.3

21

1,2-Dichlorobutane

3.96

2°

1.3

22

1,3-Dichlorobutane

4.21

2°

2.6

23

1,4-Dichlorobutane*

1.95

1°

1.0

*

All reactions were run at 22°C. Product isomer has relative reactivity value set to 1. Nd: Not determined, resolved signal for product could not be found. ‡ Substrate not used in experiment, but included for comparison purposes.



The alkanes studied (entries 1-16) show remarkably consistent relative reactivity values for the secondary and tertiary hydrogen atoms. Secondary hydrogen atoms give relative reactivity values in the range of 2.4-2.8. The values for the tertiary hydrogen atoms, 2-chloro-2-methylbutane (entry 8) and 2-chloro-2,3-dimethylbutane (entry 12), demonstrate an expected increase in relative reactivity of 3.7 and 4.0, respectively. Since phenyl substitution stabilizes the transition state through inductive and resonance effects, increased relative reactivity values of 12.5 (entry 17) for the benzylic secondary hydrogen atoms and 5.1 for the homobenzylic secondary hydrogen atoms (entry 18) are observed. Finally, the destabilizing nature of the electron withdrawing inductive nature of a chlorine atom and its proximity to the reacting center is illustrated with the decreased relative reactivity values at the 2- and 1-positions (entries 20-21). Students are asked to summarize their data in a figure similar to the one shown in Figure 8.

Figure 8. Relative reactivity values for pentane, hexane, 2-methylbutane, 2,3-dimethylbutane, 2,2,4-trimethylpentane, propylbenzene, and 1-chlorobutane (nd not determined).

Relative reactivity values of alkane substrates calculated by GC analysis by Adduci (29), Russell and Haffley (14), Markgraf (30), and Scala (31) are listed in Table 4 and show excellent agreement with those calculated using NMR spectroscopy in the present study.

Table 4. Relative Reactivity Values for Multiple Substrates



Photochlorination and thermal initiation methods of 2,4-dimethylpentane and 2,2,4-trimethylpentane (entries 1-3) give relative reactivity values for the secondary hydrogen atoms in the range of 2.4-2.7. The low relative reactivity values for the tertiary hydrogen atoms of 2,4-dimethylpentane are due to a preferred eclipsed conformation of the molecule that hinders the approach of the chlorine radical. 2,2,4-Trimethylpentane exists in a similarly hindered conformation, resulting in an even lower reactivity value for the tertiary hydrogen atom (entry 3). Fortunately, 2,3-dimethylbutane exists without any destabilizing interactions and gives a relative reactivity of 3.7 for the tertiary hydrogen atom (entry 4). Similarly, 2-methylbutane gives relative reactivity values of 2.9 and 3.6 for the secondary and tertiary hydrogen atoms (entry 5). Fredricks and Tedder studied the gas phase chlorination of 1-chlorobutane and determined relative reactivity values of 0.5, 1.5, 2.7, and 1.0 for the 1-, 2-, 3-, and 4-dichlorobutane isomers (32), again in very good agreement with values calculated using NMR spectroscopy. Structural Analysis Using 1D TOCSY NMR Spectroscopy Since nearly all of the products have contiguous spin systems that often span the entire molecule, the 1D 1H TOCSY experiment provides an excellent method for generating edited spectra of each product. Distinctive signals that can provide structural detail that would normally be obscured beneath starting material can be observed using the 1D 1H TOCSY experiment. Students in more advanced courses, with more NMR experience, can use these spectra to determine which characteristic deshielded signal belongs to which isomer, thereby generating their own chemical shift list for each product table. When products do not have any deshielded signals appropriate guidance is given. We have applied this version of the experiment in our advanced organic chemistry class. Students carry out the synthesis in one class period, submitting their samples for 1H NMR spectroscopy at the end of the class. They examine their 1D 1H NMR data before the following class period, and we then engage in brief discussion about that data and the 1D TOCSY experiment. They then spend time at the NMR workstation and choose which well-resolved signals to irradiate with the 1D TOCSY experiment. These experiments are queued up and data acquisition occurs overnight. However, even our advanced students can’t synthesize all possible products, so data sharing is still needed so that students can develop a complete model. Figure 9 shows the 1D 1H NMR of the reaction products resulting from the monochlorination of pentane along with a series of 1D 1H TOCSY spectra acquired by irradiation of the deshielded signals at 4.02, 3.77, and 3.52 ppm. The TOCSY spectra clearly reveal signals hidden beneath the starting materials signals or that overlap with other monochlorinated isomers. Students then use the number of signals, chemical shift, and the splitting patterns of certain protons to assign structure. For example, 2-chloro- and 1-chloropentane are straightforward to assign since they show distinctive sextet (A2) and triplet (C1) splitting patterns that are indicative of a deshielded methine and methylene, respectively. The doublet (A1) and triplet (A5) for the two methyl groups of 93



2-chloropentane and the slightly distorted triplet, (C5) of the methyl group for 3-chloropentane further corroborate these assignments. The deshielded methine (B3) of 3-chloropentane shows a complicated multiplet pattern caused by coupling with the adjacent diastereotopic hydrogen atoms, however the presence of only three signals and the clear triplet (B1) of the symmetric methyl groups means that this TOCSY spectrum can be assigned to 3-chloropentane.

Figure 9. Stacked spectra showing the 1D 1H NMR spectrum of the reaction products from the monochlorination of pentane and a series of 1D TOCSY experiments (A-C) generated by irradiation of signals at 4.02, 3.77, and 3.52 ppm, respectively with 150 ms spin-lock time and 512 scans. When the starting material contains deshielded signals the use of TOCSY NMR spectra becomes even more powerful. Figure 10 shows the stacked plot of the 1D 1H NMR of the reaction products resulting from the monochlorination of 1-chlorobutane and a series of 1D TOCSY spectra acquired by irradiation of the signals at 5.72, 3.96, 4.21, and 1.91 ppm, respectively. In this case, the region between 3.8 and 3.3 ppm, which contains 1-chlorobutane as well as overlapping signals from the products, is cleanly resolved in the 1D TOCSY spectra. Similar to the analysis for pentane, the symmetric 1,4-dichlorobutane can be assigned immediately since it contains 2 signals (D1 and D2). 1,1-Dichlorobutane can be assigned to the isomer with the very deshielded triplet (A1) and the distorted triplet (A4), an artifact of the TOCSY experiment. 1,3-Dichloromethane shows a distinctive doublet (C4) and sextet (C3) indicative of the methyl and methine. Finally, 1,2-dichloromethane can be assigned to spectrum B by either an analysis of the three sets of signals 94



(B1, B2, and B3) that show second order splitting patterns due to the neighboring diastereotopic protons, or by the triplet (B4) which can be assigned to the terminal methyl group. The remaining alkane substrates can be analyzed using a similar approach.

Figure 10. Stacked spectra showing the 1D 1H NMR spectrum of the reaction product 1-chlorobutane and a series of 1D TOCSY experiments (A-D) generated by irradiating the signals at 5.72, 3.96, 4.21, and 1.91 ppm, respectively with 150 ms spin-lock time and 512 scans.

Conclusions We have found that high-field 1H NMR spectroscopy is a powerful tool for the analysis of a variety of monochlorinated products arising from the free radical chlorination of alkanes and substituted alkanes. The substrates that we have chosen give at least one characteristic well-resolved signal at 400 MHz. Our organic students process their data and integrate each of the signals that is listed. Their calculated relative reactivity values are in excellent agreement with literature values. The range of substrates that can be investigated means that students can see trends and develop more comprehensive models to help explain the importance of substitution and functionality at the developing radical. For more advanced students, a series of 1D 1H TOCSY NMR experiments can be taken to help them identify which deshielded signal belongs to which product. This latter approach not only gives students more experience with using NMR for structural analysis, but also introduces them to a new NMR experiment with which they may not be familiar. 95


Acknowledgments The author would like to thank the Organic Chemistry and Advanced Organic Chemistry students for their useful discussions and feedback during the development of this laboratory experiment.

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