• Home
  • About
  • Chemistry
    • Solvent of the Week
    • Compound of the Week
    • Reagent of the week
    • Publications
    • Translations
    • Glassware designs
    • Advanced Preparative Separation
    • Videos
    • A day in a mineral lab
    • A day in a wine lab
    • A day in a polyurethane lab
  • Philosophy
    • Poor Matthew
    • On Australian coins
    • On global warming
    • On aluminium cans
    • Questions to ask potential housemates
    • Why chemistry skills are now less valued than they were
    • Tribute to Mr John Clarke
  • Photos
  • Blog
MJLPHD

Matthew's list of specialty gases—compounds with boiling points below 35 °C

30/9/2016

0 Comments

 
When I was working recently with plumbers we had much discussion about gas fitting and which compounds can be plumbed. Plumbers are also frequently using a flame for welding and soldering. One such product that is easy to carry is a small yellow bottle that the plumbers know only as MAPP gas. I at first wondered if it were propane, butane or acetylene. I later learned that it was none of these and in fact propylene.

Below is a list of non-alkane compounds that I believe can be plumbed. The ones with BP of 15–35 °C will probably need a heated pipe.
Species                                                   Formula                                      BP (°C)
Helium                                                     He                                           −269
Hydrogen                                                 H2                                           −253
Deuterium                                                D2                                           −253
Carbon Monoxide                                   CO                                          −191.5
Argon                                                        Ar                                            −186
Nitrogen                                                   N2                                           −196
Oxygen                                                     O2                                           −183
Ozone                                                       O3                                           −112
Phosphine                                              PH3                                          −88
Nitrous Oxide                                        N2O                                           −88
Hydrogen Chloride                               HCl                                           −85
Acetylene                                          H−C≡C−H                                     −84
Carbon Dioxide                                     CO2                                         −78.5
Tetrafluoroethylene                        F2C=CF2                                      −76
Hydrogen Bromide                               HBr                                          −67
Sulphur hexafloride                             SF6                                           −64
Hydrogen Sulphide                              H2S                                          −60
Propylene (MAPP gas)                  H3C−CH=CH2                              −47
Selenium hexafluoride                       SeF6                                        −46.6
Sulphur tetrafluoride                           SF4                                          −38
Hydrogen Iodide                                   HI                                            −35
Chlorine                                                 Cl2                                           −34
Ammonia                                              NH3                                          −33
1,1,1,2-Tetrafluoroethane (R134a)   F3C−CFH2                               −26
Dimethyl ether                              H3C−O−CH3                                  −24
Chloromethane                                  CH3Cl                                         −24
1-Chloro-1,2,2,2-tetrafluoroethane   F3C−CFClH                           −12
1-Butene                                    H2C=CH−CH2−CH3                          −6.5
Methylamine                                    CH3NH2                                       −6
trans-2-Butene                        H3C−CH=CH−CH3                              0.9
cis-2-Butene                            H3C−CH=CH−CH3                              3.7
Bromomethane                                  CH3Br                                           4
Methyl mercaptan                             H3C−SH                                        6
Ethyl methyl ether                           EtOMe                                            7
Phosgene                                              COCl2                                          8
Ethylamine                                  CH3CH2NH2                                      16
Hydrogen Cyanide                               HCN                                           25
Disulphur decafluoride                       S2F10                                          30
1,1-Dichloro-1-fluoroethane (R141b)   CCl2F−CH3                          32
matthew_list_of_specialty_gases.xlsx
File Size: 10 kb
File Type: xlsx
Download File
0 Comments

Site visit - Kakadu blue cypress oil

8/12/2015

0 Comments

 
PictureCallitris intratropica
On 17-Jul-2015 while visiting Darwin on a personal holiday I was invited for a site visit by Vince Collins, the owner of Kakadu blue cypress oil. Vince makes a blue oil by steam distillation of bark and heartwood from Callitris intratropica—a tree that only grows in the tropics and is native to Northern Australia.  This essential oil is said to have many sought after properties such as wart removal, treatment of burns and bug bites, and the alleviation of anxiety.
Vince holds a patent for his distillation process and has won a major victory at the high court of Australia to protect it.
Picture
Matthew Leonard watches as Vince Collins decants blue cypress oil from his still.
The steam distillation takes 90–100 hours. As the oil contains an excess of guaiol, the distillate is placed into a fridge at 18 °C for 20 hours and a large portion of the guaiol is collected as a crystalline precipitate. This leaves the blue oil as a rich, low viscosity consumer product for various essential oil purposes.
A large amount of the guaiol precipitate was being stockpiled but a use had not yet been found for it. Vince suspected that it was only 60% guaiol, whereas I (Matthew) felt that it's level of crystallinity indicated a purity of around 90%. A later analysis by GC-MS and C-NMR showed the filtrate to be 85% guaiol.
Picture
In my lab at RMIT, I was able to recrystallize the guaiol from 2-propanol/water as white needles, or from hot methanol as six-sided prisms.
Picture
Guaiol recrystallizing in 2-propanol with a small amount of water added.
Picture
Guaiol recrystallized from methanol as six-sided prisms.
 The ultra-pure guaiol gave a clean NMR and had a melting point of 95-96 °C. The previously reported melting point of guaiol was 92-93 °C. The true melting point of guaiol, along with its purification method and characterization is soon to be published in a peer-reviewed journal.
Picture
13C-NMR of pure and crude guaiol
Picture
FTIR of guaiol
We continue to seek novel synthetic uses for guaiol as a start material in order to find a use for Vince's side product. We beleive that the combination of cheap availability, the fused five/seven membered rings, and the three chiral centres make guaiol an ideal candidate for synthetic pursuits.
Picture
0 Comments

Publishing a journal article—a case study on the peer-review system

26/9/2015

0 Comments

 
Picture
I recently published a chapter of my PhD thesis as a full paper in RSC Advances. The reviewers' comments are worth sharing. I'd like to thank the editors of RSC advances for their professional handling of the situation. Things could have gone badly for all concerned if not for their careful and thoughtful efforts.
My article is titled "Bromo–nitro substitution on a tertiary alpha carbon—a previously uncharacterized facet of the Kornblum substitution". It is a complex subject and thus became a very long article of 18 pages. It was very polished by the time we submitted it. About one month after submission we received the following response:
Thank you for your submission to RSC Advances, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below. We sought an additional report on this occasion as we felt that there was insufficient information from the first two reports to make an informed decision.

I have carefully evaluated your manuscript and the reviewers’ reports, and the reports indicate that some revisions are necessary.

Please submit a revised manuscript which addresses all of the reviewers’ comments. Further peer review of your revised manuscript may be needed. When you submit your revised manuscript please include a point by point response to the reviewers’ comments and highlight the changes you have made. Full details of the files you need to submit are listed at the end of this email.
Editor.

REVIEWER REPORT(S):
Referee: 1

Recommendation: Reject

Comments:
This manuscript describes a very specialized work and the kinetic study is of moderate importance. The manuscript is too long and presented in an inattractive way. I do not recommend publication.

Additional Questions:
Does the work significantly advance the understanding or development in this field? : No

Are the conclusions of the work convincing and sufficiently supported by experimental evidence?: No

Is the experimental section sufficiently detailed to allow others to reproduce the work?: Yes

Are the reported claims adequately discussed in the context of the literature?: Yes

Are the number of tables and figures in the manuscript appropriate and clear?: No


Referee: 2

Recommendation: Major revisions

Comments:
The authors have reported a Kornblum reaction on a tertiary carbon next to a carbonyl group and have examined the reaction kinetics carefully. In addition they have also proposed several possible mechanisms. The results are interesting and should be published. However, I do think that the manuscript needs a major overhaul in order for it to be accepted by the journal of RSC Advances.
One major problem associated with the manuscript is the drawings. Since the authors mentioned that part of it was taken from a Ph. D thesis, it is understandable for the poor quality of drawings. However, for a publication in a privileged journal such as RSC Advances, the authors need to produce better quality figures. Some of the bond angles are just random. Please redraw figures 2,3,13,14,15 and 16. They also need to adjust the size of all drawings to match the font size of the text.
In table 1, entries 31 and 33, the two entries “benzyl in place of phenyl” and “butyl in place of phenyl” are not appropriate since they are not R groups.
Additionally the language used in this manuscript is too casual to be in a scientific article, please change some of the everyday phrases used here and there.


Additional Questions:
Does the work significantly advance the understanding or development in this field? : Yes

Are the conclusions of the work convincing and sufficiently supported by experimental evidence?: Yes

Is the experimental section sufficiently detailed to allow others to reproduce the work?: Yes

Are the reported claims adequately discussed in the context of the literature?: Yes

Are the number of tables and figures in the manuscript appropriate and clear?: Yes


Referee: 3

Recommendation: Accept

Comments:
The Kornblum substitution represents the replacement of a halogen atom by a nitro group on an organic molecule. Historically, this reaction has been discovered in more than half a century ago, and has been frequently employed to prepare aliphatic nitro compounds. Although using primary and secondary alkyl halides can produce corresponding products in moderate to high yields, related reactions with tertiary halides receive much less success. In this manuscript, authors reported a Kornblum substitution reaction occurring on tertiary alkyl halide sites alpha to an anilide carbonyl, which can afford products in 70-99% yields. Regarding the debate on mechanisms of the Kornblum substitution for tertiary alkyl halides, authors has investigated from the perspective of substitution rates for substrates with different functionalities. They proposed a negatively charged transition state during the process comparing to typical SN1/SN2 mechanisms for Kornblum reactions, as the Hammett plots showed a positive ρ value.

Additional Questions:
Does the work significantly advance the understanding or development in this field? : Yes

Are the conclusions of the work convincing and sufficiently supported by experimental evidence?: Yes

Is the experimental section sufficiently detailed to allow others to reproduce the work?: Yes

Are the reported claims adequately discussed in the context of the literature?: Yes

Are the number of tables and figures in the manuscript appropriate and clear?: Yes
We took a close look at all of the comments and wrote the following statement to address the comments and describe changes that we made.
We have read the comments made by the three reviewers and we have done our absolute best to address these. We remain open to our article being published in RSC Advances.

While it is our view that referee 1 read our manuscript carelessly and without an open mind, we would be pleased if you would pass on our thanks to referees 2 & 3 for their careful and thoughtful work. We explain below why we disagree with the sentiment of referee 1.

We here address the reviewers’ comments and state any changes made.

Referee 1: This manuscript describes a very specialized work and the kinetic study is of moderate importance. The manuscript is too long and presented in an inattractive way. I do not recommend publication.

·         The kinetic study was necessary for the Hammett plots in order for us to infer a negatively charged transition state and show that this reaction goes by way of a different mechanism to standard Kornblum substitutions. It also serves to give chemists who try this reaction in the future an idea of how quickly to expect the reaction to be complete.

·         We acknowledge that the manuscript is long, but it is our view that, given the complex nature of the subject material, a long article was necessary in order to fully describe and investigate. As the title states, this is a previously uncharacterized facet of a name reaction. This meant that a review into the original works and a great deal of data both had to be included in detail. While we have endeavoured to keep it as pithy as possible, we feel that any further culling of material would diminish the impact of the work.

·         It disappoints us that Referee 1 found our mode of presentation to be inattractive. But since the referee does not describe in what way they feel the manuscript to be inattractive, it is impossible for us to remedy.

Referee 2: The authors have reported a Kornblum reaction on a tertiary carbon next to a carbonyl group and have examined the reaction kinetics carefully. In addition they have also proposed several possible mechanisms. The results are interesting and should be published. However, I do think that the manuscript needs a major overhaul in order for it to be accepted by the journal of RSC Advances.
One major problem associated with the manuscript is the drawings. Since the authors mentioned that part of it was taken from a Ph. D thesis, it is understandable for the poor quality of drawings. However, for a publication in a privileged journal such as RSC Advances, the authors need to produce better quality figures. Some of the bond angles are just random. Please redraw figures 2,3,13,14,15 and 16. They also need to adjust the size of all drawings to match the font size of the text.
In table 1, entries 31 and 33, the two entries “benzyl in place of phenyl” and “butyl in place of phenyl” are not appropriate since they are not R groups.

Additionally the language used in this manuscript is too casual to be in a scientific article, please change some of the everyday phrases used here and there.

·         We feel that Referee 2’s comment that “Some of the bond angles are just random” is an overstatement. We have had a close look at the bond angles in all of our figures and we can find only one that needs a very minor adjustment—the alkene shown on the bottom right of figure 2. We have updated this figure to give the alkene a bond angle of 120°. The Referee asks for us to re‑draw figures 2, 3, 13, 14, 15 and 16. As mentioned above we have re-drawn figure 2 with a slight correction to the bond angle of the alkene. Figure 3 however has nothing wrong with the bond angles. In fact we have drawn these same two compounds in our 2014 paper that was published in RSC Advances. This paper is reference number 10 in the manuscript. For the full version see: [M. J. Leonard, A. R. Lingham, J. O. Niere, N. R. C. Jackson, P. G. McKay and H. M. Hügel. Alternative synthesis of the anti-baldness compound RU58841. RSC Advances, 2014, 27, 4, p14143–14148.]; you will note that in figure 5 of this paper the bond angles are identical to what is drawn in figure 3 of our current manuscript. Figures 13–16 are our suggested mechanisms. We have drawn here transition state intermediate species that, by necessity, have some non-standard bond angles. These non-standard bond angles have been kept to a minimum. They are not ‘random’ and drawing them any other way would make the depiction of these species ambiguous and unreadable.

·         We would like to address Referee 2’s comment that “Since the authors mentioned that part of it was taken from a Ph. D thesis, it is understandable for the poor quality of drawings.”. While the content was taken from Matthew’s PhD thesis, all of the figures were re‑drawn for this manuscript. We therefore have changed the preamble near the top of page 1 slightly, so as to add the word ‘content’. So “The following is taken, in part, from the PhD thesis of the primary author, Matthew Leonard.” has been changed to “The following content is taken, in part, from the PhD thesis of the primary author, Matthew Leonard.”.

·         The Referee states that “They also need to adjust the size of all drawings to match the font size of the text.”. Does Referee 2 mean to ask us to change the atom font size to match that of the text? This would make the atom labels unusually small and very difficult to read. Or does the referee want the images made smaller? We again feel that this would make the images hard to follow in what is a very complex piece of subject matter. Either way we feel that this request is a curly one that is not easily remedied and does not need remedying in the first place. Anyone who has worked for a long time in the field of synthetic organic chemistry would know that atom sizes and their fonts can hardly ever be matched to the font size of the text. The atom and font sizes need to be presented in whatever way is appropriate for the reader to be able to easily comprehend them along with the surrounding text. We feel that we have done this and that Referee 2 is being difficult by making this request. We therefore have left all of the drawings in the figures ‘as is’.

·         We know that benzyl and n‑butyl are not R groups but we placed them in Table 1 so as to save space, as we were aware that ours was already a very long article. Given Referee 2’s comment, we have given further thought the inclusions of compounds 31–34 in Table 1. We have come to the conclusion that we disagree with Referee 2 on this matter. It is not ambiguous to describe these compounds as “benzyl in place of phenyl” and “n‑butyl in place of phenyl” because the image of the backbone of the compound library moiety is placed right beside these two entries. We also briefly describe the use of these two compounds in the text immediately below. We feel therefore that a chemist who reads this article will find it easy to understand what we mean. It is important that these four compounds be left in Table 1 as this table denotes compound numbers for all of the novel compounds that are characterized at the end of the article. Any alteration to the way these compounds are described in Table 1 would add extra length to the article without conveying any more information to the reader. As we feel that unnecessary inclusions should be avoided, we have left this section ‘as is’.

·         We have tried to use scientific language as much as possible without losing any of the meanings that we wished to convey. We have combed through the manuscript and found that any of the language that may appear casual at first is in fact necessary in order to convey our meanings to the reader with the greatest possible brevity.

Referee 3: The Kornblum substitution represents the replacement of a halogen atom by a nitro group on an organic molecule. Historically, this reaction has been discovered in more than half a century ago, and has been frequently employed to prepare aliphatic nitro compounds. Although using primary and secondary alkyl halides can produce corresponding products in moderate to high yields, related reactions with tertiary halides receive much less success. In this manuscript, authors reported a Kornblum substitution reaction occurring on tertiary alkyl halide sites alpha to an anilide carbonyl, which can afford products in 70-99% yields. Regarding the debate on mechanisms of the Kornblum substitution for tertiary alkyl halides, authors has investigated from the perspective of substitution rates for substrates with different functionalities. They proposed a negatively charged transition state during the process comparing to typical SN1/SN2 mechanisms for Kornblum reactions, as the Hammett plots showed a positive ρ value.

·         We thank Referee 3 for putting so much thought into our findings. It is an excellent affirmation for us to know that the way in which we presented this complex topic could be readily comprehended.
One week later we received the following email from RSC Advances:
Thank you for submitting your revised manuscript to RSC Advances. After considering the changes you have made, I am pleased to accept your manuscript for publication in its current form. I have copied any final comments from the reviewer(s) below, for transparency.

You will note that the previous reviewer (2) has recommended major revisions. However, given that their grievances revolve mainly around the overall presentation of the manuscript, as opposed to pertinent issues regarding the discussion or experimental work, it is my opinion that further revision at this stage would be redundant and would only delay publication.

Please note that if you have requested Accepted Manuscript publication we will publish your article shortly and send you an email once it is available online. We will also email you information on how to access your RSC Advances article proofs shortly.
Editor.

REVIEWER REPORT(S):
Referee: 2

Recommendation: Major revisions

Comments:
The author has not addressed all the problems raised before. Instead he has tried to argue his way out. I don’t know whether the author has downloaded the PDF version of his paper or not, the quality of the overall paper is not that great. Clearly the drawings are too big and some of the drawings are ugly. Please just download any JACS paper and see how they present their drawings. As for the two entries in Table 1, it seems that the author does not know the meaning of “precision”. If benzyl or butyl is not a R group, then they should not be in that box. In light of all the above, I can not recommend its acceptation by the journal.

Additional Questions:
Does the work significantly advance the understanding or development in this field? : Yes

Are the conclusions of the work convincing and sufficiently supported by experimental evidence?: Yes

Is the experimental section sufficiently detailed to allow others to reproduce the work?: Yes

Are the reported claims adequately discussed in the context of the literature?: Yes

Are the number of tables and figures in the manuscript appropriate and clear?: No
I wrote back to RSC Advances:
Dear Editors,

That is great news! We are very pleased to have our paper published in RSC Advances. We can see that the referees comments would have made the matter unclear and we'd like to thank you for taking an interest and looking so closely and so carefully at our paper.
bromo–nitro_substitution_on_a_tertiary_alpha_carbon—a_previously_uncharacterized_facet_of_the_kornblum_substitution.pdf
File Size: 871 kb
File Type: pdf
Download File
Bromo–nitro substitution on a tertiary alpha carbon—a previously uncharacterized facet of the Kornblum substitution.
Matthew J. Leonard, Peter G. McKay and Anthony R. Lingham.
RSC Advances, 2015, 5, page 76401 - 76418. Received  26-Jul-2015, Accepted 03-Sep-2015. DOI: 10.1039/C5RA14798K.
0 Comments

Common questions asked at job interviews for synthetic organic chemistry

3/7/2015

2 Comments

 
Here is a list of questions that I have come across and some recommended answers to each.
  • You have three compounds mixed together: compound A (amino acid), compound B (amine) and compound C (carboxylic acid). How would you separate them?
Most obvious answer: Liquid liquid extraction using water and an organic solvent (like ethyl acetate). The amine will enter the organic phase when the aqueous phase is made basic, the carboxylic acid will enter the organic phase when the aqueous phase is made acidic. The amino acid will be zwitterionic and will have a charge on it at any pH, meaning that it will remain in the aqueous phase under acidic or basic conditions.
Picture
  • How might you make paracetamol (known in the USA as acetaminophen)?
Most obvious answer: Nitration of Phenol. Place phenol into dilute sulphuric acid and add sodium nitrate (NaNO3). This will give a mixture of ortho-nitrophenol (BP 215 °C) and para-nitrophenol (BP 279 °C), two compounds which can be separated by distillation. Take the para-nitrophenol, reduce the nitro group to an amine by any number of methods. Para-aminophenol can then be acylated, most easily using acetic anhydride (which will give acetic acid as a by-product) or any number of other acylating reagents, for example acetyl chloride, which will give HCl as its by-product.
Picture
Preparation of paracetamol
In a job interview you should stop right there. But I hear the more curious chemist ask: How is N acylation carried out without any O acylation? Acylations are highly pH dependent. An acid medium would prevent reaction at the OH but it would also protonate the NH2 to give NH3+ and prevent acylation at the N. The acylation step is therefore done in a water/sodium acetate solution. This keeps the hydroxyl from becoming deprotonated, but does not protonate the NH2. At this pH the acetic anhydride reacts so slowly with the water as to be negligible compared with the rate of reaction with the amino group. A slight molar excess of acetic anhydride is used and the reaction is shaken and occurs at room temperature. Excess acetic anhydride is quenched slowly by water on workup and the reaction is seen to occur in high yield (>90%).
  • Name and describe a carbon-carbon bond forming reaction.
Most obvious answer: It depends on what else is bonded to the two carbons you want bonded together. Wikipedia has a list of over 100 carbon-carbon bond forming reactions. Choose any, but perhaps choose one of the most obvious and widely known. My top five picks are: Grignard reaction, Diels-Alder reaction, Aldol reaction, Michael reaction and Friedel-Crafts reaction.
  • Are you familiar with the Diels-Alder reaction? What is the catalyst?
Most obvious answer: The Diels-Alder reaction is a concerted cycloaddition where a 1,3-butadiene (a diene) reacts with an alkene (a dienophile) to give a cyclohexene. It can be widely used with many different functional groups in place of hydrogen. As it proceeds by a concerted mechanism, it does not have a catalyst, but it can be placed under either thermal or photochemical control to achieve stereospecificity.
Picture
General Diels-Alder reaction
  • Is it possible to form a C-C bond to an aryl carbon?
Most obvious answer: Yes. You can alkylate or acylate using the Friedel-Crafts reaction which uses an alkyl or acyl chloride and is catalyzed by AlCl3 under reflux and with anhydrous conditions.
Picture
Not a chemistry question, but I was once asked:
  • When we call your referees, what bad things might they say about you?
I think the best answer to this is: "I don't know. You'll just have to ask them and find out".
Another non-chemistry question I was asked recently:
  • When do you see yourself in five year?
I answered "Here", which apparently was the right answer, but I still wasn't offered the job.
2 Comments

Flammability and the carbon-hydrogen (C-H) bond

2/6/2015

0 Comments

 
I had a conversation recently with Replas, a company that uses recycled soft plastics to make picnic tables, park benches and bollards. They have been making this product for 20 years here in Australia but lately they have had a spate of incidents in which their product has burned and they wish to explore cheap ways to reduce the flammability of their product.
PictureDiethyl ethylphosphonate
I am reminded of my time working at Applied Polymers, where I had a project that involved flammability testing of rigid foam polyurethane. In this case the formula included diethyl ethylphosphonate (DEEP) as a flame retardant. I altered the levels of DEEP and tested the flammability of the products by cutting the foams into a wafer biscuit shape that was placed on a wire mesh and moved into a laminar flame. The flame was a mixture of air and butane, with the butane coming straight from a BBQ bottle.
Years later I have not worked with polymers for some time but have just carried out my PhD in pure chemistry. I am generally acquainted with the principle that the more C—H bonds are present, the more flammable a substance will be. I have learned that perfluorohexane and it's homologues are non combustible as they lack C—H bonds. I have read someplace that the C--F bond is so stable that it does not undergo cission during combustion. One time during my PhD I decided to test the paradigm of combustion relying on C--H bonds by attempting to ignite a solvent called formamide. I found that formamide was absolutely impossible to ignite at room temperature.
Picture
Perfluorohexane and Formamide
I learned during my Honours year that cellulose is less combustible than lignin. This is why when burning white paper not a lot of heat is given off and the flame is unimpressive and diffusive. High lignin newsprint on the other hand, which is cheaper anyway but turns yellow within one year, gives a much better flame and is more suitable for starting a fire. Lignin has perhaps two carbons for each oxygen, which makes it far more hydrocarbony than cellulose which has one carbon per oxygen.
Picture
Picture
Lignin
Some time ago I obtained a book called "Flames, their structure, radiation and temperature" by A. G. Gaydon and H. G. Wolfhard. I hadn't yet had time to read it and thought it was going to be about explosions, flames in house fires and perhaps largely a treatise of mathematical formulae. To my pleasant surprise, it is actually written with the PhD chemist in mind. I have the 3rd edition from 1970. The authors include the following paragraph in their preface:
Picture
"Our aim is to present as clearly as possible the underlying physical processes occurring in flames. We fully realise, of course, the need for quantitative measurements, but have avoided purely mathematical discussion; indeed we have little enthusiasm for abstract mathematical treatments of combustion, these usually involving many unknown and often unknowable parameters."
Picture
The topic of chapter 2 is premixed flames. Here we learn that the outer flame on a Bunsen burner is not the burning of the hydrocarbon/air mixture, but is actually a diffuse flame that burns due to CO and H2, which are given off by the combustion of the fuel in the centre flame. The two flames can be separated by a glass tube known as a Smithells separator. The length of this separator is important as if it is long enough, the outer flame will no longer burn due to the gases being at a lower temperature. From this, we can take that there is some flammability in other organic bonds, albeit far less. Another section of the book describes the possibility of flames from ammonia. The flammability of the H-H bond is particularly well know, less well known is the flammability of C-O and N-H bonds. Another section of the book describes flames from halogen compounds' interaction with hydrocarbons.
Picture
The CO flame has been studied at length and is discussed in the book. It has a spontaneous combustion temperature of 609 in air and 588 in oxygen. Its heat is combustion is lower than that of alkanes, but it also has a smaller lower limit of combustion of around 10%. See image.

I remember being told in high school chemistry that the top of the inner flame is the hottest part of the Bunsen flame. The chart shows that propane and butane have a hotter flame than CO. It also shows that higher alkanes such as heptane and octane give an even hotter flame. However, these produce a flame with a higher degree of carbon zero, which gives a more luminous flame but leave a black solid residue. This is because the fuel to oxidant ratio for these hydrocarbons does not give an equal stoichiometric ratio. The lower alkanes are said to give a more clean burning flame as they produce only the oxidation product CO2; an odourless, colourless gas. Hence we have: Higher alkanes = hotter but dirtier flame.
It is also possible to get flames from nirates and nitrites (p340), which shows that N-O bonds can also contribute to overall flammability of a substance.
Another point to note is that some mixtures of hydrocarbons with air or oxygen are too rich for a flame to propagate and they give a better flame when nitrogen gas is added to the mixture. Thus we have a situation where N2 is not at all flammable itself but its addition to a mixture it can increase overall flammability.
C—H bonds of course have more energy in them compared to their combustion products, but another part of their flammability comes from the readiness of C—H rich compounds to enter the vapour phase and thus create a combustible mixture with air. A diffusion flame at microgravity shows  a lack of yellow, which seems to indicate that only the C—H bonds are combusting, but with not enough heat given off to combust the CO and H2.
Picture
Diffusion flame on Earth and on the International Space Station.
0 Comments

Old fashioned synthetic flavouring recipes

2/5/2015

0 Comments

 
I was recently handed a book titled "Manufacturers Practical Recipes". It was printed in England in 1948.
Picture
Picture
This book covers several topics including fertilisers, cosmetics, soaps, varnishes and textile treatments. Of most interest to me was the section on synthetic fruit essences and flavourings.
Picture
Picture
It amazes me what we used to allow into confectionery.
Picture
One thing that particularly caught my eye was the use of chloroform to achieve a pineapple flavour. See page 53 below: "In pineapple especially chloroform appears to round off the flavour in a very satisfying manner."
Picture
Picture1,2,3-triacetoxypropane
Acetin, which appears in the essence of apricot, pear, quince, peach and raspberry, is a portmanteau of acetic acid and glycerin. It is the esterification product of the two compounds, commonly known as triacetin or glycerol triacetate. Its correct name is 1,2,3-triacetoxypropane.
Acetin is a rather confusing name because it sounds like it might be derived from acetone. Also confusing because glycerin is nowadays more correctly called glycerol.
Picture
Picture
Neroli oil, which appears in both coffee and cherry brandy flavourings, is extract of citrus blossom.
Picture
There also appear at the back of the book, many pages of advertisements that are mixed in among the index pages.
Picture
A full page advertisement by ICI foreshadows the era of the chiseled chemist
Picture
Note the attachment of a Dreschel bottle to a Kipp's generator. I wonder which gas this chemist is generating? The outlet of the Dreschel is not attached to anything. Perhaps he hasn't yet started his reaction.
0 Comments

Extraction of the slip-additives Erucamide, Behenamide and Oleamide

2/4/2015

1 Comment

 
A co-worker came to my building to start his PhD after I had submitted my thesis. He was sponsored by Coca-Cola to study slip-additives in the HDPE films in of bottle caps. It turns out that these compounds have been leaching out and crystallizing on the surface (as polyhedra). Coca-Cola wish to quantify this leaching and as such the student has to determine a way to extract them without dissolving the HDPE. He approached me and asked for advice on which solvent the compounds would be soluble in. My first question was the molecular structure of the three compounds, which is shown below.
Picture
I then wanted to know which solvents would dissolve HDPE. A web search tells me that chlorinated and aromatic solvents will dissolve HDPE. The student tells me that these and other slip-additive compounds have been successfully extracted before using diethyl ether and that they have been run through GC-MS using DCM. Fortunately, the supplier sent a rather large sample bag of each compound. I recommended a solvent survey as laid out below in order to find a solvent in which the compounds have high solubility.
Picture
As we had plenty of the compound, I thought it would be good to run GC-MS of the pure samples. We prepared GC-MS vials with 1 mg of compound into 1 mL of DCM. We found that erucamide and oleamide dissolved easily in DCM but behenamide was very difficult to dissolve in DCM. After lots of shaking, we eventually added 10% methanol to these vials and the behenamide then slowly dissolved. Curious that the absence of the double bond could make it so much less soluble than erucamide. I am told that behenamide is the more active of the three compounds as an anti-slip agent (it produces more friction).
The compounds were more difficult to elute through GC-MS than expected. Nothing eluted on a standard method, probably due to the high molecular weight of the three compounds (337, 339 and 281 respectively). A higher temperature method still struggled to elute much of each compound. Only a very high temperature splitless method was successful with sample delivery at 300 °C; oven temperature starting at 200 °C, increasing to 250 °C at 2 °C/min, then 250–300 °C at 4 °C/min (42.5 min total). This method was harsh enough to make most (~80%) of the compound decompose on the injector port. The decomposition products for all three compounds were M-18 and eluted in around two thirds of the time of the intact compound.
It would be desirable to derivatize the free amine (-NH2 group) in order to obtain a species that travels more readily through a GC-MS column. This could be done by an acylation using acetyl chloride or acetic anhydride. Or it could be done by trifluoroacetic acid, which has the advantage of creating a compound that can be observed by 19F-NMR. But it also has the disadvantage of making a higher molecular weight product than a regular CH3 acylation.
Picture
Derivatization of Behenamide
Here the derivative is an acyclic methyl imide. The imide group is usually stabilized by being part of a heterocycle, but I see no reason why these methyl imides should not be stable enough to analyze by GC-MS. Imides however, have very acidic NH groups that will often form an alkali salt or an N-halo bond. Thus it is possible that the N-chloro methyl imide is formed if acylation is carried out by acetyl chloride. The trifluoromethyl imide is likely to be a more stable species due to the NH being less electron dense.
However, when we apply these same derivatization techniques to erucamide and oleamide, the use of acetyl chloride will give HCl as a by-product. HCl will readily undergo an alkene addition reaction at the C=C bond. As there are no functional groups nearby to impart steric or electronic effects, we can expect a 50:50 mixture of the two HCl addition products.
Picture
This will greatly complicate the mass spec interpretation as it will increase the number of species and also increase the mass of those species on a compound that has already proved hard to elute. The by- product of acetic anhydride is acetic acid and this will not be acidic enough to readily undergo and addition to an alkene. Therefore it should be far simpler to stick with acetic anhydride or trifluoroacetic anhydride for derivatization of all three compounds.
1 Comment

Extraction of essential oils by microwave irradiation

11/3/2015

0 Comments

 
It is well known that essential oils can be extracted from plants by steam distillation. This includes commonly encountered fragrant oils from pine, eucalyptus and lavender, as well as more exotic examples like lemongrass, parsley, mint, etc. Most of these oils tend to contain one major ingredient that makes up 70% or more of the mixture.
Picture
Major ingredients in essential oils
I recently had a discussion with one of my associates where we postulated that microwaving the leaves would make the distillation occur quicker and with less energy. I did a literature search later that day and found that microwave extraction of essential oils has been published. A group of Hungarian researchers in 1986 described extracting oils from a variety of plants into methanol, methanol/water and hexane [1]. In 2005 a Malaysian group described their process for microwave assisted extraction of eucalyptus oil into ethanol [2]. In 2015 a group from India described a similar extraction of lemongrass oil into water [3].
Picture
PictureMicrowave extraction kit sold by OilExTech
Microwave ‘dry’ distillation (without a solvent) has also been described in the Journal of Chromatography A in 2004 [4] and in the International Journal of Aromatherapy in 2006 [5]. More recently this process has been capitalized upon by OilExTech, who now sell a home microwave distillation kit for $150 that can be used to extract essential oils from plants and herbs grown in home gardens. Their product has been demonstrated on YouTube using lavender and orange rind.
PictureCleaning spray product from the Australian Eucalyptus Oil Company
I recently encountered the owner of 'The Australian eucalyptus oil company' at a Trash'n'treasure market. As well as the oil itself they also sell laundry power laced with their oil and a spray and wipe product, which is 85% methylated spirits:15% eucalyptus oil (I purchased this product, see left).
I asked the gentleman what batch size they use and how they distill their oil. He said that they collect the offshoots from eucalypt stumps and then carry out a steam distillation on about 100 Kg of plant matter to get about 1 Kg of essential oil. It was claimed that they have been using this same process on Blue Mallee eucalyptus in Arnold, Victoria since 1895.

It will take some time but eventually, microwave systems will be used to extract most essential oils.
References:
  1. K. Ganzler, A. Salgó and K Valkó. Microwave extraction. A novel sample preparation method for chromatography. Journal of chromatography, vol 371, p299–306, 1986.
  2. A.A. Saoud, R.M. Yunus, R.A. Aziz and A.R. Rahmat. Study of Eucalyptus Essential Oil Acquired by Microwave Extraction. Proc. WOCMAP III, Vol. 5: Quality, Efficacy, Safety, Processing & Trade in MAPs, 2005.
  3. M. A. Desai and J. Parikh. Extraction of essential oil from leaves of lemongrass using microwave radiation: Optimization, comparative, kinetic, and biological studies. ACS sustainable chemistry & engineering, DOI: 10.1021/sc500562a, published online Jan 2015.
  4. M. E. Lucchesi, F. Chemat and J. Smadja. Solvent‑free microwave extraction of essential oil from aromatic herbs: comparison with conventional hydro‑distillation. Journal of Chromatography A, vol 1043, issue 2, p323–327, 2004.
  5. N. Tigrine-Kordjania, B.Y. Meklatib and F. Chematc. Microwave ‘dry’ distillation as an useful tool for extraction of edible essential oils. International Journal of Aromatherapy, vol 16, issues 3–4, p141–147, 2006.
0 Comments

Preparation of the abandoned drugs Mexiletine and Thiola

6/2/2015

0 Comments

 
Mexiletine is an antiarrhythmic drug that is prescribed to patients with certain heart conditions. The patients take either 200 or 250 mg tablets and as the drug has a half-life of 10–12 h, they take two tablets per day.
Picture
The 200 and 250 mg tablets are the same price. Previously they were 6c each. Now, for some reason, they are $1.65 each and some patients can’t even find them at this price. These patients have had to forgo their mexiletine and experience much of the discomfort of their ailment. This new price is around $7 per gram. If we could produce mexiletine for $2 per gram and sell it at $4 per gram, we might be able to help these patients and make a profit at the same time.

Synthesis of Mexiletine.

A simple three-step synthesis is used to arrive at Mexiletine.
Picture
Synthesis of Mexiletine
The start material, which is the sodium salt of 2,6-xylenol, can be got at easily enough. Sigma-Aldrich sell 2,6‑xylenol in a 10 Kg container for US$524. But there are several other well published methods to prepare 2,6‑xylenol, most of which use phenol as a start material. One method reacts phenol with methanol using Al2O3 and MgO as catalysts.

Chloroacetone is the most difficult. It is somewhat more expensive; Sigma-Aldrich offer 500 g of it for US$205, which is about 10x their price for 2,6‑xylenol. However, it can be prepared by the chlorination of acetone. One method uses CuCl2 and acetone, both of which are cheap enough, but multi-chlorinated side products are common meaning that much effort in distillations and disposals are necessary in order to purify the chloroacetone prepared this way.

The hydroxylamine is not expensive, but it should be noted that it comes as a solution in water as the freebase quickly degrades.

The final step, a hydrogenation, requires hydrogen gas and a catalyst. The catalyst can be re-used for each batch, but the Parr hydrogenator can be a great expense, especially one that can hold 2–5 L.
Another drug which is really considered to be more of an orphan than mexiletine is thiola. Thiola is also known as tiopronin and is used to treat cystinuria. Only about 7000 people worldwide suffer from cystinuria: a condition where the patients develop kidney stones that are pure cysteine.
Picture
Cystinuria patients require three tablets of either 250 or 300 mg of thiola per day. Previously these tablets were $1 each but now they are $30 each. This new price is around $120 per gram.

Synthesis of Thiola.

A simple three-step synthesis has been used to arrive at Thiola (tiopronin) and was published in the Chinese Journal of Modern Applied Pharmacy. α-Bromopropionyl chloride and glycine were used as start materials．The mercapto group was introduced by exposure to thioacetic acid, followed by removal of the acetyl group.
Picture
Chinese synthesis of Thiola
Click here to download as PDF (245 KB):
synthesis_of_tiopronin_(chinese).pdf
File Size: 251 kb
File Type: pdf
Download File
The glycine is, of course, an amino acid and is freely available from natural sources.

The α-bromopropionyl chloride is obtained by treating 2-bromopropionic acid with thionyl chloride. I have seen Sigma-Aldrich quote a price of US$282 for 1 Kg of 2-bromopropionic acid. That is 28c per gram but I imagine that larger quantities could be found for purchase for even less per gram.

Thioacetic acid can be prepared by the reaction of acetic anhydride with hydrogen sulphide in the presence of a catalytic amount of acetyl chloride or acetyl bromide. I have seen Sigma-Aldrich quote a price of US$848 for 5 Kg of thioacetic acid. That is 17c per gram but I imagine that larger quantities could be found for purchase for even less per gram.

The deprotection step is done here using ammonia. I imagine that its ammonia dissolved in water. There are other options to deacylate a thiol that can be tried if this one proves to be inconvenient.
0 Comments

What can you do with Levoglucosenone?

13/1/2015

1 Comment

 
Last month, I had a job interview at Circa group. They are based in Melbourne and they are carrying out chemistry that involves levoglucosenone. They gave the position to somebody else for some reason, but it got me thinking about levoglucosenone.
While it has been known for several decades that levoglucosenone is obtained by the pyrolysis of cellulose, Circa have apparently developed a continuous pyrolysis process that produces the levoglucosenone more cheaply. Levoglucosenone possesses two chiral centres and this process produces pure (--) levoglucosenone. Levoglucosenone is a bicyclic oxygen heterocycle that contains a five, a six and a seven membered ring. There are a number of ways to draw it:
Picture
Levoglucosenone
The first view shows the six membered ring well but the five and seven membered rings poorly. The second view shows the five and the six membered rings well but makes the seven membered ring look more spread out than it is. The third view (which I prefer) shows the seven and five membered rings very well and the six membered ring could be viewed from into the plane of the page at the bottom right. I like this view best as it shows an equal level of vulnerability for each ring to be cleaved.
One of the most striking advantages to levoglucosenone is that it only has three oxygens to six carbons. So unlike the carbohydrate monomers that make up cellulose, levoglucosenone will be soluble in organic solvents, which makes it a candidate for many more synthetic reactions than carbohydrates ever can be. The pyrolysis process must of course be releasing CO2 in order to reduce the ratio of oxygens to carbons.
Circa are exploring a number of avenues for useful compounds from levoglucosenone. The main one they told me about is that they hydrogenate at the C=C double bond to make dihydrolevoglucosenone to use as a solvent, which they call Cyrene.
Picture
Hydrogenation of levoglucosenone
They told me that they have a pilot plant the prepares 1 Kg batches of
dihydrolevoglucosenone. They use a Parr hydrogenator with 100 g of palladium on charcoal catalyst. They do the hydrogenation neat (no solvent) and distill off 80% of the product. The other 20% remains in the flask and becomes part of the product for the next batch. Therefore the 100 g of palladium on charcoal catalyst is reused for each batch and they don't know yet how often it needs to be changed over. They soon plan to build a larger plant that can prepare 1 tonne at a time. They tell me that they have customers in the pharmaceutical industry who wish to buy dihydrolevoglucosenone to use as a dipolar aprotic solvent. They have published a paper on the use of this solvent and have measured it's BP at 202 °C.
I'm interested in pursuing ring opening products of levoglucosenone as fragrance compounds. Circa apparently haven't gone down this path but have focused more on the pure chiral centres. I asked their head chemist what happens when levoglucosenone is exposed to HBr. He told me that it reacts with the double bond so that the major product has the bromine β to the carbonyl; this is due to the partial positive charge on the α carbon that will tend to repel the incoming bromide which forms a bond by an SN2-like process.
Picture
Exposure of levoglucosenone to HBr
The reason I ask about exposure to HBr is more because cyclic ethers are known to undergo ring opening reactions. And this type of ring opening is more favoured the more ring-strain there is. Five membered rings react this way with HBr at room temperature with no catalyst. I have carried this out on 2-methyl-tetrahydrofuran and discussed it on a different entry of this blog. Bromine containing compounds are unwanted as fragrance compounds as they are going to be sprayed into the skin, but a HBr elimination later can recover the C=C double bond.
At this point it is useful for me to list a few examples of known fragrance compounds and what they smell like. The acylated versions of fragrant alcohols are frequently used as softer versions of the more raw alcohol product.
Picture
Known oxygen containing fragrance compounds
What I think would happen upon treating the bromolevoglucosenone with HBr is that the five membered ring would break open and leave either a six membered or seven membered ring, depending upon which of the two oxygens are attacked by H+. I think a tandem ring opening is highly unlikely.
Picture
Ring opening on bromolevoglucosenone
Which of the four possible products here is likely to be favoured? It's probably easier to just try it and see rather than try to predict. Let's not forget, we can also try the ring opening on the dihydrolevoglucosenone.
Picture
Ring opening on dihydrolevoglucosenone
Here we have two compounds (marked with a red asterisk) which would undergo a HBr elimination to give compounds that have a good chance at having desirable fragrant properties. The acyl groups may be cleaved back to the raw alcohols depending upon the conditions used for the elimination, but they can always be re-acylated.
Picture
HBr elimination on ring opened products
This is not the only way to open cyclic ethers. Another way to try these ring openings, which may give different products to HBr, is to use TMS-Cl and DMSO. This has been described in a 20 year old paper (D. C. Snyder. Conversion of alcohols to chlorides by TMSCl and DMSO. J. Org. Chem., vol 60, issue 8, p2638, 1995).
Another avenue I would like to pursue is to use levoglucosenone to try to chelate precious metals in order to use it for extraction. I am also curious about the solubility of nitrite ions in dihydrolevoglucosenone as I have a feeling they may be just the right shape to fit into it in a 'cage-like' manner.
Picture
Precious metals or nitrite ions may fit inside dihydrolevoglucosenone
I unfortunately do not know what levoglucosenone itself smells like. It may be with its BP and viscosity that it makes a useful fixative ingredient, rather like benzyl alcohol does.
1 Comment

Postdoctoral salaries in 2014

3/12/2014

1 Comment

 
As I am completing my PhD, I am applying for Postdoctoral fellow opportunities. During the course of my investigation I have gathered several examples of salaries and I share them here. This is intended to be a statement of facts rather than a passing of judgement. I have observed the American Professors to be very reluctant to admit what salaries they are offering or paying. I have converted all the salaries to Australian dollars. Further examples to add to this list are welcomed.
Picture
Postdoc salaries in 2014:

  • In June 2014, a postdoc at University of Rochester who I spoke with in person was earning US$39,000 which equaled AU$41,964.
  • The following week I shared the above salary information with a Professor at University of Maryland who I spoke with at a conference. She told me that she had a postdoc whom she paid US$37,000 which equaled AU$39,812.
  • One posted at Swinburne University (Melbourne) was quoted as paying Academic Level B: AU$81,290 – $96,435.
  • One posted at University of Melbourne was posted as paying in the bracket AU$62,973 - $85,452, but went on to give the exact dollar amount of AU$79,609.
  • One posted at Heriot-Watt University in Edinburgh was offering to pay £30-37k. £37k equaled AU$66,008. I had an email exchange with the Professor who told me that this is a typical salary for an early career researcher in the UK.
  • One at Wageningen University, Netherlands was offering €3830 per month, which equaled AU$65,217.
  • One at Ferrier research institute in Wellington, New Zealand was posted as paying in the bracket NZ$69,837 - $84,135, but stated that the actual salary offered will be determined after consideration of expertise. I emailed and asked if this meant that they have the discretion to offer anywhere in that range and they said yes. I applied for this position. The top dollar of this bracket (NZ$84,135) equaled AU$75,536. I applied for the position but it was later cancelled.
  • One at RMIT (Melbourne) in the nano technology area was posted as being in the bracket $59,488 - $80,690, but went on to give the exact dollar amount of AU$75,172.
  • One at the University of Queensland was posted as offering $74,625 to $80,107. It did not say where in this range it would pay.
  • In August 2014, CSIRO had several postdoctoral positions advertised as paying AU$78-88k.
  • In November 2014, RMIT (Melbourne) had a two year fixed term research fellow position in electrochemistry which was posted as offering $84,939 to $100,867 + 17% super. It did not say where in this range it would pay.
  • One at the University of Sheffield (UK) was posted in November 2014 as a three year fixed term Postdoctoral position paying in the bracket £29,552 to £31,342. Another extremely similar sounding one at the University of Nottingham was paying a bracket of £25,513 to £31,342. The top dollar of both of these brackets (£31,342) equaled AU$57,904.
  • One at Swinburne University (Melbourne) was posted in Dec 2014 as Postdoctoral research fellow in the area of "high temperature processing" for a 1 year fixed term over 2015. It quoted the salary range of AU$57,086 - $96,435. It did not say where in this range it would pay.

Also please note, Australian salaries have a requirement to pay 10% on the top into the employees' superannuation. Temporary residents who come for a two year Postdoc can apply for this money when they depart which by all rights could be ~$15000. Australian residents can't access this money until they are 60, by which time much of the money has been wasted or taken by the superannuation company.
1 Comment

How to extract aliquots over time from a reaction in DMF to monitor by GC-MS

18/11/2014

1 Comment

 
During my PhD, I prepared a compound library of α‑nitroisobutyranilides by substituting α‑bromoisobutyranilides. This reaction was done using NaNO2 in DMF at room temperature. I monitored the reaction by GC-MS to collect rate data to characterize the mechanism of the reaction. The method I used to take the aliquots is simple and highly transferable to other reactions where a reactant is placed into DMF with a water soluble reagent.
Picture
α‑Nitroisobutyranilides from α‑bromoisobutyranilides
The reactant compound (1-2g) was exposed to NaNO2 4.00 g (13.6 mmol) and 40 mL of DMF. Aliquots were taken periodically by the removal of 1 mL of the reacting mixture and doing a mini liquid/liquid extraction using 2 mL of DCM and washing four times with 3 mL of water in a 5 mL screw cap vial. As the DCM layer stays at the bottom, the water portion is easily drawn off. It contains a small amount of NaNO2 and an even smaller amount of HBr. It can be discarded down the sink after each wash.
The DCM layer is then dried over anhydrous MgSO4 and transferred to a GC-MS vial by passing it through a Pasteur pipette that had been plugged with a small amount of cotton.
Picture
5 mL screw cap vial and prepared cotton Pasteur pipettes.
I used anhydrous MgSO4, but the monohydrate is also adequate. Any greater than 1 water per molecule of MgSO4 will not effectively dry the DCM. For example, MgSO4.3H2O or MgSO4.7H2O will not work.
This method quenches the reaction as it washes off the reagent which is water soluble. As the reaction is stopped the proportions of the reactant and product organic compounds will remain the same. In my case the GC-MS was out of order for several weeks and I continued to take aliquots in this way and label them. When the GC-MS was back online, I ran all of the samples and was still able to collect excellent data (although I had to top-up the DCM in some of the vials).
Picture
Labelled GC-MS vials
1 Comment

A carbohydrate chemistry project

5/10/2014

1 Comment

 
PictureRing opening of sucralose
At the start of my PhD, my supervisor gave me a project in which I would try to do a ring opening of sucralose using periodate to get a tetra-aldehyde product.
PictureMolecular structure of Guar gum
The idea was to optimize this process and then to transfer these same conditions to convert guar gum to its tetra-aldehyde, convert the aldehyde groups to alkynes by a Corey–Fuchs reaction and then do click chemistry (copper catalyzed azide-alkyne cycloaddition) with a variety of azides in order to functionalize guar gum.
Looking back on it now it seems a bit far fetched. I gave it a try but I eventually found my way into another project involving isocyanates and hydantoins. To begin my investigation, I carried out a solvent survey of sucralose and guar gum. The results, posted below, reminded me that carbohydrates really don't dissolve in much.
Picture
Solubility of sucralose and guar gum in selected solvents
While I didn't get any further than this, the next step would be to try blends of water with organic solvents. I would also like to try cyclohexanone.
1 Comment

Rotavaping DMF

1/10/2014

0 Comments

 
I have found that researchers in many synthesis labs are unaware that dimethylformamide (DMF) can be removed by a rotary evaporator. Providing the product compound is not heat sensitive, removal by evaporation is a much better option than a liquid/liquid workup which would waste a lot of solvent.

Picture
Dimethylformamide
Picture
A 100 mL non-reversible splash-guard
To rotavap DMF, Dow Corning high vacuum grease must be freshly applied to the joins and Keck clips used to hold the flask onto a non-reversible splash-guard.
With the water bath at 55 °C the vacuum will need to be lowered to 25 Torr; at 70 °C the required vacuum is only 25 Torr.
Picture
A 100 mL pre-weighed flask and a 500 mL non-reversible splash-guard attached to a rotary evaporator
The utility of the non-reversible splash-guard is not so much the prevention of mess or loss from bumping, rather that it reduces the distance that the DMF fumes must travel to be removed from the flask. This is because DMF vapours will quickly condense as they get further away from the flask which is in a hot water bath (55-70 °C) and come into contact with the glass parts of the rotavap that are at room temperature (~20 °C). Shortening this distance makes DMF removal from a mixture much easier.
Picture
Note the shortened distance that the DMF vapours will have to travel before condensing when using this splash-guard. It is ~4 cm less.
Removing DMF is slow and is prone to bumping so only lower the pressure gradually. You might want to leave a note for your co-workers saying that you are removing DMF and go for a cup of coffee.
0 Comments

IR spectra using a KBr disc or a diamond ATR. Which is better?

2/9/2014

0 Comments

 
The old fashioned way to run IR spectra is by preparing a KBr disc. Sometime in the last decade, the diamond attenuated total reflectance (ATR) was introduced. Some people consider this input method to give the same result. However, the KBr disc method gives greater resolution than the ATR. You'll also find that the ATR method gives a lot of interference below 600 wavenumbers, which results in it only being practical to measure down to 650 cm-1, whereas with the KBr disc method one can go down to 450 cm-1.
Compare the spectra of the same compound from a recent publication of mine. I've analyzed the same compound using both methods so as to illustrate the difference. You can see that some of the smaller peaks that are clearly distinguishable in the KBr spectrum get lost in the noise in the ATR spectrum.
Picture
Spectrum taken using KBr disc method
Picture
Spectrum taken using ATR method
Note that both spectra were obtained with the same instrument and the same editing software.
So which should you use? If the compound is easy to make and its structure has already been proven with NMR and mass spec, then the IR is mostly a formality and you don't need the high resolution version. It might take you 20-30 min to prepare a KBr disc, while the ATR method will only take 5 min. The ATR derived spectrum still provides an unambiguous indicator of the unmistakable  functional groups such as carbonyl, hydroxyl and nitrile. However, if the compound is hard to make, you ought to characterize it in high resolution so that, especially the fingerprint region, can be matched at a later date (potentially in a natural product synthesis).
My advice is to use the ATR method when you need to characterize a library of compounds. If you're only analyzing a small handful of compounds (less than 10) then stick to the traditional KBr disc method.
0 Comments

Oxygen free conditions

3/8/2014

1 Comment

 
I recently felt the need to apply oxygen free conditions to a reaction that I had done previously under air so that I could determine whether O2 took part in its mechanism. This required doing the reaction under nitrogen, but also the removal of dissolved O2 from the solvent. O2 can be displaced from solvents by bubbling nitrogen gas through for 30 min. I was using DMF and I found precedence for O2 removal in a 1972 Organic Syntheses entry where an oxygen sensitive chromium reagent was employed. Note that many techniques to remove O2 ignore or even introduce water to the solvent and or nitrogen.
I learned that our building nitrogen at RMIT is obtained by vapour run off from a tank of liquid nitrogen at the bottom of the building. I wished to test this nitrogen and to be confident that it was free of any oxygen so that I knew if my reaction had was occurring in the presence of O2. A way to do this is described in 'The Chemist's Companion: A Handbook of Practical Data, Techniques, and References' by Gordon and Ford, Wiley publishing, 1972. Here it is described to use pyrogallol in strong alkaline solution which will absorb any O2 and turn red in the process.
Picture
The recipe calls for 5 g of pyrogallol (1,2,3-trihydroxybenzene) into a solution of 100 mL of water with 120 g of KOH.
Pyrogallol comes as a white shard-like crystal power.
The instructions given in the old chemists manuals say that this will be a colourless solution that will turn red/brown as it chemically absorbs O2.
Picture
Pyrogallol crystals
Simply preparing the above described solution on the bench with no effort to exclude air resulted in a dark red solution that becomes closer to brown solution. See image below.
Picture
Oxidized solution of pyrogallol in KOH/water.
I found that the only way to prepare the pyrogallol solution mostly free of colour was to place the 5 g of pyrogallol into the empty Dreschel and vacuum out the air and fill with nitrogen. I then prepared the 120 g of KOH into 100 mL of water solution in a beaker and bubbled N2 gas through it using a rubber tube/Pasteur pipette for 30 min. With the Dreshcel under slight positive pressure of N2, I opened it and quickly poured the contents of the beaker through. I sealed the bottle and found that I had made a solution that was almost colourless. It was clear enough to see through.
Picture
The pyrogallol solution immediately after it has been prepared. N2 is bubbling through.
Note that while passing nitrogen through such a solution removes O2 but adds some H2O.
Trying to get a colourless version of the solution into a Dreschel bottle outside of a glovebox is impracticable. I was able to prepare one with only a slight redness to it but that was still clear enough to see through. This nicely verified the quality of my building's nitrogen as the colour did not get any redder, even after 18h of bubbling
Picture
The setup after 18 h. Note that the pyrogallol solution in the Dreschel bottle is still the same shade of red.
This setup is of course lacking a Schlenk line and is to be avoided for future experiments.
After I finished the reaction and opened the Dreschel to clean up, it's contents became dark red upon just a few seconds exposure to air.
1 Comment

Rotavap etiquette

7/7/2014

0 Comments

 
Picture
I know of synthesis labs where each researcher has their own rotavap. For the rest of us mere mortals, here are some tips.

Fair use and leaving things how you found them are the main themes. It is customary to empty the receiving flask into the waste container after use. The seals at the recieving flask and the gas release tap should be wiped clean and coated with Dow Corning high vacuum grease. If for some reason you used any other type of grease it should all be removed thoroughly using an appropriate solvent (hexane and ethyl acetate). If you used Dow Corning high vacuum grease on the join between flask and vacuum tube to achieve very low vacuum even this must be washed off from here when you are finished as the default condition for this join should be ungreased.
You don't have to use a splash guard if you are confident without one. However if you do use a splash guard, this does not excuse you from cleaning the vacuum tube with acetone after each use. Just because your mixture didn't bump, some of your compound may still have entered the vapour phase enough to land on the inner walls of the tube which can drip down into the next user's flask (If you can smell it, it's there). Apart from removing the vacuum tube for cleaning which should always be done, there are a few other ways to improve this cleaning, such as filling a beaker with acetone and sucking it straight up into the tube with no flask there, or filling a flask with a solvent and simply rotavapping clean solvent through to wash everything into the receiving flask.
If you are in a lab where two or three rotavaps are linked to the one pump, communication is the key at the start. Tell the person next to you what solvent you are removing and they ought to reciprocate by telling you the same. If you walk away, leave a note with your name and the solvent being removed. You can write this note on the glass part of the rotavap with a Sharpie.
A common scenario is a novice removing water who decides to speed up their process by occupying both rotavaps at once for several hours at the exclusion of others. If you want to use more than one rotavap at a time it should be brief and well communicated - or done at night time when not many people are around.
Another problem is somebody who alters the settings on somebody else's flask when they are not around. This is not only rude but potentially mayhem is a precious mixture is bumped. Don't touch somebody else's rotavap unless they asked you to or unless you see that there is clearly a hazard.
When you are done cleaning the rotavap, leave the water bath on 40 °C unless it is the end of the day when it can be switched off, as well as the chiller.
0 Comments

On the use and handling of 2-Bromo-2-methylpropionic acid

22/5/2014

0 Comments

 
Picture2-Bromo-2-methylpropionic acid
2-Bromo-2-methylpropionic acid (CAS: 2052-01-9) is a useful reagent to make synthetic intermediates. A white solid at RT, it can be prepared from the acid bromide equivalent reagent, which is known as α-Bromoisobutyryl bromide (liquid at RT) by quenching it with water.
2-Bromo-2-methylpropionic acid can be left over in a workup after doing a reaction using a slight excess of α-bromoisobutyryl bromide, it is easily removed by liquid/liquid extraction with bicarbonate added to the aqueous phase. It can be ordered from Sigma Aldrich for a low price, but it I found it had a shorter shelf life than expected, after 1 year my NMR showed a second similar compound. C-NMR is better to analyze this compound as it gives three distinct peaks, whereas its H-NMR has one good peak but observing the hydroxyl is less reliable. However, I have discovered that it is remarkable easy to kugel rohr this reagent and it should be purified by kugel rohr before use. The compound looks very white and flakey when it is pure, like grated coconut, but after 1 year it has a slight yellow colour and instead of flakes it forms large crystalline shards. It has an acrid smell to it no matter how pure it is.
Picture2-Amino-2-methylpropionic acid and 2-nitro-2-methylpropionic acid
If 2-bromo-2-methylpropionic acid is reacted with an amine to give the amide, the bromo group can then be substituted for a nitro using a Kornblum type reaction with NaNO2 in DMF. I am still pursuing a technique to prepare the nitro equivalent of this reagent, which would be called 2-nitro-2-methylpropionic acid. The amino equivalent exists and is a kind of quasi amino acid, but the nitro version would have the advantage of not being zwitterionic which would make it a more versatile organic soluble reagent. Due to a lack of resources, this project is currently on the back burner.
0 Comments

A creative setup for anhydrous reactions

1/3/2014

0 Comments

 
Picture
I can't be the first person to do something like this. This is how I did the last two reactions of my PhD after RMIT declined to provide me with a Schlenk line. Using unloved glassware and rubber tubes, I cut things to size and clamped them in place to fit together a single tap system to toggle between vacuum and nitrogen. The nitrogen comes from the blue tap and passes through CaCl2 before entering the 'system'. Excess nitrogen exits through the bubbler at the bottom by passing through silicone oil that prevents the entry of moist air. I had the bubbler at the top at first, but the oil was too easily sucked into the system so I moved it to the bottom. House vacuum comes from the grey tap and the vacuum and nitrogen are both available to the splitting tap on the right which is labelled and easy to reach. As I was doing this reaction in 1,2-DCE at 70 °C, I chose to use an air condenser which is easier to flame dry than a water condenser.
In case you are wondering, the red taps are for steam, the green tap is water and the blue tap is air. The internal width of this fumehood is 93 cm.
Picture
Here I have used the setup again, this time for a reaction in DMF at 140 °C. I allowed a slight positive pressure of N2 to bubble slowly through the system which is an exit point for any unexpected pressure. When used in this way the air condenser worked perfectly well to contain the DMF; the top was cool even when the bottom was at 140 °C. I placed the fan there merely as a precaution.
A retired Professor friend of mine reminds me that more effective anhydrous conditions can be achieved when the nitrogen/vacuum delivery inlet is instead placed at the top of the condenser. I will remember this for next time.
He also shares with me a design for the bubbler which makes it harder or near impossible to suck air back into the system. It is made up of two Dreschel bottles (like the one containing the CaCl2 in the above image) which are placed in series, with the first reversed. The second is almost filled with oil, which the nitrogen bubbles through. Any suck-back results in the oil in the second bottle sucking into the first, and only after almost the whole volume of oil has been transferred can air get in. Turning up the nitrogen transfers the oil back to the second bottle.
0 Comments

On the use and handling of Titanium tetrachloride

19/2/2014

0 Comments

 
PictureTitanium tetrachloride
Titanium tetrachloride (also called titanium (IV) chloride or TiCl4) is a strong Lewis acid. It is highly oxophilic and reacts instantly with water to form TiO2 and HCl vapours. It is a clear, colourless liquid at RT. Less pure samples may have a colour or solid particulates but it can be re-purified by distillation. It is not compatible with ethereal solvents as it is known to form crystalline diether complexes. It is non-polar and is soluble in/compatible with benzene and chlorinated solvents. I recently used TiCl4 in an attempt to catalyze a reaction.
It is a bit tricky to use, but does not require strict anhydrous conditions to the point of using a syringe or cannula. I was able to remove it from the bottle using a Pasteur pipette. Further I was able to comfortably monitor the result by C-NMR by placing my compound in CDCl3 and then adding TiCl4 before transfer to an NMR tube. I was concerned about HCl escaping from the solution in the NMR tube so I sealed the top with para-film but this proved not to be a problem. I thought a TiO2 precipitate might form which could interfere with the NMR by disturbing the homogeneity but this too turned out to be not a problem and I was able to view the signals of my start material and the product.
PictureTiCl4 before addition to compound/solvent in flask. The white fumes are TiO2 and HCl.
I felt that the reaction had not worked cleanly enough. Given the oxophilicity of TiCl4, this could be due to a methoxy or a nitro group (both of which were present on my compound but on the other half of the molecule to where I aimed for the reaction). TiCl4 is known to reduce nitro groups and in my case it looked like mine had been replaced with an amino and an alkene.
PictureYellow Ti(IV)Cl4 complexed with nitrile(s)
I decided to try with a homologue compound that contained a nitrile group in the place of the methoxy. I ran this reaction in a flask in 1,2-DCE (above) instead of an NMR tube in CDCl3. With the first compound, the mixture instantly looked like brown gunk. However, with this second compound, a beautiful bright yellow precipitate was formed (right). The start material was white so I think that this yellow precipitate was a Ti(IV)Cl4 complex where the nitrile group has acted as either one or two ligands. When I worked up this reaction by addition of water, the yellow vanished. Rotavapping the organic layer returned over 80% of my start material as a pure white solid and it was possible to make the yellow complex again from the recovered product. This yellow colour seems to be from delocalization of d-orbital electrons in the Ti(IV), rather than freely moving conjugated electrons in the organic compound. It therefore seems that TiCl4 prefers to coordinate with nitriles groups more than methoxy groups, which in a sense can 'protect' the rest of the molecule from the oxophilic attack of TiCl4.
The Ti(IV)Cl4 complex might be breaking up by the action of water, or it may be the HCl produced by the addition of water which removes the ligands from the Ti(IV). If I could suck off the 1,2-DCE/TiCl4 in a vacuum trap I could run a crystal structure on the yellow product and determine its configuration. While I have not so far had the resources to follow this up, it may be useful to other workers.
0 Comments

On refractive index of a compound

12/1/2014

0 Comments

 
PictureA oil compound recently purified by bulb to bulb distillation.
When synthesizing a library of compounds, we characterize their properties for later workers to match and compare. This involves H-NMR, C-NMR, IR, Rf, accurate mass spec and maybe elemental analysis or a crystal structure. If it is a solid at room temperature we are expected to measure its melting point. However if it is an oil a melting point is not required. While it is possible to freeze an oil and measure the point that it melts as it returns to room temperature, this is not expected because melting point is mostly an indication of purity that can be performed simply. Measuring low melting point compounds is also hard for other workers to repeat. Furthermore, a simpler method to determine the purity of an oil is to measure their refractive index.
Refractive index is a dimensionless number which is a measure of the speed that light travels through a medium compared with the speed of light in a vacuum. For example, the refractive index of water is 1.33 meaning that light travels 1.33 times slower in water than it does in a vacuum. Refractive index is always more than 1 and for most compounds it is between 1.3 and 1.7. It is typically measured to four decimal places as long as the substance is clear (allows light to pass through). When measured at a standard temperature (20 °C) it is, like melting point, constant for each compound. Refractive index, like melting point, is also easily altered by a small amount of an impurity .
PictureIsoeugenol, Methyl eugenol and Methyl isoeugenol.
It is common to measure the refractive index of an oil in the fragrance chemistry industry. This is largely due to a higher proportion of end use compounds being oils, but it can also be used to assess the desirability of essential oil extracts which are not pure compounds but are combinations of fragrant oils with ratios that vary depending on how the plant has been grown. The refractive index for an ingredient can be compared with previously measured batches of ingredients. Very similar compounds have refractive indexes that are generally close but are readily distinguished by this method. For example the refractive indexes for Isoeugenol, Methyl eugenol and Methyl isoeugenol at 20 °C are 1.5720-1.5770, 1.5320-1.5360 and 1.5660-1.5690 respectively. The maker of a fragrant product (eg perfumer) may use this knowledge to test the purity of a purchased batch of an ingredient in a simple way and compare it to literature values as well as their own earlier samples. This is important for keeping the end product consistent for the consumer, whether it be a perfume, cosmetic or cleaning product. Refractive index allows purity testing without access to an NMR and fulfills the same function as melting point for solid compounds.
Despite refractive index being a well established method for purity of oils, most journals don't require it for novel compounds even though they require melting points. While this seems strange to me I am relieved; my University lacks the equipment to measure refractive index and it would be tedious extra work to have it measured elsewhere.
0 Comments

Purification of an amine

26/12/2013

0 Comments

 
Picture2‐Amino‐N‐[4‐cyano‐3‐(trifluoromethyl)phenyl]‐2‐methylpropanamide
A recent part of my PhD project required purification of the compound 2‐Amino‐N‐[4‐cyano‐3‐(trifluoromethyl)phenyl]‐2‐methylpropanamide. This primary amine was sticky and kept a low Rf with most common solvents. I experimented with silica deactivation to increase its Rf from 0.08 in 50% hexanes/50% EtOAc.
I was advised to first run the blank TLC plate in 1-3% triethylamine (TEA) in EtOAc. I was also advised to carry out the blank run this way two or three times. I tried 1% and 3% and did the blank run one, two and three times to obtain six results. I found that with 1% TEA the Rf increased to 0.09 and 3% TEA increased it to 0.10. There was no change in Rf when the blank run was carried out one, two or three times.
I had some diazobicyclooctane (DABCO) and I tried to deactivate with this and also to carry out the run itself with a small amount of DABCO in the solvent. I found that this worked poorly and that the DABCO was viewable itself under UV light which interfered with viewing the compound.
Picture
After reading this website I decided to try an ammonia strategy.  I found a bottle of 28% ammonia in water and added 4 mL of this to 96 mL of MeOH to create a 1% ammonia in MeOH solution (it should be remembered that this is 3% water). I then ran TLCs in DCM with 5% (A) and 10% (B) '1% ammonia in MeOH'. As another option I ran a TLC with 10% '1% ammonia in MeOH' in tert-butylmethyl ether (TBME) (C). Solvent system C (10% '1% ammonia in MeOH' / 90% TBME) gave a discrete non-tailing spot with an Rf of 0.62. I therefore used this for a flash column to purify the amine.
0 Comments

Crystal form of a drug

24/11/2013

1 Comment

 
Picture
Earlier this year I had a conversation with a process chemist from Pfizer (Groton, Connecticut). We spoke about crystallography and why crystal form of a drug is important for its bioavailability.
Many people, even those who know a lot of chemistry, think that a pill with 80 mg of an active drug compound is the same product when it comes from a generic provider. Governments in Australia and USA also seem to think this as they subsidize only the cheaper generic version of drugs when prescribed to low income earners.
As I learned, these are not the same ingredients as they often differ by crystal form. Many compounds can be present in more than one crystal polymorph, or they can be present in crystals of varied size and size distribution. This is called crystal form and a consistent crystal form is achieved by adherence to a repeatable method of preparation. Pfizer determine optimal dose of a drug compound on it being prepared with a consistent crystal form. When they develop a drug through clinical trials with patients they optimize its dosage to perhaps 25 mg, 70 mg or 110 mg by careful monitoring of the patients taking part. When taken orally, crystal form can greatly influence bioavailability of a drug. Some reach their target better when absorbed through the stomach, others the intestine. Therefore the dose chosen to deliver the optimal drug availability to the patient is based upon Pfizer's consistent crystal form.
A less uniform crystal form in the generic version of the drug disturbs this carefully optimized dose for the patient. For example, the drug may be intestinally absorbed with some being 'lost' in the stomach - 80 mg may be actually delivering 60 mg to the intestine when in the consistent crystal form prepared by Pfizer. In the generic version, the crystal form may dissolve more readily in the stomach and only 20 mg survives to be absorbed in the intestine. The opposite can also be true - a drug made with a crystal form that is easy for the stomach to dissolve and only a small amount is 'lost' to the intestine where absorption is less effective, while the generic version takes more undissolved drug with it to the intestine.
A random crystal form disturbs and even ignores the intended dose for the patient.Generic drugs are therefore often less effective than the brand name version. You might want to think about this the next time you or a loved one goes to the pharmacy.
1 Comment

Testing of our new polarimeter

30/10/2013

0 Comments

 
Back in July 2012 we finally got a polarimeter at RMIT. How had we been doing chiral syntheses up until that point? Good question! We are now carrying out several chiral synthesis projects.
Picture
Polarimeter
Picture
Display
Picture
I hadn't done any chiral syntheses up to that point (largely as we had no polarimeter). I'd just returned from America where I had purchased (S)-Naproxen sodium in a shop called 'DollarTree'. This actually cost US$1.07 due to state tax. I found a method to test optical rotation of (S)-Naproxen by extraction from over the counter pills. This was largely meant for undergraduates, but I carried it out in order to learn some polarimetry. The procedure was as follows:
Picture
3 tablets of naproxen sodium (220 mg per tablet) were placed in MeOH (15 mL) and swirled. When the outer blue coating began to loosen and peel away, the white centres of each tablet were quickly removed from the MeOH and placed into a separate flask. They were then dissolved in fresh MeOH (20 mL), which took about 20 min at RT. The solution was passed through filter paper to remove tablet components such as TiO2 and micro crystalline cellulose. The MeOH was removed by rotavap to get clean white crystals of naproxen sodium. To make the freebase, the naproxen sodium was then rinsed into a sep funnel with hydrochloric acid and ethyl acetate (or other water immiscible solvent). The naproxen sodium anion is now protonated and no longer ionic so resides in the organic phase. The HCl becomes NaCl and lives in the aqueous phase. The organic phase was then dried with MgSO4, passed through filter paper and rotavaped to get clean white crystals of naproxen that were ready for optical rotation tests.
British Pharmacopedia 1988 gives specific optical rotation of (S)-Naproxen as 63.0° to 68.5°, when measured at 4% w/v in UV grade chloroform. As we had no UV grade chloroform, I measured the extracted freebase in UV grade DCM to get a specific optical rotation of 63.9°. I therefore declared my naproxen from 'DollarTree' to be the pure S enantiomer. This was quite preferable to the R enantiomer, which is said to be a liver toxin.
0 Comments

Lavoisier's methods to make nitrogen

29/10/2013

3 Comments

 
Picture
Ever been frustrated by impure nitrogen? Imagine how Lavoisier felt. He had to discover nitrogen and then make his own. I've pulled this snippet from page 169 of his book (which was translated into English during his lifetime by his contemporaries). Additions by me are in brackets:

"The azotic gas (N2) may be procured from atmospheric air, by absorbing the oxygen gas which is mixed with it by means of a solution of sulphuret of potash (K2S), or sulphuret of lime (CaS). It requires twelve or fifteen days to complete this process, during which time the surface in contact must be frequently renewed by agitation, and by breaking the pellicle which forms on the top of the solution. It may likewise be procured by dissolving animal substances in dilute nitric acid very little heated. In this operation, the azote is disengaged in form of gas, which we receive under bell glasses filled with water in the pneumato-chemical apparatus. We may procure this gas by deflagrating nitre with charcoal, or any other combustible substance; when with charcoal, the azotic gas is mixed with carbonic acid gas (CO2), which may be absorbed by a solution of caustic alkali, or by lime water, after which the azotic gas remains pure. We can procure it in a fourth manner from combinations of ammoniac (NH3) with metal oxyds, as pointed out by Mr de Fourcroy: The hydrogen of the ammoniac combines with the oxygen of the oxyd, and forms water, whilst the azote being left free escapes in form of gas."
3 Comments
<<Previous

    Matthew's Chemistry blog.

    A chronicle of tips, tricks & stories

    Contributions from readers are welcome and should be emailed to matthew.leonard742@gmail.com

    Archives

    September 2016
    December 2015
    September 2015
    July 2015
    June 2015
    May 2015
    April 2015
    March 2015
    February 2015
    January 2015
    December 2014
    November 2014
    October 2014
    September 2014
    August 2014
    July 2014
    May 2014
    March 2014
    February 2014
    January 2014
    December 2013
    November 2013
    October 2013

Powered by Create your own unique website with customizable templates.